thesis inflammation cancer

• Systematic Review
• Open access
• Published: 02 September 2024

Phytochemicals regulate cancer metabolism through modulation of the AMPK/PGC-1α signaling pathway

• Sajad Fakhri 1   na1 ,
• Seyed Zachariah Moradi 1   na1 ,
• Seyed Yahya Moradi 2 ,
• Sarina Piri 2 ,
• Behrang Shiri Varnamkhasti 1 ,
• Sana Piri 1 ,
• Mohammad Reza Khirehgesh 1 ,
• Ankur Bishayee 3 ,
• Nicolette Casarcia 4 &
• Anupam Bishayee 4  

BMC Cancer volume  24 , Article number:  1079 ( 2024 ) Cite this article

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Due to the complex pathophysiological mechanisms involved in cancer progression and metastasis, current therapeutic approaches lack efficacy and have significant adverse effects. Therefore, it is essential to establish novel strategies for combating cancer. Phytochemicals, which possess multiple biological activities, such as antioxidant, anti-inflammatory, antimutagenic, immunomodulatory, antiproliferative, anti-angiogenesis, and antimetastatic properties, can regulate cancer progression and interfere in various stages of cancer development by suppressing various signaling pathways.

The current systematic and comprehensive review was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria, using electronic databases, including PubMed, Scopus, and Science Direct, until the end of December 2023. After excluding unrelated articles, 111 related articles were included in this systematic review.

In this current review, the major signaling pathways of cancer metabolism are highlighted with the promising anticancer role of phytochemicals. This was through their ability to regulate the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) signaling pathway. The AMPK/PGC-1α signaling pathway plays a crucial role in cancer cell metabolism via targeting energy homeostasis and mitochondria biogenesis, glucose oxidation, and fatty acid oxidation, thereby generating ATP for cell growth. As a result, targeting this signaling pathway may represent a novel approach to cancer treatment. Accordingly, alkaloids, phenolic compounds, terpene/terpenoids, and miscellaneous phytochemicals have been introduced as promising anticancer agents by regulating the AMPK/PGC-1α signaling pathway. Novel delivery systems of phytochemicals targeting the AMPK/PGC-1α pathway in combating cancer are also highlighted in this review.

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Introduction

Cancer is one of the major causes of death worldwide. There are several manifestations of this deadly disease, such as lumps, unusual bleeding, protracted coughing, weight loss, and decreased appetite [ 1 , 2 , 3 ]. Factors effective in causing cancer include smoking, obesity, an unhealthy diet, excess alcohol consumption, lack of exercise, sickness, exposure to ionizing radiation and environmental pollutants, or infection with viruses, bacteria, and certain parasites. Cancer occurs due to neoplastic growth in an irregular manner, which often forms a mass of cancer cells [ 4 , 5 , 6 ]. Under physiologic conditions, complex signaling pathways are involved in the development of cancer. Oxidative stress, apoptosis, autophagy, and inflammation are the most important pathways that affect cancer, engaging pro-inflammatory cytokines and apoptotic mediators. Therefore, the control of regulatory mechanisms, such as the release of cytokines or chemokines, oxidative stress and the process of apoptosis, has a significant function in the management of cancer [ 7 ]. Studies have demonstrated that several signaling pathways have considerable function in cancer pathogenesis. These include the Ras/extracellular signal-regulated protein kinase (ERK), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways [ 8 ]. Several other dysregulated signaling pathways are responsible for cancer metabolism such as carbohydrate, lipid, and protein metabolism. An altered metabolism may advance the proliferation and survival of cancer cells [ 9 ].

Cancer treatments include a variety of approaches tailored to improve patient outcomes and effectively manage the disease, depending on the specific type and stage of cancer. These approaches include surgical intervention, chemotherapy, targeted therapy, radiation therapy, hormone therapy, and immunotherapy, as well as complementary and integrated therapies, such as herbal treatments. Healthcare professionals select treatment modalities based on the patient’s clinical status, medical history, and potential side effects. The appropriate and judicious combination of these modalities may lead to improved treatment outcomes and reduced adverse effects, ultimately contributing to an enhanced quality of life for the patient. Over the years, more than 300 chemotherapeutic drugs have been used in the treatment of cancer, such as taxol, vincrictine, cis -platin, 5-fluorouracil, bevacizumab, erlotinib, nivolumab, ipilimib, santin, and olaparib. However, these drugs are very toxic and may create resistance, which leads to tumor recurrence and metastasis [ 10 ]. Therefore, alternative treatment methods, such as the use of bioactive plant secondary metabolites (phytochemicals) should be considered [ 1 , 11 ].

Phytochemicals, also known as plant secondary metabolites, have been the focus of extensive research in recent years due to their potential health benefits, including their anticancer properties. Phytochemicals may be obtained from various sources, including whole grains, fruits, vegetables, nuts, and spices [ 12 ]. Phytochemicals have remarkable chemical diversity and possesses various bioactivities, including, anti-inflammation, antioxidative, antimicrobial, antiviral and antiaging properties, and have been widely investigated for their anticancer potential [ 13 ]. Preclinical studies have indicated that phytochemicals are able to modulate various oncogenic and oncosuppressive cell signaling pathways, such as the PI3K/Akt/mTOR/P70S6K [ 14 ], peroxisome proliferator-activated receptor (PPARs) [ 15 ], nuclear factor erythroid 2-related factor 2 (Nrf2), Janus kinase (JAK)–signal transducer and activator of transcription (STAT) [ 16 ], hypoxia-inducible factor-1 (HIF-1), transforming growth factor-beta (TGF-β) [ 17 ], toll-like receptors (TLR)/nuclear factor-κB (NF-κB)/Nod-like receptor protein (NLRP), MAPK, ERK, and p38 signaling pathways [ 18 , 19 , 20 ]. Phytochemicals also target multiple dysregulated pathways of cancer metabolism, such as carbohydrate, lipid, and protein metabolism. This ability of phytochemicals to target multiple pathways involved in cancer development and progression is one of the key reasons why they may have potential in cancer treatment. Traditional cancer therapies often target specific molecular pathways, but phytochemicals simultaneously modulate multiple signaling pathways, potentially making them more effective in combating the complex nature of cancer. Phytochemicals not only have direct anticancer effects, but also influence the metabolic pathways within cancer cells. For instance, researchers have discovered that several phytochemicals hinder cancer cell growth by disrupting crucial metabolic processes, such as carbohydrate metabolism, lipid metabolism, and protein synthesis [ 21 ]. By disrupting these essential pathways, phytochemicals can potentially starve cancer cells of the nutrients they need to survive and proliferate.

The use of phytochemicals has unique advantages for medical applications, providing a novel approach to cancer prevention and improving patient outcomes and treatment efficacy, resulting in more effective treatment strategies. Additionally, studies have demonstrated that phytochemicals are a cost-effective option that mitigates the common adverse side effects of traditional treatments and decreases drug resistance, providing a safer and more patient-friendly alternative. These benefits are crucial in the field of medicine, where personalized and targeted therapies are essential for optimizing patient care and improving overall health outcomes. In this line novel analytical methodologies (e.g., Liquid chromatography-tandem mass spectrometry) is necessary to identify active phytochemicals of traditional medicine [ 22 ]. In addition, novel drug delivery systems will pave the road in combating different diseases [ 23 , 24 ].

Numerous phytochemicals are being tested in vitro and in vivo experiments. Moreover, various clinical trials also utilize phytochemicals in combination with other approved drugs. These clinical trials involve the rigorous testing and evaluation of phytochemicals in real-world settings, providing valuable insights into the effectiveness and safety of plant ingredients. By integrating plant-based therapeutic appriaches with established treatments, it is possible to enhance the overall efficacy and outcomes of clinical trials, ultimately contributing to the advancement of medical science and patient care.

Cancer metabolism refers to the unique metabolic characteristics and alterations that occur in cancer cells when compared to normal cells. Cancer cells exhibit specific metabolic requirements and mechanisms to maintain their rapid growth and reproduction. Metabolic reprogramming has been established as the hallmark of cancer. Key aspects of cancer metabolism are heightened glucose absorption and glycolysis, regardless of oxygen availability (the Warburg effect), modified lipid processing, elevated glutamine utilization, and alterations in mitochondrial activity. These pathways provide cancer cells with a flexible metabolic characteristic and offer chances for survival for cancer cells under stress. Comprehending cancer metabolism is crucial to developing specific treatments that capitalize on the metabolic defects of cancer cells without damaging normal cells. Researchers are investigating the disrupted metabolic pathways in cancer cells to pinpoint possible drug targets and create novel therapeutic approaches. There are several signaling pathways that play a crucial role in regulating cancer cell metabolism. Some of the key signaling pathways involved in cancer cell metabolism include, PI3K/Akt/mTOR pathway, AMPK, HIF, p53, Wnt/β-catenin, and Nrf2 pathway. These signaling pathways interact with each other and with other cellular processes to coordinate the metabolic reprogramming that occurs in cancer cells. Targeting these pathways with specific inhibitors or modulators holds promise for developing novel therapeutic strategies to selectively target cancer metabolism.

As a critical signaling pathway, 5´-adenosine monophosphate-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), has recently been highlighted as a promising target in combating cancer [ 25 ]. The dysregulation of the AMPK/PGC-1α axis is associated with many types of malignancies and may affect tumor development, metastasis, and treatment outcomes. In cancer cells, alterations in AMPK and PGC-1α activity can lead to metabolic reprogramming that supports the high energy demands of rapidly proliferating cells. For example, AMPK activation regulates mTOR signaling and inhibits cell growth, whereas PGC-1α overexpression promotes mitochondrial function and accelerates oxidative metabolism. The modulation of the AMPK and PGC-1α signaling pathways by phytochemicals presents a novel approach to targeting cancer cells and disrupting their metabolic processes. By elucidating the complex processes and mechanisms by which phytochemicals interact with these keys signaling pathways, researchers aim to develop innovative strategies for combating cancer and improving patient outcomes.

The influence of phytochemicals on cancer cell metabolism via altering the AMPK/PGC-1α signaling pathway has not been thoroughly investigated in existing literature, and no previous reviews have been published in this area. The aim of this review is to explore the impact of phytochemicals on the regulation of cancer metabolism through modulation of the AMPK/PGC-1α signaling pathway. By examining the current literature and summarizing the findings from in vitro and in vivo studies, we aim to elucidate the molecular mechanisms underlying the anticancer effects of phytochemicals targeting this key metabolic pathway. Ultimately, this review aims to provide a systematic review of the therapeutic potential of phytochemicals in cancer treatment and highlight their role in modulating cellular metabolism for improved patient outcomes. It’s the first systematic review on the promising anticancer role of phytochemicals through the regulation of AMPK/PGC-1α signaling pathway. We have also summarized various novel drug delivery systems for phytochemicals targeting AMPK/PGC-1α pathway and combat cancer.

The core role of AMPK/PGC-1α signaling pathway in cancer metabolism

The AMPK, a type of enzyme called a serine/threonine kinase, has remained similar in various species through evolution. It has a significant function in controlling cellular energy and redox homeostasis and affects all aspects of energy metabolism and mitochondrial biogenesis [ 26 ]. The AMPK enzyme has a heterotrimeric structure consisting of three subunits: α, β, and γ. The α subunit plays a catalytic role, the β subunit has a scaffolding function, and the γ subunit is a regulatory component. There are at least 12 known isoforms of AMPK identified in various cells and tissues [ 27 , 28 ]. The α subunit is present in both the cell membrane and nucleus [ 29 ]. The N-terminus of the β subunit binds to carbohydrates and inhibits AMPK signaling, affecting glycogen synthesis in the liver and muscle [ 28 , 30 ]. The γ subunit connects to the β subunit through its N-terminus and helps activate the enzyme [ 31 ]. AMPK gets activated when adenosine triphosphate (ATP) production decreases due to factors like hypoxia, or low oxygen, or lack of nutrients [ 32 ]. This phosphorylation mediates by liver kinase B1 (LKB1), calcium/calmodulin-dependent protein kinase kinase-β (CaMKKβ), and protein phosphatase 2 C and 2 A (PP2C and PP2A) [ 33 , 34 ]. However, evidence indicates that LKB1 has an important function in AMPK phosphorylation and activation in energetic stress conditions [ 33 ].

The activation of AMPK can cause inhibition of the anabolic pathway and stimulation of the catabolic pathway [ 34 , 35 ]. Adenosine monophosphate (AMP) has a higher affinity for attachment to the γ subunit of AMPK than adenosine diphosphate (ADP) [ 33 ]. Furthermore, AMP, in contrast to ADP, can promote LKB1-induced AMPK phosphorylation [ 33 ]. In times of abundant energy, enzymes like TGF-β-activated kinase 1 (TAK1), PP2A, PP2C, and dependent protein phosphatase 1E (PPM1E) inactive AMPK through dephosphorylation [ 36 ].

Reactive oxygen species (ROS) can active AMPK signaling, through direct and indirect mechanisms. Direct activation takes place via S-glutathionylation of cysteines on the AMPK α and β subunits. While indirect activation is mediated by changes in the cellular ATP/AMP and ATP/ADP ratios [ 37 ]. Numerous studies indicate that the activation of AMPK could be a potential treatment for various cancer types by inhibiting cancer promoting metabolic processes, arresting the cell cycle, and acting as a cyclooxygenase-2 (COX-2) inhibitor, decreasing cancer stemness [ 38 ]. AMPK increases autophagy and mitophagy by activating UNC-51-like kinase 1 (ULK1) and death-associated protein 1 (DAP1), respectively.

AMPK starts the apoptotic program through the activation of p53, p21, p27 and retinoblastoma protein (pRb) arrests cell cycle through the inhibition of HUR and the concomitant activation of cyclin A, cyclin B1, and cyclin D1 [ 39 , 40 , 41 ]. AMPK inhibits metabolic pathways in tumor cells, such as the Warburg effect, depriving cancer cells of energy and fuels [ 42 ]. The activation of AMPK signaling results in the reduction of mammalian target of rapamycin complex 1 (mTORC1) via the phosphorylation of tuberous sclerosis complex 2, also known as tuberin (TSC2) and regulatory-associated protein of mTOR (RAPTOR) [ 43 ]. This process suppresses oncogenic signaling, thereby restricting the proliferation and migration of cancer cells [ 44 ]. Furthermore, AMPK activation induces autophagy, inhibits glycolysis, and promotes mitochondrial oxidative metabolism through mTORC inhibition [ 45 ]. AMPK phosphorylates and deactivates oncogenic yes-associated protein (YAP) through Hippo tumor suppressive signal during glucose deprivation [ 46 ]. Studies suggest that AMPK phosphorylates and counteracts the oncogenic activity of glioma-associated oncogene 1 (Gli-1), the central transcription factor that regulates cell proliferation and differentiation in the Hedgehog pathway, particularly in medulloblastoma [ 47 ]. The LKB1, also called serine/threonine kinase 11 (STK11), is a known activator of AMPK, is tumor suppressor that act via the inhibition of mTORC1, and its deactivation is indicated in various cancers, include lung adenocarcinoma [ 43 ].

In epigenetic reprogramming, AMPK affects DNA methylation by phosphorylating and activating the tumor suppressor TET methylcytosine dioxygenase 2 (TET2) at S99 [ 48 ]. Metformin, a biguanide antidiabetic drug, activates AMPK, leading to the phosphorylation of checkpoint blocker programmed cell death ligand 1 (PD-L1) at S195. This process causes PD-L1 degradation through endoplasmic reticulum-associated protein degradation (ERAD) and enhances antitumor immunity [ 49 ]. Metformin enhances the expression of NF-κB via the AMPK/SIRT1 pathway, ultimately resulting in cellular apoptosis [ 50 ]. AMPK-mediated phosphorylation of enhancer of zeste homolog 2 (EZH2) inhibits polycomb repressive complex 2 (PRC2) cancer-promoting function and associated with improved survival outcome in breast and ovarian cancer [ 51 ].

Numerous experimental evidence in rats supports the tumor-suppressor action of AMPK. First, the loss of AMPKβ1 in the prostate accelerates the onset of prostate adenocarcinoma [ 52 ]. Second, elevated ubiquitin conjugating enzyme E2 (UBE2O) expression in various cancers induced the degradation of AMPKα2, therefore increasing the development and spread of tumors [ 53 ]. Third, the loss of AMPKα1 in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) accelerates the formation of leukemia and lymphoma [ 54 ]. Fourth, the inactivation of AMPKα1 promotes MYC (a hallmark of tumorigenesis)-driven lymphomagenesis by inducing HIF-1α-dependent aerobic glycolysis [ 43 ]. Fifth, depleting AMPKβ1 accelerates the onset of T-cell lymphoma after the inactivation of the p53 gene [ 43 ]. Finally, MAGE-A3/6-TRIM28, a cancer-specific ubiquitin ligase, induces the ubiquitination and degradation of AMPK. This process promotes mTOR signaling and contributes to malignant transformation in lung, breast, and colon tissues [ 55 ].

There are conflicting perspectives on whether AMPK actions may function in cancer development. AMPK plays a role in metabolic adaptation by participating in the signaling pathways associated with metabolic stress in tumor microenvironment (TME), which include nutrient starvation, matrix detachment, oxidative stress, and hypoxia [ 34 ]. As a result, activating AMPK may enhance the resistance of tumor cells to metabolic stress and maintain ATP levels by reprogramming energy metabolism [ 25 , 34 ]. One study indicates that in low glucose conditions, the AMPK-p38-PGC-1α pathway induces metabolic homeostasis in cancer cells [ 56 ]. AMPK provides the metabolic requirements for cancer cells that are growing during autophagy, thus promoting cell growth and survival. On the other hand, autophagy causes chemoresistance in cancer cells [ 25 ]. AMPK enhances mitochondrial respiration through MYC, resulting in efficient glutamine metabolism for energy production [ 34 ]. It has been reported that the effects of AMPK on tumor development may depend on the nutrient levels in the TME. In the absence of nutrients, AMPK may promote tumor growth and support survival, while in the presence of nutrients, AMPK may suppress tumor development [ 57 ]. AMPK phosphorylates and deactivates acetyl-CoA carboxylases 1/2 (ACC1/2) to maintain nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) homeostasis, thereby promoting cancer cell survival and breast cancer progression [ 58 ].

AMPK is involved in EGF/Akt signaling, a process disrupted in malignant transformation and cancer metastasis through the activation of Akt, leading to oncogenic procedure [ 59 ]. AMPK promotes T-ALL cells survive by inhibiting aerobic glycolysis, increasing mitochondrial oxidative metabolism, and decreasing metabolic stress and apoptosis [ 45 ]. During metabolic stress, AMPK activation causes resistance to oxidative stress and DNA damage in tumor cells in the bone marrow [ 60 ]. Studies indicated that the activation of AMPK-SKP2-Akt axis and AMPK-PDHc cascade is linked to a dismal prognosis in breast cancer [ 61 ]. Sirtuin 3 (SIRT3), a mitochondrial protein that removes acetyl groups, increases AMPK expression and leads to increased lymph node metastasis in cervical cancer cells. In colorectal cancer cells, non-muscle myosin IIA (NMIIA) triggers AMPK signaling, promoting the expression of mTOR, which increases growth and invasion [ 50 ]. Experimental evidence in rats supports the continuous function of AMPK in cancer advancement. In an acute myeloid leukemia (AML) model, AMPK inactivation decreased leukemia-initiating cells (LIC) and decelerated leukemogenesis [ 60 ]. In a lung cancer model, AMPK loss diminished tumor development, underscoring the essential role of AMPK activation in tumorigenesis [ 62 ].

One of the key regulators of cell metabolism is a member of the PGC-1 transcriptional co-activator family, known as PGC-1α. The PGC-1 family has three members: PGC-1α, PGC-1β, and PGC-1-related coactivator (PRC) [ 63 ]. PGC-1α primarily regulates mitochondrial biogenesis (mitobiogenesis) and function, including oxidative phosphorylation (OXPHOS), fatty acid/lipid metabolism, and the regulation of ROS levels [ 64 ]. The activation of PGC-1α in brown adipose tissue and in skeletal muscle contributes to an increase in metabolic activity and heat production as a response to cold exposure, exercise, and fasting [ 63 , 65 ]. The PGC-1α predominantly localizes within metabolically active tissues, including the liver, heart, muscles, kidneys, adipose tissue, and the brain [ 66 ]. PGC1α activity and mitochondrial function decline with age, potentially contributing to age-related cancer. However, exercise and a calorie-limit diet have been shown to enhance PGC1α activity, promoting healthy aging and potentially acting as protective factors against age-related cancer [ 64 ].

Numerous studies indicate the expression of PGC-1α is closely associated with cancer progression. PGC-1α has a function in maintaining metabolic homeostasis in microenvironments with high energy demands and restricted nutrition supplies in cancer cells. Overexpression of PGC-1α is identified in various type of cancers [ 67 ]. Similar to normal cells, PGC-1α mainly influences mitochondrial respiration, detoxification ROS, fatty acid oxidation (FAO), and glucose- or glutamine-derived lipogenesis in cancer cells [ 68 , 69 ]. However, literature contains conflicting reports, as both increased and decreased levels of PGC1α expression were related to cancer and a worse prognosis. Even within a specific cancer, include breast cancer, there exist discrepancies in the reported PGC1α levels [ 64 ]. Melanoma cells that overexpress PGC-1α demonstrate elevated mitochondrial oxidative metabolism, effective detoxification of ROS, dependence on OXPHOS, and resistance to apoptosis and chemotherapy [ 63 , 70 , 71 ]. In contrast, melanoma cells expressing low levels of PGC-1α, depend on glycolysis to survive, making them more vulnerable to apoptosis induced by ROS [ 70 ]. Nevertheless, despite the enhanced proliferation and survival associated with PGC-1α overexpression, it concurrently suppresses the invasive properties of these cells [ 71 ]. Furthermore, in melanoma, BRAF and inhibition of mTORC1/2 inhibits the melanocyte lineage factor (MITF), which, in turn, downregulates PGC-1α and increases glycolytic metabolism [ 72 ].

Under metabolic stress, the switch from glucose to fatty acid usage helps cells survive and occurs in various cancer types. PGC-1α induces the transactivation of FAO genes via PPARα and sirtuin 1 (SIRT1) [ 67 , 73 , 74 ]. When cells are deprived of glucose, PGC1α breaks down, leading to the aggregation of ROS and apoptosis [ 75 ]. In nutrient deprivation conditions, p53 has both cytoprotective and cytotoxic functions, while PGC-1α regulates p53 stress-dependent transcription, enhancing its activation of genes for cell cycle arrest and metabolism [ 75 , 76 ]. Receptor-interacting protein 1 (RIP1) regulates p53 via PGC-1α signaling. RIP1 inactivation reduces PGC-1α expression and OXPHOS, promoting glycolysis. Excessive glycolysis lowers nicotinamide adenine dinucleotide (NAD) levels, impairing DNA repair and activating p53-mediated cell growth inhibition [ 77 ]. MYC regulates glucose and glutamine metabolism, along with mitobiogenesis in cancer cells. C-MYC attaches to the promoter of PGC-1α and inhibits its transcription. The ratios of PGC-1α to MYC are associated with metabolic phenotypes in tumors, including pancreatic ductal adenocarcinoma, ranging from OXPHOS-based to glycolytic [ 78 , 79 ].

Pancreatic cancer stem cells express high levels of PGC-1α due to the absence of c-MYC. The strong expression of PGC-1α is implicated in mitochondrial respiration, as well as sensitivity to metformin treatment [ 78 ]. This ratio can be controlled by the transcription factor Forkhead box O3a (FOXO3a). Similar to PGC-1α, FoxO3a expression levels are correlated with cancer and adverse outcomes at both high and low levels [ 64 , 80 ]. Estrogen-related receptor (ERR) and PGC-1α are downstream proteins of kinase suppressor of Ras 1 (KSR1), a molecule that promotes Ras-induced transformation in breast cancer [ 81 ]. PGC-1α can mimic the actions of the natural ligands that ERR typically binds to, even though ERRα itself doesn’t bind to estrogens. Similar to PGC-1α, ERRα functions in the quick response to metabolic stress [ 64 , 82 ]. The PGC-1α/ERRα axis can influence glucose, glutamate, and fatty acid metabolism, as well as the TCA cycle, thereby stimulating the proliferation of breast cancer cells, even in conditions of low nutrients or hypoxia. Furthermore, in breast tumors, the PGC-1α/ERRα axis is involved in angiogenesis, metastasis, and resistance to chemotherapy [ 64 , 83 ]. High level of PGC-1α in mammary tumor cells induces dependence on the folate cycle for nucleotide synthesis and tumor proliferation [ 84 ]. Studies indicate that increased levels of PGC-1α, and its associated glutaminolysis genes, forecast a poor prognosis in breast cancer and demonstrate a negative association between the expression of PGC-1α and patient survival [ 83 ].

Evidence indicates a mutual influence and activation between androgen receptor (AR) and PGC-1α in prostate cancer. The androgen/AR/AMPK/PGC-1α signaling axis promotes mitochondria biogenesis, glucose oxidation, and FAO, which provides structural units and ATP for cancer cell growth [ 67 , 85 ]. PGC-1α-mediated tumor suppression primarily occurs through the induction of cell death. In addition, PGC-1α plays a role in tumor suppression by enhancing antioxidant defense via the upregulation of enzymes, including manganese-dependent superoxide dismutase and Nrf2, which can help prevent oxidative DNA damage and the development of cancer [ 64 , 86 ]. The function of PGC-1α in advanced tumor stages is hypothesized to be shaped by both the microenvironment and the metabolic conditions of the tumor [ 87 ]. Evidence indicates that PGC-1α has a function in promoting and inhibiting tumor progression, depending on the microenvironment and the metabolic conditions of the tumor [ 64 ]. For instance, one study demonstrated that in melanoma, treatments that inhibit BRAF upregulate PGC-1α and ID-2, its downstream target, leading to the suppression of metastasis-related genes [ 71 ]. In contrast, evidence suggests that the downstream effectors of PGC-1α, specifically β-oxidation and fatty acid/lipid metabolism, play an essential role in promoting metastasis [ 88 ]. Furthermore, chemoresistant metastatic cells exhibit heightened metabolic patterns involving both glycolysis and increased OXPHOS [ 64 ]. Expression of PGC is upregulated by AMPK, ERRα, and p53. In contrast, PGC is downregulated through hypermethylation.

To fully understand the mechanisms underlying PPARGC1A methylation and its possible therapeutic implications, more research is necessary, as the precise significance of this alteration in cancer is currently unclear [ 64 , 67 , 89 , 90 ]. Glycogen synthase kinase-3β (GSK-3β) phosphorylates the PGC-1α protein, which is then degraded via the ubiquitin-proteasome pathway. The breakdown of the PGC process is inhibited by the nuclear protein necdin, a tumor suppressor, thus preserving OXPHOS integrity [ 64 , 91 ]. Inflammatory cytokines, including TGF-β, tumor necrosis factor-α (TNF-α), interleukin- 6 (IL-6), and TNF-related weak inducer of apoptosis (TWEAK), suppress the expression of PGC1α [ 64 , 92 , 93 ]. The E3 ligase Parkin orchestrates the elimination of dysfunctional mitochondria via mitophagy. Deactivating mutations of Parkin result in the accumulation of ZNF746, a transcriptional repressor of PGC-1α. Numerous studies suggest the presence of Parkin deletions in various types of cancers [ 64 , 94 ].

MicroRNAs (miRNAs or miR)-485, miR-485-3p, and miR-5p, along with miR-23a and miR-217, downregulate PGC-1α. However, these miRNAs are inhibited in certain tumors [ 95 , 96 , 97 ]. Finally, in various types of carcinomas, the expression of MYC is upregulated, subsequently inhibiting PGC1 through acetylation by general control non-depressible 5 (GCN5) enzyme. This finding reinforces the inverse relationship between MYC and PGC-1α [ 64 ]. Autophagy exhibits tumor-suppressive functions during early tumorigenesis, but it may support the survival of cancer cells in established tumors [ 64 ]. Mitophagy has an important function in normal tissue function but is implicated in tumor cell resistance to stress, hypoxia, and DNA damage [ 98 , 99 ]. Recent studies indicated that melanoma has two types of cells, one with high levels of PGC-1α and the other with very low levels of PGC-1α. In breast cancer, PGC-1α activates PPARα, ERRα, Nrf1, and Nrf2, which leads to development of mitochondrial biogenesis and OXPHOS and can generate large amounts of ATP for tumor growth [ 100 ]. The function of PGC-1α in prostate cancer is similar to that of melanoma. It has been demonstrated that c-MYC directly regulates PGC-1α in pancreatic adenocarcinoma. C-MYC binds to the PGC-1α promoter and inhibits its transcription. Further, the ratio of c-MYC/PGC-1α controls the metabolic behavior of pancreatic cancer cells [ 63 ].

Methodology of literature search

Based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria, the current systematic and comprehensive review was conducted. Thus, a systematic literature search was performed through electronic databases, including PubMed, Scopus, and Science Direct for articles written in the English language. The last search was performed at the end of December 2023. The systematic search in databases was carried out by applying the following keywords: (tumor OR cancer OR malignant* OR neoplasm OR melanoma OR leukemia) found in title or abstract AND (herb* OR plant* OR natural product OR polyphenol* OR phenolic compound* OR terpene* OR alkaloid* OR flavonoid* OR glucosinolate* OR coumarin*) AND (AMPK OR PGC-1alpha OR PGC-1α) were found in title/abstract. The search process was executed by two independent researchers (S.F. and S.Z.M.). Accordingly, the review process was finalized through discussion with a senior author (A.B.) to resolve disagreements. Initially, 265 articles of the 717 articles, which were obtained from the primary electronic search, were excluded due to duplication. Furthermore, 101 review articles were excluded. To evaluate the results based on the title and full text of the articles, 177 and 61 unrelated articles were exempted, respectively. Finally, after excluding unrelated articles, 111 related articles were included in this systematic review (Fig.  1 ).

PRISMA flowchart on the process of literature search and selection of relevant studies

Anticancer phytochemicals targeting AMPK/PGC-1α signaling pathway

Several recent studies have highlighted the modulatory roles of various phytochemicals against AMPK/PGC-1α. Accordingly, alkaloids, phenolic compounds, terpenes/terpenoids, and several miscellaneous compounds have shown potential in the modulation of AMPK/PGC-1α pathway to combat cancer.

Phenolic compounds

The most widespread type of secondary metabolite in plants are phenolic compounds. Phenolic compounds are identified by an aromatic ring with a characteristic hydroxylated structure. There are two main types of phenolic compounds: non-flavonoids and flavonoids. Non-flavonoids include stilbenes, phenolic acids, tannins, coumarins, and lignans [ 101 , 102 , 103 , 104 ]. Flavonoids include flavanols, flavonols, flavones, flavanones, anthocyanidins, and isoflavonoids. Phenolic compounds display a variety of advantageous traits, such as antibacterial, anticancer, anti-inflammatory, cardioprotective, antiviral, and antimutagenic effects [ 101 , 102 , 103 , 104 ]. The most notable phenolic substances with anticancer properties are the subject of research presented in the following paragraphs, emphasizing the pathways linked to cancer metabolism, especially AMPK/PGC-1α, that underlie their anticancer action.

Resveratrol

Resveratrol (Fig.  2 ), an extensively researched polyphenol, possesses a broad range of pharmacological properties, including anticarcinogenic, antibacterial, antioxidant, and anti-inflammatory effects [ 105 , 106 , 107 , 108 ]. Resveratrol induced apoptosis and inhibited the migration, proliferation, and invasion of in vitro and in vivo models of ovarian [ 109 ], breast [ 110 ], leukemia [ 111 ], colon [ 112 , 113 ], prostate [ 114 ], and glioblastoma [ 115 ] cell lines via inhibiting glycolysis and fatty acid synthase. Resveratrol also reversed the Warburg effect and downregulating acetyl-CoA carboxylase-α via targeting pyruvate dehydrogenase, AMPK/mTOR, STIM1, NF-κB, AMPK-YAP, and c-Jun NH 2 -terminal kinase (JNK)-mediated p62/SQSTM1 signaling pathways.

Chemical structures of common phenolic compounds in the regulation of cancer metabolism AMPK/PGC-1α

Quercetin (Fig.  2 ) is a naturally occurring flavonoid that is prevalent in fruits and vegetables and mechanistically displays antioxidant, anti-inflammatory, and anticancer properties in a variety of cellular and animal models. It has been shown to have biological actions that include anticancer, anti-inflammatory, immunoprotective, and antiviral activities [ 116 , 117 , 118 , 119 ]. Quercetin induced apoptosis and autophagy and suppressed viability, migration, and proliferation of various human cancer cell lines, such as lung [ 120 ], cervical [ 121 ], colon [ 122 , 123 ], and breast [ 124 ] cancer. This was due to quercetin’s ability to interfere with AMPK, epidermal growth factor receptor (EGFR), Akt/AMPK/mTOR, and SIRT1/AMPK signaling pathways.

Isoquercitrin

It has been reported that isoquercitrin (Fig.  2 ), a naturally occurring flavonoid found in various plant species, including Mangifera indica and Rheum nobile , significantly inhibited the proliferation of human liver cancer cells Huh7 and HepG2 [ 7 , 125 ]. This was achieved through the inhibition of viability and colony growth, activation of the apoptotic pathway, and dysregulation of autophagy via the activation of the AMPK/mTOR/p70S6K pathway [ 126 ].

Curcumin (Fig.  2 ) is a phenol compound that can be extracted from Curcuma longa L. (Zingiberaceae family). Curcumin possesses significant biological activities, including antioxidant, anti-inflammatory, antimicrobial, neuroprotective, and anticancer activities [ 127 , 128 , 129 , 130 ]. It has been reported that curcumin inhibits growth, angiogenesis, and metastasis of 4T1, B16, CT26, A204, RD, SJCRH30, and SMMC-7721 cell lines by inducing apoptosis, fatal energetic impairment, and cell cycle arrest, mainly through the inhibition of NF-κB, suppression of ATP-synthase activity, and the activation of AMPK [ 131 , 132 , 133 ].

Epigallocatechin gallate

Epigallocatechin gallate (EGCG) (Fig.  2 ) is a phenolic compound derived from green tea. It is well-known for its antioxidant, anti-inflammatory, neuroprotective, and antineoplastic properties [ 134 , 135 , 136 , 137 , 138 ]. EGCG exerted significant anticarcinogenic activity in H1299 lung cancer cells in vitro via targeting AMPK, mTOR, and Akt signaling [ 139 ]. Moreover, treatment with EGCG leads to apoptosis and suppression of the proliferation of HT-29 cells via interfering with COX-2, AMPK, vascular endothelial growth factor (VEGF), and Glut1-related pathways. In addition, treatment decreased the formation and synthesis of fatty acid, lipid droplets formation, energy metabolism, mitochondrial oxidation/glycolysis, lipolysis, and fatty acid β-oxidation was reported as the main anticancer activities of EGCG in both HCT-116 and HT-29 cancer cells [ 140 , 141 ].

Apigenin (Fig.  2 ), a 4′,5,7-trihydroxyflavone, is predominantly found in plants and belongs to the Apium genus, including parsley and Chinese celery. This bioactive molecule exhibits a wide range of biological activities, including antiviral, anti-inflammatory, and antioxidant, and anticancer properties [ 128 , 129 , 130 , 142 ]. Apigenin promoted autophagy and apoptosis in the H1975 cell line via targeting HIF-1α, c-MYC, glucose metabolism, Glut1, Glut4, monocarboxylate transporter 1 (MCT1), and AMPK [ 143 ]. Moreover, apigenin exert significant in vitro and in vivo anti-carcinoma activities in gastric cancer models by interfering with AMPK, ULK1, mTOR, p62, protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), and HIF-1α [ 144 ].

Isoliquiritigenin

Isoliquiritigenin (Fig.  2 ), a chalcone compound from the natural source locorice, has exhibited noteworthy biological activities, such as antitumor, antiviral, anti-inflammatory, antispasmodic, antidiabetic, and antioxidant effects [ 145 , 146 ]. Treatment with isoliquiritigenin led to the inhibition of growth of colorectal cancer cells via regulating AMPK/mTOR-mediated glycolysis and HIF-1α signaling. Similarly, isoliquiritigenin promoted the suppression of Glut4-mediated glucose uptake by targeting PDHK1/PGC-1α in gastric cancer cells [ 147 , 148 ].

Hispidulin (Fig.  2 ) is a naturally occurring flavone isolated from the Artemisa and Salvia plants, which are widely accepted as traditional medicinal plants. Hispidulin possesses various biological activities, including antioxidant, antifungal, neuroprotective, and antiproliferative properties [ 105 , 106 , 149 ]. Hispidulin suppressed the growth, proliferation, and metastasis of hepatocellular carcinoma cells by targeting ERK, AMPK, and AMPK/mTOR signaling pathways [ 150 ].

Rottlerin (Fig.  2 ), a phytoconstituent with vital biological properties, such as anticancer, antibacterial, antifilarial, and anti-inflammatory activities, is found in the pericarp of Mallotus philippensis. Its multifaceted pharmacological effects against cancer are promising. Rottlerin promoted apoptosis and autophagy in prostate cancer cells by interfering with the AMPK and PI3K/Akt/mTOR signaling pathways [ 151 ]. Moreover, suppression of the Wnt/β-catenin and mTORC1 signaling pathways were noted to be the main antitumor effects of rottlerin in several in vitro models of breast and prostate cancer cells [ 152 ].

Baicalin and baicalein

Baicalin (Fig.  2 ) is a major bioactive glycosyloxyflavone that can be isolated from root of the Scutellaria baicalensis plant [ 153 ]. Baicalin has anticancer, hepatoprotective, anti-inflammatory, neuroprotective, cardioprotective, antioxidant, renal protective, and antibacterial advantages [ 154 , 155 , 156 ]. Baicalin exerts significant anticancer activity against several in vitro models of cancer, including non-small cell lung cancer (NSCLC) via regulating AMPK/Nrf2 and activating SIRT1/AMPK signaling [ 157 , 158 ]. Baicalin can hydrolyzed to its metabolite and aglycone form, baicalein (Fig.  2 ), which has garnered significant attention from cosmetic, food, and pharmaceutical industries for its exceptional antioxidant, neuroprotective, anti-inflammatory, cardioprotective, anticancer, hepatoprotective, and antiviral properties [ 154 , 155 , 156 ]. Baicalein suppresses the growth of PC-3 and DU145 cells in in vitro models of prostate cancer by activating AMPK/ULK1 and inhibiting mTORC1 signaling [ 159 ]. In a similar study, baicalein promoted apoptosis and autophagy in glioblastoma cells (U251) through activation of AMPK [ 160 ]. Moreover, baicalein showed meaningful anticarcinoma activities in H1299, A549, PC9, and H1650 cell lines as in vitro models of NSCLC via facilitation of apoptosis and increasing p-ERK1/2, FOXO3a, and RUNX3 [ 161 ].

Other phenolic compounds

Kaempfero, (Fig.  2 , a natural flavonol found in plants and plant-derived foods) [ 162 ], luteolin (Fig.  2 , a flavonoid that is known for its antioxidant and anti-inflammatory properties) [ 163 ], morusin (Fig.  2 , prenylated flavonoid produced from Morus alba Linn) [ 164 ], glycycoumarin (Fig.  2 , a major coumarin in licorice) [ 165 ], and cyanidin 3- O -glucoside (Fig.  2 , an anthocyanidin glycoside found in legumes) [ 166 ], are some of the known polyphenolic compounds that inhibit growth and glycolysis in various in vitro and in vivo models of hepatic carcinoma. This was achieved by inducing apoptosis, senescence, and cell cycle arrest through targeting AMPK, NF-κB, Akt, and CDK1/cyclin B. In addition, interfering with AMPK, HIF-1α, AMPK-mTOR, Sirt3/HIF-1α, PI3K/Akt/mTOR, and CaMKKβ-AMPK-mTOR signaling pathways was identified as the primary anticarcinogenic activity of ellagic acid (Fig.  2 , a bioactive polyphenolic agent found Punica granatum L.) [ 167 ], honokiol (Fig.  2 , a lignan polyphenol found in several Magnolia species) [ 168 ], gallotannin (Fig.  2 , a specific type of hydrolyzable tannin present in vegetables) [ 169 ], and pomiferin (Fig.  2 , a bioactive prenylated flavonoid isolated from Derris montana , Citrus aurantium ) [ 170 ] in different in vitro and in vivo lung cancer models. Furthermore, multiple preclinical models of colon carcinoma illustrated the capability of other phenolic compounds to promote apoptosis, inhibit epithelial-mesenchymal transition (EMT), invasion, and growth, and induce cell cycle arrest by targeting several signaling pathways, including AMPK/mTOR, AMPK/MAPK/XAF1, TGF-β1, NF-κB, CaMKKβ-AMPK, and JAK2/STAT3 signaling. Of those phenolics, such as ampelopsin (Fig.  2 , a flavanonol flavonoid known as dihydromyricetin) [ 171 ], isoangustone A (Fig.  2 , a flavonoid obtained from Glycyrrhiza glabra ) [ 172 ], brosimone I (Fig.  2 , a flavonoid isolated from jackfruit) [ 173 ], and salidroside (Fig.  2 , a tyrosol glucoside isolated from Rhodiola rosea ) [ 174 ], have exerted promising antineoplastic potential by targeting AMPK signaling. Moreover, in PANC-1 and MIA-PaCa2 pancreatic cancer cells, fisetin (Fig.  2 , a flavonoid found in several fruits and vegetables) [ 175 ], eupatilin (Fig.  2 , a flavonoid derived from Artemisia asiatica ) [ 176 ], and isoorientin (Fig.  2 , a flavone C-glycoside constituent) [ 177 ] interfered with AMPK/mTOR, VEGF, and AMPK. Also, isorhamnetin (Fig.  2 , a monomethoxyflavonol extracted from leaf of Ginkgo biloba ) [ 178 , 179 ], hyperoside (Fig.  2 , a flavonol glycoside present in genera Hypericum and Crataegus) [ 180 ], silibinin (Fig.  2 , a bioactive compound derived from Silybum marianum L.) [ 181 ], and typhaneoside (Fig.  2 , a phenolic component isolated from Typha angustifolia L.) [ 182 ] are some of the known polyphenolic compounds with variant biological effects that showed significant anticarcinoma potential against in vitro and in vivo models of breast, skin, renal, melanoma, and leukemia cancers by interfering with several metabolism-related pathways, including AMPK/mTOR/p70S6K, PI3K, and Akt signaling pathways (Table  1 ).

Alkaloids are naturally occurring organic nitrogen compounds found in various organisms, particularly plants, and are hypothesized to have substantial pharmacological and biological activities. These activities include neuroprotective, antibacterial, antifungal, and antitumor properties [ 129 , 153 , 183 , 184 ]. The following section presents information on how various alkaloids target the AMPK/PGC-1α signaling pathway, which ultimately regulates cancer metabolism.

Berberine (Fig.  3 ) is a phytocompound extracted from Berberis vulgaris and Berberis aristata plants. It is classified as an isoquinoline alkaloid and has a variety of pharmacological properties, including anti-inflammatory, immunomodulatory, antidepressant, and antineoplastic effects [ 185 , 186 , 187 ]. Berberine led to the suppression of growth, migration, and invasion of a colorectal cancer cell line via suppressing fatty acid synthesis and downregulating the activities of AMPK, NF-κB, and integrin β1 signaling [ 188 , 189 , 190 ]. Similarly, berberine attenuated the growth and proliferation of U87MG [ 191 ], HepG2 [ 192 ], PANC-1 [ 193 ], B16F10 [ 194 ], and AGS [ 195 ] cells in in vitro models of glioblastoma, hepatocellular, pancreatic, melanoma, and gastric cancer, respectively. This was done by inhibiting DNA synthesis, AMPK/mTOR/ULK1, mTORC1, COX-2, ERK, and the AMPK/HNF4α/WNT5A pathway.

Chemical structures of common alkaloids in the regulation of cancer metabolism through AMPK/PGC-1α

Chaetocochin J and neferine

Chaetocochin J (Fig.  3 ) and neferine (Fig.  3 ) are natural alkaloids with significant antimetastatic, antiproliferative, and neuroprotective properties. These alkaloids play a crucial role against HCT-116 and SW480 in vitro colorectal cancer cell models via interfering with Ulk-1-PERK, AMPK, AMPK-mTOR, and PI3K/Akt/mTOR pathways [ 196 ].

Stachydrine

Targeting the LIF/AMPK and PI3K/Akt/mTOR axis was reported to be the main anticarcinoma activity of stachydrine (Fig.  3 , an active constituent obtained from of Castanea sativa Mill.) and coptisine (Fig.  3 , an isoquinoline alkaloid present in Chinese goldthread) in several in vitro models of hepatocellular carcinoma [ 197 , 198 ].

Other alkaloids

Fangchinoline (Fig.  3 ), a miscellaneous alkaloid extracted from Stephania tetrandra , exerted anticancer effects on lung and colorectal cancer via promoting apoptosis, autophagy, suppression of metastasis, and EMT through regulation of the AMPK/mTOR/ULK1 and Akt-mTOR pathways [ 199 , 200 ]. Aloperine (Fig.  3 , a quinolizidine alkaloid isolated from Sophora alopecuroides L.) [ 201 ], hydroxycamptothecin (Fig.  3 , an active ingredient found in Nothapodytes nimmoniana ) [ 202 ], hernandezine (Fig.  3 , a bisbenzylisoquinoline alkaloid derived from Thalictrum glandulosissimum ) [ 203 ], ethoxysanguinarine (Fig.  3 , a benzophenanthridine alkaloid obtained from Macleaya cordata ) [ 204 ], cryptolepine (Fig.  3 , an alkaloid that can be found in Cryptolepis sanguinolenta ) [ 205 ], angustoline (Fig.  3 , an active ingredient of Camptotheca acuminata ) [ 206 ], and 11-methoxytabersonine (Fig.  3 , an active ingredient isolated from M. cochinchinensis ) [ 207 ], are some of the valuable alkaloids found in several vegetables and fruits. They have been shown to possess crucial antimetastatic potential against various in vitro and in vivo cancer models, including thyroid, bladder, pancreatic, breast, melanoma, esophageal, and lung cancers. They do so by targeting AMPK, Akt, AMPK-mTOR-ULK1, ERK, ROS/AMPK, AMPKα1/2-LKB1, JNK, LKB1/AMPK/ELAVL1/LPACT2, and AMPK/mTOR signaling pathways (Table  2 ).

Terpenes/terpenoids

Terpenes, a hydrocarbon, and terpenoids, which are terpenoids that contain oxygen, are potent organic compounds obtained from plants that provide a wide variety of therapeutic benefits. Terpenes and terpenoids consist of a structure made of isoprene units, which are five-carbon unit components. The bonds between various isoprene units form the main structure of these compounds. Terpenes and terpenoids possess significant anticancer activities against variant types of carcinomas via interaction with apoptosis, autophagy, and metabolism-related signaling pathways [ 208 , 209 , 210 ]. In the following section, we provide an overview of research carried out on the most notable terpenes and terpenoid substances that possess substantial anticancer properties via modulation of the AMPK/PGC-1α signaling pathway.

Furanodiene and β-elemene

Furanodiene (Fig.  4 ) and β-elemene (Fig.  4 ) are two bioactive sesquiterpenes that exert significant anticancer activity against MCF-7, breast cancer [ 211 ], and A549, lung cancer [ 212 ], cells by alteration of mitochondrial function, suppression of DNA methyltransferase 1 expression, and activation of the AMPKα and ERK1/2 signaling pathways.

Chemical structures of common terpenes/terpenoids in the regulation of cancer metabolism through AMPK/PGC-1α

Ursolic acid

Ursolic acid (Fig.  4 ) is a naturally occurring pentacyclic triterpenoid carboxylic acid that is present in many fruits and vegetables, such as oregano, apples, peppermint, cranberries, lavender, bilberries, and elder flower. Ursolic acid possesses a wide spectrum of pharmacological activities such as antibacterial, cardioprotective, hepatoprotective, anti-inflammatory, and antiproliferative effects [ 213 ]. It can inhibit tumor growth and is increasingly being recognized as a promising molecule for both preventing and treating cancer. Ursolic acid suppresses the growth of hepatocellular carcinoma cells through the alteration of the glycolytic pathway, AMPKα, and pERK1/2 signaling pathways [ 214 ]. Moreover, treatment with ursolic acid leads to the induction of apoptosis and the suppression of the proliferation in MCF-7 and MDA-MB-231 cells by interfering with Akt, ERK, ROS, and AMPK pathways [ 215 ].

Triptolide (Fig.  4 ) is a primary active ingredient isolated from Tripterygium wilfordii Hook F. with notable anticancer potential. This phytocompounds can promote apoptosis and autophagy in lung and prostate cancer cells via activation of the CaMKKβ-AMPK and regulation of AMPK/mTORC2 signaling pathways [ 216 , 217 ].

Yuanhuacine

Yuanhuacine (Fig.  4 ) is another diterpene terpenoid that showed antitumor activity in the A549 cell line via regulating AMPK/mTOR axis [ 218 ].

Other terpenoids

Nummularic acid (Fig.  4 , a triterpenoid derived from the Fraxinus xanthoxyloides ) [ 219 ], celastrol (Fig.  4 , an active ingredients isolated from Tripterygium wilfordii ) [ 220 , 221 ], gitogenin (Fig.  4 , a natural component extracted from Allium rotundum and Yucca gloriosa ) [ 222 ], oleanolic acid (Fig.  4 , a pentacyclic triterpenoid derived from Phytolacca americana ) [ 223 ], poricoic acid A (Fig.  4 , a tricyclic triterpenoid isolated from Poria cocos) [ 224 ], and plectranthoic acid (Fig.  4 , a pentacyclic triterpenoid in Ficus microcarpa ) [ 225 ] are some of the other triterpenoid components that possess considerable anticarcinoma activities in several in vitro and in vivo models of prostate, colorectal, lung, leukemia, and breast cancer via inducing cycle arrest and apoptosis and interfering with numerous signaling pathways, including mTOR/S6K, AMPK/mTOR, and AMPK signaling (Table  3 ).

Miscellaneous phytochemicals

Research on the most important miscellaneous phytocompounds with notable anticancer activities are summarized in the following section, with an emphasis on the cancer metabolic pathways that underlie their anticancer action. Osthole (Fig.  5 ) is a natural coumarin agent with several pharmacological activities that can be isolated from Cnidium spp. Osthole suppressed the growth of various malignant phenotypes by promoting ferroptosis and apoptosis and suppressing glycolysis, AMPK/Akt, and the GSK-3β/AMPK/mTOR signaling pathway [ 226 , 227 , 228 ]. Targeting of AMPK/miR-299-5p/ATF2, AMPK, E-cadherin/AMPK/mTOR, and ROS/AMPK/mTOR axes was described as the major anticancer mechanism of numerous miscellaneous phytocompounds, such as 6′-O-galloylpaeoniflorin (Fig.  5 , an active ingredients extracted from paeoniflorin) [ 229 ], gambogic acid (Fig.  5 , a xanthonoid compound isolated from brownish) [ 230 ], gracillin (Fig.  5 , a steroidal saponin that can be extracted from Dracaena draco ) [ 231 ], aspiletrein A (Fig.  5 , a steroidal saponin found in Aspidistra letreae ) [ 232 ], and schizandrin A (Fig.  5 , a dibenzocyclooctadiene lignan) [ 233 ], against several in vitro and in vivo models of lung carcinoma. In addition, ginkgolic acid (Fig.  5 , an active ingredient in Ginkgo biloba L.) and periplocin (Fig.  5 , a plant-derived glycoside) diminished the growth and development of PANC-1 and BxPC-3 cell lines in vitro models of pancreatic cancer by suppressing lipogenesis, promoting apoptosis, and activating AMPK-mTOR signaling [ 234 , 235 ]. In similar studies, panduratin A (Fig.  5 , a major active ingredient isolated from Boesenbergia rotunda ) [ 236 ], bixin (Fig.  5 , an apocarotenoid extracted from Bixa orellana ) [ 237 ], β-sitosterol (Fig.  5 , an active phytosterol) [ 238 ], physciosporin (Fig.  5 , a natural constituent obtained from Pseudocyphellaria faveolata ) [ 239 ], hydroxycitric acid (Fig.  5 , a derivative of citric acid in Garcinia cambogia ) [ 240 ], and isogambogenic acid (Fig.  5 , an active component from Garcinia hanburyi ) [ 241 ], showed remarkable antineoplastic effects against numerous in vitro models of cancer, including melanoma, glioma, colorectal, breast, leukemia, and gastric adenocarcinoma, by diminishing metastasis, mitochondrial respiration, aerobic glycolysis, EMT, cancer metabolism, and cell proliferation by disrupting AMPK/PGC-1α, mTOR, and AMPK and interconnected signaling pathways. Table  4 presents miscellaneous phytochemicals targeting AMPK/PGC-1α in cancer.

Chemical structures of miscellaneous phytochemicals in the regulation of cancer metabolism through AMPK/PGC-1α

Novel delivery systems of phytochemicals in cancer

Novel delivery systems and formulations of phytochemicals play a crucial role in enhancing the bioavailability, stability, and efficacy of these natural compounds. Phytochemicals obtained from plants have favorable health effects such as anti-inflammatory, antioxidant, and anticancer characteristics. However, their poor solubility, low stability, and limited absorption in the body can hinder their therapeutic potential. By developing innovative delivery systems, such as nanoparticles, liposomes, micelles, and nanoemulsions, researchers can overcome these challenges and improve the targeted delivery of phytochemicals to specific tissues or cells [ 242 , 243 ]. This progress improves the therapeutic impact of phytochemicals and introduces new opportunities for personalized medicine and disease therapy.

The effectiveness of many phytochemicals is limited due to rapid metabolism, low bioavailability, poor water solubility, and systemic elimination. To address these challenges, scientists have investigated novel drug delivery systems, including lipid-based nanoparticles, polymeric nanoparticles, micelles, exosomes, nanogels, and mesoporous silica nanoparticles [ 130 , 244 , 245 , 246 ]. In the following section, novel delivery systems of phytochemicals, with their anticancer potentials, are reviewed.

Liposomal curcumin has demonstrated potential in cancer treatment through in vitro, in vivo, and clinical studies. Other novel delivery systems for curcumin against cancer include graphene oxide, poly(glycerol subcategory) nanoparticles, and nanodelivery systems, such as polymer nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, liposomes, niosomes, and nanoemulsions. These delivery systems have enhanced the therapeutic effectiveness of curcumin against various types of cancer, primarily because of its antiproliferative and proapoptotic effects on tumor cells. However, potentially serious side effects, including interactions with other drugs and the toxic aspects of nanoparticles, may occur. More high-quality studies are needed to determine clinical efficacy [ 247 , 248 , 249 , 250 ]. The potential of curcumin-loaded nanoparticles to reduce oxidative stress and apoptosis in various conditions, including cancer, through the AMPK pathway, has been analyzed. A study on curcumin nanoparticles demonstrated their ability to reduce palmitate-induced oxidative stress in the heart and protect it from apoptosis by activating the AMPK pathway [ 251 ]. Curcumin phytosomes combine curcumin with phospholipids to enhance this phytochemical’s bioavailability. Curcumin has been extensively studied for its potential health benefits, including its effects in fighting cancer. Research has shown that phytosome curcumin can inhibit thrombin-induced cell growth and migration through AMPK in breast cancer [ 252 ]. Curcumin’s phytosome formulation, such as Meriva ® Phytosome ® technology, enhanced the bioavailability of curcuminoids and ensured optimal absorption in the body [ 253 ]. Phytosome curcumin has demonstrated potential effects on cancer, especially in relation to breast cancer. Research has shown that phytosome curcumin can inhibit thrombin-induced cell growth and migration through AMPK in breast cancer [ 252 ].

Several nanodelivery systems have been developed to enhance the effectiveness of EGCG in cancer treatment. It has been shown that liposomal co-delivery systems, including EGCG and paclitaxel, induce apoptosis in cancer cells more effectively than either of these compounds alone [ 254 ]. Gold and lipid-based nanoparticles have also been investigated as delivery systems for EGCG [ 255 , 256 ].

A recent study demonstrated that delivering EGCG in nanoparticles increased cytotoxicity in breast cancer cell lines. Furthermore, a co-delivery nanosystem of EGCG and rutin has been suggested for their potential anticancer and antibacterial effects [ 257 ]. These studies suggest that nanodelivery systems may enhance the potential of EGCG in cancer treatment. The anticancer effects of EGCG nanoemulsion on lung cancer have been analyzed, and the results indicate that nano EGCG may inhibit lung cancer cell proliferation, colony formation, migration, and invasion by activating protein signaling pathways and inhibiting AMPK [ 139 ].

In one study, resveratrol was bioconjugated with gold nanoparticles using polyvinylpyrrolidone as a cross-linker. This led to improved delivery performance and enhanced the antitumor effects of resveratrol [ 258 ]. Another study investigated the targeted delivery of resveratrol to mitochondria by conjugating it to triphenylphosphonium (TPP), resulting in the potentiation and induction of mitochondrial-mediated apoptosis. Similarly, nanocarrier-based delivery systems have also been investigated to enhance the bioavailability and therapeutic potential of resveratrol [ 259 ].

Ginsenosides

Ginsenosides are important bioactive compounds that can be found in ginseng roots. These compounds have been studied for their potential health benefits, such as anticarcinoma, antioxidant, neuroprotective, and anti-inflammatory properties. Ginsenosides have demonstrated therapeutic potential in triggering apoptosis in tumor cells, decreasing proliferation, invasion, and metastasis, as well as reversing multidrug resistance [ 260 ]. These ginsenosides have been encapsulated or modified in various nanodelivery systems, such as polymeric nanoparticles, liposomes, micelles, and biomimetic nanoparticles, to enhance drug bioavailability and targeting ability [ 261 ]. In addition, ginsenosides serve as chemotherapeutic adjuvants and membrane stabilizers in a novel multifunctional liposome system that demonstrates antitumor efficacy and active targeting abilities [ 262 ]. Ginsenosides have been reported to activate the AMPK pathway, which can regulate metabolic reprogramming and reverse the Warburg effect in breast cancer [ 263 ]. New ginsenoside delivery systems have been developed to effectively target the AMPK pathway for cancer therapy, according to recent findings [ 264 , 265 , 266 ].

Conclusion, challenges/pitfalls, and future perspectives

As a major area of extensive attention, cancer metabolism has been an emerging hallmark of cancer. Targeting the major dysregulated metabolic pathways by multi-targeting phytochemicals could be a promising strategy to combat cancer cells. Despite the benefits behind targeted therapies, many cancer cells cannot be treated using just one type of treatment. Furthermore, considering the complexity of cancer metabolism, it is necessary to find new treatments that can target multiple dysregulated pathways. Accordingly, phytocompounds have indicated potential in combating cancer dysregulated pathways, but with fewer side effects than other commonly used treatments. Such potentials have introduced phytochemicals as promising compounds for prevention and treatment of cancer through regulating different signaling pathways.

Amongst those dysregulated pathways, AMPK/PGC-1α and interconnected pathways plays critical roles in cancer metabolism. In this line, alkaloids, phenolic compounds, terpenes/terpenoids, and several miscellaneous phytochemicals, represent major candidates in modulating cancer metabolism (Fig.  6 ). Phytochemicals have also demonstrated potential in the regulation of downstream signaling pathways of AMPK/PGC-1α, including angiogenesis, apoptosis, inflammation, and oxidative stress (Fig.  7 ).

Targeting AMPK/PGC-1α and interconnected signaling pathways by phytochemicals in cancer

Targeting the downstream signaling pathways of AMPK/PGC-1α by phytochemicals including angiogenesis, apoptosis, inflammation, and oxidative stress

The instability, low solubility/selectivity, poor bioavailability, rapid metabolism, and chemical degradation of phytochemicals limit their therapeutic applications in cancer. Employing novel delivery systems kindly overwhelmed such pharmacokinetic limitations by increasing bioavailability. Accordingly, lipid-based nanoparticles, polymeric nanoparticles, micelles, nanogels, cyclodextrin, gold, and mesoporous silica nanoparticles, have been critically employed to drawback the pharmacokinetic limitations of phytochemicals in targeting the AMPK/PGC-1α signaling pathway. Several phytochemicals have demonstrated notable antitumor effects by regulating cancer metabolism via influencing different signaling pathways, such as AMPK/PGC-1α, NF-κB, PI3K/Akt/mTOR, HIF-1α, ERK1/2, and the AMPK/mTORC2 axis. As a result, they suppress cancer metabolism, cell growth, invasion, and EMT. Phytocompounds are recognized as excellent and promising substances for the treatment of cancer.

Phytochemicals targeting AMPK/PGC-1α in cancer treatment face several challenges and limitations. One major challenge is the limited bioavailability of phytochemicals due to poor absorption and quick metabolism in the body. This can lead to decreased levels and lower concentrations of the phytochemicals when reaching their targeted tissues, diminishing their efficacy. It can also be difficult to determine how a certain phytochemical will interact with AMPK/PGC-1α signaling pathways in various types of cancer due to cancer biology being very complicated and cancer cells differing greatly from one another. Furthermore, the potential for off-target effects and interactions with other medications or treatments can pose as a risk. Another significant challenge and limitation in the use of phytochemicals targeting AMPK/PGC-1α in cancer treatment is the lack of extensive clinical studies to confirm and validate their effectiveness and safety. Promising outcomes in cell cultures and animal models require accurate clinical trials before being used in clinical practice. Insufficient clinical evidence makes it difficult to safely endorse the use of phytochemicals as a conventional therapy for cancer patients. Therefore, more well-designed clinical trials are needed to bridge the gap between preclinical research and the clinical application of phytochemicals targeting AMPK/PGC-1α in cancer therapy. While phytochemicals show promise as potential therapeutic agents in cancer treatment, further research is needed to address these challenges and optimize their use in clinical settings.

In summary, the current systematic review underlines the significance of targeting the AMPK/PGC-1α signaling pathway in cancer metabolism by multi-targeted phytochemicals. Future studies should focus on evaluating the effects of phytochemicals during well-controlled clinical trials in combating cancer.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

Acetyl-CoA carboxylases 1/2

Protein kinase B

Acute myeloid leukemia

Adenosine monophosphate

Adenosine monophosphate-activated protein kinase

Androgen receptor

Adenosine triphosphate

Calcium/calmodulin-dependent protein kinase kinase-β

Cyclooxygenase-2

Death-associated protein 1

Epidermal growth factor receptor

Epithelial-mesenchymal transition

Endoplasmic reticulum-associated protein degradation

Extracellular signal-regulated protein kinase

Estrogen-related receptor

Enhancer of zeste homolog 2

Fatty acid oxidation

Fatty acid synthase

Forkhead box O3a

General control non-depressible 5

Glioma-associated oncogene 1

Glycogen synthase kinase-3β

Hypoxia-inducible factor-1

Interleukin- 6

Janus kinase

c-Jun NH2-terminal kinase

Kinase suppressor of Ras 1

Leukemia-initiating cells

Liver kinase B1

Mitogen-activated protein kinase

Monocarboxylate transporter 1

Mammalian target of rapamycin

Mammalian target of rapamycin complex 1

Nicotinamide adenine dinucleotide

Nicotinamide adenine dinucleotide phosphate hydrogen

Nuclear factor-κB

Nod-like receptor protein

Non-muscle myosin IIA

Nuclear factor erythroid 2-related factor 2

Non-small cell lung cancer

Oxidative phosphorylation

Programmed cell death ligand 1

Protein kinase R (PKR)-like endoplasmic reticulum kinase

Peroxisome proliferator-activated receptor-gamma coactivator-1α

Phosphoinositide 3-kinase

Protein phosphatase 2 A

Protein phosphatase 2 C

Protein phosphatase 1E

Retinoblastoma protein

PGC-1-related coactivator

Polycomb repressive complex 2

Regulatory-associated protein of mTOR

Receptor-interacting protein 1

Reactive oxygen species

Signal transducer and activator of transcription

Serine/threonine kinase 11

TGF-β-activated kinase 1

T-cell acute lymphoblastic leukemia/lymphoma

TET methylcytosine dioxygenase 2

Transforming growth factor-beta

Toll-like receptors

Tumor microenvironment

Tumor necrosis factor-α

Triphenylphosphonium

Tuberous sclerosis complex 2, also known as Tuberin

TNF-related weak inducer of apoptosis

Ubiquitin conjugating enzyme E2

UNC-51- like kinase 1

Vascular endothelial growth factor

Yes-associated protein

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Sajad Fakhri and Seyed Zachariah Moradi contributed equally to this work and are joint first authors.

Authors and Affiliations

Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran

Sajad Fakhri, Seyed Zachariah Moradi, Behrang Shiri Varnamkhasti, Sana Piri & Mohammad Reza Khirehgesh

Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran

Seyed Yahya Moradi & Sarina Piri

Pine View School, Osprey, FL, 34229, USA

Ankur Bishayee

Department of Pharmacology, College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA

Nicolette Casarcia & Anupam Bishayee

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SF: Conceptualization, Methodology, Data Curation, Writing – Original Draft, and Writing – Review & Editing; SZM: Methodology, Data Curation, and Writing – Original Draft; SYM, SP (Sarina Piri), BSV, SP (Sana Piri), and MRK: Writing – Original Draft; AB (Ankur Bishayee): Writing – Original Draft and Writing – Review & Editing; NC: Writing – Review & Editing; AB (Anupam Bishayee): Conceptualization, Writing – Original Draft, Writing – Review & Editing; Supervision, Project administration. All authors read and approved the final manuscript.

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Fakhri, S., Moradi, S.Z., Moradi, S.Y. et al. Phytochemicals regulate cancer metabolism through modulation of the AMPK/PGC-1α signaling pathway. BMC Cancer 24 , 1079 (2024). https://doi.org/10.1186/s12885-024-12715-7

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Inflammation and Cancer: What is the Connection? 

Inflammation is normal. It’s an essential process our bodies use to fight infections and heal wounds. But inflammation that persists can be harmful, and in some cases can increase the risk of cancer. 

Dana-Farber research into the connections between inflammation and cancer has led to new programs focused on early cancer detection and intervention. Learn more about inflammation, how to manage it, and when to seek help. 

What is inflammation?  

Inflammation is a complex process initiated by the immune system. Immune cells circulate throughout the body and respond to alarm signals, such as wounds, infections, or irritations. When alerted, these cells release molecules that call for aid, summoning more specialized immune cells into the affected area. This accumulation of cells and secretion of molecules causes inflammation. 

Inflammation appears as swelling or redness near an injury, such as a cut or sprain. It might also cause fever, aches, and pains in response to an infection.  

“When the injury or infection is resolved, the inflammatory response stops,” says Nilay Sethi, MD, PhD, a researcher and oncologist in Dana-Farber Brigham Cancer Center’s Division of Gastrointestinal Oncology . “If the process persists, it can become chronic inflammation. And that’s when things can go wrong.” 

Why does inflammation persist if it’s not supposed to?  

There are many situations that can lead to chronic inflammation. Examples include: 

• Autoimmune disease: Autoimmune diseases are rare and involve cases where immune cells mistake healthy cells for diseased ones. A person with autoimmune hepatitis, for example, has immune cells that continually attack healthy liver cells, leading to chronic inflammation and injury to the organ. 
• Irritants : Environmental exposures can also cause inflammation to occur and persist if the exposure continues. A smoker or a person who is exposed to asbestos might experience inflammation in the lungs caused by the continual presence of irritants in the lung tissue.  
• Obesity and diabetes : Fat deposits, called adipose tissues, send out inflammatory signals, which can become out of balance when the body contains an excess amount of fat. Inflammatory processes can also be triggered by diabetes and dysregulation of the processing of sugar in the body. 
• Aging: As we age, systems in the body change. Joints may develop arthritis and become inflamed. Plaque may accumulate in arteries and cause inflammation. The risk of diabetes also increases with age. A term called “inflammageing” has been coined to capture this idea, says Lachelle D. Weeks, MD, PhD , a physician-scientist in Dana-Farber Brigham Cancer Center’s Adult Leukemia Program . “As we age, we are at an increased risk of developing certain inflammatory conditions.” 

Do inflammatory conditions increase my risk of cancer?  

In individual organs, inflammation that persists over a long time in response to continued injury or illness can increase the risk of cancer. As an example, if a person develops non-alcoholic fatty liver disease, immune cells will continually work to repair the liver, putting the organ in an inflammatory state.  

The organ’s cells will respond with efforts to make repairs. But these repair efforts can put cells into a state in which they start dividing quickly. These cells might also have damaged DNA that will be passed along as cells divide. Most of the time, cellular repair mechanisms or tissue surveillance will correct or remove damaged cells without consequence. But sometimes, instead of healing the organ, abnormal cells could begin to take over and form cancer.  

Inflammation is known to increase the risk of several cancers. For example: 

• Reflux disease can cause persistent inflammation at the junction of the stomach and esophagus, a condition called Barrett’s esophagus , which increases the risk of cancer; 
• Inflammatory bowel diseases, such as Crohn’s disease or ulcerative colitis, can increase the risk of colorectal cancer ; 
• Smoking can cause persistent inflammation and damage in the lungs that can increase the risk of lung cancer. 

While inflammation increases the risk of cancer, it does not always lead to cancer.  

“The increased risk of cancer varies from person to person and can depend on many other factors, including whether a person has a genetic risk for cancer,” says Sethi, whose research has helped identify some of the ways that inflammation affects the gastrointestinal system and can increase cancer risk.  

Are inflammatory conditions related to blood cancer?  

Inflammation can influence the development of blood cancer. Inflammation caused by arthritis, heart disease, or other conditions can result in elevated levels of inflammatory molecules throughout the body. This is called systemic inflammation. 

Weeks’ research has shown that systemic inflammation and aging can contribute to a condition called CHIP (clonal hematopoiesis of indeterminate potential) . CHIP occurs when blood cells acquire mutations and then divide and spread and become more and more common in a person’s bloodstream.  

CHIP can be a precursor to cancer, but the link to cancer depends on the types of mutations in the cells. In some cases, the mutations increase the risk of cancer. In other cases, they don’t.  

“It is important to understand that blood cancers are extremely rare,” says Weeks. “We only start to consider blood cancer as a possibility if a patient has low blood counts or evidence that their bone marrow is not functioning well.”  

What can I do to reduce inflammation and lower my risk of cancer? 

A healthy lifestyle will go a long way to reducing inflammation. This includes eating fresh, whole foods whenever possible, exercising, and getting good sleep. If you smoke, consider quitting. (Get help here .) If you drink alcohol , consider stopping or limiting your intake. In addition, try to eat fewer ultra-processed foods if possible. 

Following the recommended cancer screening guidelines is also important because screening helps identify cancer early, when it is more treatable. 

In addition, Sethi and Weeks both recommend that you listen to your body and see your doctor if something doesn’t feel right.  

“Inflammation that warrants seeing a doctor usually isn’t subtle,” says Weeks. “If you experience unexplained and persistent joint pain, abdominal pain, fevers, or swelling, see your primary care doctor.” 

How can Dana-Farber help? 

Experts at Dana-Farber are committed to finding cancer early, and recently launched the Dana-Farber Centers for Early Detection and Interception . The Centers focus on earlier intervention for those with a high risk of developing future cancers, including both blood cancers and solid tumors.  

The Centers aim to: 

• Transform cancer care from reactive to proactive through early detection, including evaluations of precursor conditions that might be related to inflammation, such as CHIP for blood cancers or Barrett’s esophagus. 
• Improve screening access, particularly in communities in which screening rates are lower, to diagnose cancer at an earlier stage. 
• Identify treatment options for patients at risk, including offering clinical trials that aim to intercept precursor conditions and stop cancer before it starts or progresses further.  

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Inflammation and Cancer : Modelling the consequences of radiotherapy- and Hmgb1-induced inflammation on early-stage skin cancer progression in zebrafish larvae

• Luke J Deane
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Student thesis : Doctoral Thesis › Doctor of Philosophy (PhD)

• Inflammation

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Inflammation and Cancer: Triggers, Mechanisms, and Consequences

Affiliations.

• 1 Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt/Main, Germany; Frankfurt Cancer Institute, Goethe University Frankfurt, 60596 Frankfurt/Main, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: [email protected].
• 2 Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. Electronic address: [email protected].
• PMID: 31315034
• PMCID: PMC6831096
• DOI: 10.1016/j.immuni.2019.06.025

Inflammation predisposes to the development of cancer and promotes all stages of tumorigenesis. Cancer cells, as well as surrounding stromal and inflammatory cells, engage in well-orchestrated reciprocal interactions to form an inflammatory tumor microenvironment (TME). Cells within the TME are highly plastic, continuously changing their phenotypic and functional characteristics. Here, we review the origins of inflammation in tumors, and the mechanisms whereby inflammation drives tumor initiation, growth, progression, and metastasis. We discuss how tumor-promoting inflammation closely resembles inflammatory processes typically found during development, immunity, maintenance of tissue homeostasis, or tissue repair and illuminate the distinctions between tissue-protective and pro-tumorigenic inflammation, including spatiotemporal considerations. Defining the cornerstone rules of engagement governing molecular and cellular mechanisms of tumor-promoting inflammation will be essential for further development of anti-cancer therapies.

Keywords: cancer; cell plasticity; cytokine; inflammation; mechanisms; metastasis; tumor microenvironment; tumor progression.

Copyright © 2019 Elsevier Inc. All rights reserved.

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Conflict of interest statement

Conflict of interest : The authors declare no competing financial interests.

Figure 1:. Evolutionary and functional differences and…

Figure 1:. Evolutionary and functional differences and similarities between inflammation in cancer and inflammation during…

Figure 2:. Types of inflammation in cancer:…

Figure 2:. Types of inflammation in cancer: different timing and different inducers

(A) Cancer-associated inflammation…

Figure 3:. Pro-tumorigenic actions of inflammation in…

Figure 3:. Pro-tumorigenic actions of inflammation in progression, metastasis and growth

(A) Injury, infection or…

Figure 4:. Increased cell plasticity within the…

Figure 4:. Increased cell plasticity within the tumor microenvironment (TME)

An intricate reciprocal interplay between…

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An investigation of the relationship between the systemic inflammatory response, body composition and outcomes in patients with cancer

Ross, Dolan (2020) An investigation of the relationship between the systemic inflammatory response, body composition and outcomes in patients with cancer. PhD thesis, University of Glasgow.

Globally cancer remains one of the leading causes of mortality. Overall, it has been esti-mated that one in three people will develop can¬cer in their lifetime, and one in four will die from it. While a curative intent will always be the aim of any surgical or oncological treatment a significant proportion of patients will go on to develop locally advanced or metastatic disease. Patient outcomes are not solely determined by host or tumour factors but rather by a complex interaction of both. Indeed, the systemic changes associated with cancer including reduced appetite, weight loss and poorer performance can significantly impact on both the quality and quantity of life in patients with cancer. As a result, accurate and realistic prognostication is vitally important and can guide clinical decision making. In its simplest form the systemic inflammatory response is a reaction to tissue injury brought on by ischaemia, necrosis, trauma, hypoxia or cancer. It is increasingly clear that cancer progression and outcomes are dependent on a complex interaction between both tumour and host characteristics including the systemic inflammatory response. Clinically, the commonest means of measuring the systemic inflammatory response in patients with cancer is with the use of biochemical or haematological markers. In practice this means an elevated C-reactive protein (CRP), hypoalbuminaemia or increased white cells (WCC), neutrophil and platelet counts. The work presented in this thesis further examines the relationship between the systemic inflammatory response, body composition, tumour metabolic activity and outcomes in patients with cancer. The effect of the systemic inflammatory response on outcomes in patients with cancer was examined directly. The relationship between the systemic inflammatory response and changes in body composition and their relationship to outcomes was then examined with cross-sectional and longitudinal studies. Finally, the question of the driving force behind the relationship between the systemic inflammatory response and changes in body composition was examined by looking at tumour metabolic activity in patients with cancer. The results of the two large meta-analyses in both operable and advanced cancers can be seen in Chapter 3 and 4. In operable cancer the systemic inflammatory response had independent prognostic value, across tumour types and geographical locations. On meta-analysis there was a significant relationship between an elevated Neutrophil Lymphocyte Ratio (NLR) and both overall (p<0.00001) and cancer specific survival (p<0.00001), between an elevated Lymphocyte Monocyte Ratio (LMR) and both overall (p<0.00001) and cancer specific survival (p<0.00001), between an elevated Platelet Lymphocyte Ratio (PLR) and both overall (p<0.00001) and cancer specific survival (p=0.005) and between an elevated Glasgow Prognostic Score (GPS)/modified Glasgow Prognostic Score (mGPS) and both overall (p<0.00001) and cancer specific survival (p<0.00001). In advanced cancer the systemic inflammatory response also had prognostic value, across tumour types and geographical locations. On meta-analysis there was a significant relationship between an elevated NLR and both overall survival (p<0.00001) and cancer specific survival (CSS) (p<0.00001), between an elevated PLR and overall survival (p=0.0003) and between an elevated GPS/mGPS and both overall (p<0.00001) and cancer specific survival (p=0.0001). The majority of studies in these two meta-analyses were retrospective in nature, however the results of a further large systematic review focusing solely on randomised control trials can be seen in Chapter 5. In this review the GPS/mGPS was shown to have prognostic value in Non-Small Cell Lung Cancer (NSCLC), oesophageal cancer, pancreatic cancer, prostate cancer and breast cancer. While the NLR was shown to have prognostic value in nasopharyngeal cancer, oesophageal cancer, pancreatic cancer, biliary cancer, prostate cancer and multiple cancer types. Therefore, the prognostic strength of the systemic inflammatory response has been confirmed across over 400 papers including 36 prospective randomised control trials. However, the question still remained about the level of systemic inflammation in cancer patients as a whole. In order to answer this a further systematic review was undertaken in Chapter 6. This examined the prevalence of cancer associated systemic inflammation as measured by the GPS/mGPS and its implications for the ongoing care of patients with cancer. In this review which contained 140 studies including 40,893 patients the percentage of patients who were systemically inflamed varied from 28% to 63% according to tumour type. The most commonly studied cancer overall was colorectal cancer in which 40% of patients were systemically inflamed. In operable disease the percentage of patients who were systemically inflamed varied from 21% to 38% in gastroesophageal and colorectal cancer respectively. Again, the most commonly studied cancer was colorectal cancer and 38% were systemically inflamed. In inoperable disease the percentage of patients who were systemically inflamed varied from 29% to 79% in prostate and haematological cancers respectively. This confirmed that the systemic inflammatory response was common in both operable and inoperable cancers and could prove to be a fruitful target for therapeutic interventions in the future. The results of Chapter 3-5 show that the two most widely validated methods of monitoring the systemic inflammatory response are the GPS/mGPS and NLR. These are considered to be cumulative scores and composite ratios respectively. The results of Chapter 7 focuses on comparing the prognostic value of both cumulative scores and composite ratios in patients undergoing surgery for colon cancer (n=801). When adjusted for Tumour Node Metastasis (TNM) stage, NLR>5 (p<0.001), Neutrophil Lymphocyte Score (NLS, p<0.01), Platelet Lymphocyte Score (PLS, p<0.001), LMR<2.4 (p<0.001), Lymphocyte Monocyte Score (LMS, p<0.001), Neutrophil Platelet Score (NPS, p<0.001), CRP Albumin Ratio (CAR, p<0.001) and mGPS (p<0.001) were significantly associated with cancer specific survival. In patients undergoing elective surgery (n=689) the majority of the composite ratios/scores correlated with age (p<0.01), BMI (p<0.01), T-stage (p<0.01), venous invasion (p<0.01) and peritoneal involvement (p<0.01). When NPS (myeloid) and mGPS (liver) were directly compared their relationship with both overall and cancer specific survival was similar. These results suggest that both composite ratios and cumulative scores had prognostic value, independent of TNM stage, in patients with colon cancer. However, cumulative scores, based on normal reference ranges, were simpler and more consistent for clinical use. The importance of the relationship between the systemic inflammatory response and changes in physical function have long been reported particularly in the setting of patients with advanced cancer. This relationship was examined further in Chapter 8 which was a post hoc analysis of a previously completed randomised control trial assessing the effect of corticosteroid use on analgesic requirements in patients with advanced disease (n=40). It showed that patients with an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 2 and an mGPS of 2 had a higher Interleukin-6 (IL-6, p=0.017) level and poorer overall survival (p<0.001) when compared to patients with an ECOG-PS of 0/1 and an mGPS of 0. This work provides supporting evidence for the potential therapeutic targeting of IL-6 in patients with advanced cancer which is currently being explored with the use of immunomodulatory agents such as tocilizumab. These results suggest that there is considerable merit in combining monitoring of the systemic inflammatory response using acute phase proteins and other factors such as performance status in patients with cancer. Indeed this method of prognostication is given greater weight by the results of Chapter 10 which show in 730 patients with advanced cancer that on multivariate cox regression analysis ECOG-PS (HR 1.61 95%CI 1.42-1.83, p<0.001), mGPS (HR 1.53, 95%CI 1.39-1.69, p<0.001) and Body mass index/Weight Loss (BMI/WL) grade (HR 1.41, 95%CI 1.25-1.60, p<0.001) remained independently associated with overall survival. In patients with a BMI/WL grade 0/1 both ECOG and mGPS remained independently associated with overall survival. This further suggests that the ECOG/mGPS framework may form the basis of risk stratification of survival in patients with advanced cancer. The use of CT scanning to determine the quantity and quality of skeletal muscle in patients with cancer is an increasing area of research and clinical interest. The two most commonly used software packages for image analysis are ImageJ and Slice-O-Matic. In Chapter 2 the differential impact of the use of these software packages is examined in patients undergoing surgery for colorectal cancer (n=341). In this study, Bland-Altman analysis showed that ImageJ gave consistently higher values for all body composition parameters (p<0.001), resulting in more patients classified as having a high subcutaneous fat index (SFI, p<0.001) and visceral fat index (VFI, p<0.001) and fewer patients being classified as having a low skeletal muscle index (SMI, p<.0001) and skeletal muscle density (SMD, p<0.001). In addition, SFI, VFI, SMI and SMD were significantly associated with shorter overall survival when calculated with ImageJ (all p<0.05). These results suggest that with the drive towards the incorporation of CT derived body composition analysis to standard clinical practice there must be a concurrent drive towards standardisation irrespective of the software package used. Skeletal muscle is a very physiologically active tissue and the quantity and quality of skeletal muscle can have a direct impact on outcomes in patients with cancer. In Chapter 9 the effect of the systemic inflammatory response on body composition and outcomes in patients with operable colorectal cancer (n=650) is examined. In this study on univariate survival analysis, age, ASA, TNM stage, mGPS, BMI, SFI, visceral obesity (VO), SMI and SMD were significantly associated with overall survival (all p<0.05). Furthermore, a low SMI and SMD were significantly associated with an elevated mGPS (<0.05). On multivariate analysis, SMI (HR 1.50, 95%CI 1.04-2.18, p=0.031), SMD (HR 1.42, 95%CI 0.98-2.05, p=0.061) and mGPS (HR 1.44, 95%CI 1.15-1.79, p=0.001) remained independently associated with overall survival. This study therefore delineates the relationship between the loss of quantity and quality of skeletal muscle mass, the systemic inflammatory response and survival in patients with operable colorectal cancer. The results of Chapter 11 add further weight to the prognostic relationship between markers of the systemic inflammatory response, physical function and body composition in patients with advanced cancer (n=289). In this study ECOG-PS, mGPS, timed up and go (TUG), 2 minute walk test (2MWT), hand grip strength (HGS), combined objective performance tests (COPT), SMI and SMD had prognostic value (all p<0.05). However, none of these factors, with the exception of HGS (HR 1.63, 95%CI 1.03–2.59, p=0.04), displaced the prognostic value of ECOG-PS within the ECOG-PS/mGPS framework. These results validate the clinical utility of the ECOG-PS/mGPS framework in the assessment of patients with advanced cancer. Furthermore, in Chapter 12 the results of the longitudinal monitor of body composition in patients with operable colorectal cancer (n=470) have shown that the majority of patients did not change their SMI (81%) or SMD (72%) status on follow-up. In male patients those who maintained a low SMI were older (p<0.001), received less adjuvant chemotherapy (p<0.05), had a higher mGPS/NLR (both p<0.05), had a BMI≥25, had pre-op VO and follow up VO (all p<0.01). In female patients those who maintained a low SMI were older (p<0.01), had more open surgery (p<0.05), had a higher mGPS (p<0.05), had a BMI≥25, had pre-op VO and follow up VO (all p<0.01). On Cox-regression analysis patients who maintained a low SMI and SMD on follow up had worse overall survival (p<0.05). However, when adjusted for age, sex, TNM stage and mGPS neither a maintained low SMI nor SMD was independently associated with survival. This suggests that a low skeletal muscle mass and quality are established early in the disease course, maintained following resection of the primary tumour and associated with VO and the presence of a systemic inflammatory response. The relationship between tumour metabolic activity and the systemic inflammatory response was examined in Chapter 13. This systematic review contained twelve studies including 2,588 patients and showed that the majority of studies showed a direct relationship between the tumour and bone marrow glucose uptake as measured by positron emission tomography CT (PET-CT) scanning and the host systemic inflammatory responses as measured by CRP (n=2), albumin (n=2), WCC (n=3), neutrophils (n=2) and platelets (n=2). The majority of the studies (n=8) also showed a direct relationship between tumour and bone marrow glucose uptake and poor outcomes. This suggests a direct relationship between the tumour and bone marrow glucose uptake and host systemic inflammation. This may suggest new approaches for more optimal therapeutic targeting and monitoring strategies in patients with cancer. Furthermore, Chapter 14 showed in patients undergoing curative radiotherapy for lung cancer (n=119) that on univariate survival analysis, lung cancer stage (p<0.01), mGPS (p<0.05), NLR (p<0.01), SMD (p<0.05) and Total Lesion Glycolysis (TLG, p<0.001) were associated with overall survival. An elevated TLG was associated with sex (p<0.05), TNM stage (p<0.001), mGPS (p<0.01) and maximized standardised uptake values (SUVmax, p<0.001). On multivariate survival analysis only a TLG>68.89 (HR:2.03, 95%CI 1.35-3.07, p<0.001) remained independently associated with OS. This suggests that Tumour glucose uptake was associated with activation of the systemic inflammatory response but not lower skeletal muscle mass in patients with lung cancer. This suggests that the early targeting of the systemic inflammatory response could provide a fruitful treatment strategy aimed at maintaining skeletal muscle mass and function while also improving quality of life and outcomes in patients with cancer. In summary, the systemic inflammatory response has a direct relationship with changes in body composition and outcomes in patients with cancer. Interestingly this association would seem to be independent of tumour metabolic activity and potentially tumour stage. Cancer related changes in body composition and their associated effect on performance status seem to be established early in the disease process and maintained despite treatments targeting the tumour specifically, be they oncological or surgical. Given that an elevated systemic inflammatory response is not currently targeted, the present results would suggest that the die is cast in these patients. However, it may be that new treatment strategies targeting the inflammatory response as early as possible in the disease progression may arrest or reverse any skeletal muscle loss and improve outcomes in patients with cancer.

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Targeting Inflammation Emerges as a Strategy for Treating Cancer

August 19, 2022 , by Edward Winstead

Inflammation is considered a hallmark of cancer. There is evidence that inflammation may both promote and constrain tumors.

In 1863, a German pathologist observed white blood cells in cancerous tissues. White blood cells are part of the body’s inflammatory response, which is activated to fight invaders, such as pathogens, and heal damaged tissue.

Based on his observation, the pathologist, Rudolf Virchow, proposed a new idea about the origins of cancer. Some tumors, he suggested, may start at sites of chronic inflammation—that is, places where inflammation persists after it is no longer needed.

His basic idea has stood the test of time. Chronic inflammation in certain parts of the body, such as the cervix or the colon, can increase the risk of cancer in those organs.

But Virchow’s observation marks just the beginning of a story about cancer and inflammation that is still being written.

Today, inflammation is considered a hallmark of cancer . Researchers are exploring the potential role of inflammation in many aspects of cancer, including the spread of the disease within the body and the resistance of tumors to treatment.

In the coming years, researchers hope to learn more about whether patients with cancer might benefit from treatments that target inflammation around tumors. Some early studies have yielded promising results.

"The numerous and diverse links between cancer and inflammation all present opportunities to develop therapies," said Michael Karin, Ph.D., of the University of California, San Diego, who studies mechanisms of inflammation.

Although much of the research on potential therapies is in the early stages, Dr. Karin predicted that “strategies to inhibit cancer-related inflammation will one day become a mainstay of modern cancer therapy.”

The complex relationship between cancer and inflammation

An inflammatory process begins when damaged tissues release certain chemicals, including histamines and prostaglandins. In response, white blood cells travel to the damaged tissues and produce substances that cause cells to divide and grow to rebuild tissue. The inflammatory process ends when the injury has been healed.

When inflammation occurs at the wrong times or becomes chronic, however, problems can arise. Many researchers describe inflammation as a double-edged sword.

“On the one hand, the immune system is constantly vigilant, monitoring the body for foreign invaders, such as pathogens,” said Stephen Hewitt, M.D., Ph.D., of the Experimental Pathology Laboratory in NCI’s Center for Cancer Research . “But on the other hand, inflammation that is not effectively controlled can potentially contribute to the development and growth of cancers.”

In some cases, tumor cells may take advantage of the inflammatory environment to actually exclude tumor-fighting immune cells.

The immune system is also on alert for threats from inside the body—that is, tumors. “Scientists have observed that there may be tumor cells in our bodies that we never know about, because the immune system is going out and killing those tumor cells,” said Dr. Hewitt.

What’s more, cancer treatments such as immunotherapy may kill cancer cells by activating some of the inflammatory processes used to fight pathogens. So, researchers have been studying the interplay between inflammation and immunotherapy, noted Dr. Karin.

In short, there is evidence that inflammation may both promote and constrain tumors. Over the past decade, researchers have used this knowledge to explore new treatments for cancer, including anti-inflammatory drugs.

A small clinical trial recently demonstrated the potential value of this approach. Researchers enrolled 24 patients with breast cancer that had spread to tissue near the breast, but not to other parts of the body (locally advanced), or that had spread to other parts of the body (metastatic).

The patients received chemotherapy plus an anti-inflammatory drug called L-NMMA, which blocks the production of nitric oxide, a molecule involved in inflammation.

Researchers are planning a phase 3 trial to test the anti-inflammatory drug L-NMMA to treat metaplastic breast cancer, a rare and often lethal form of the disease. 

The treatment regimen shrank the tumors in approximately half of the patients in the study . (Based on historical data, the researchers estimated that about a third of the patients would have responded to chemotherapy alone.) Three patients with locally advanced breast cancer had all signs of their cancers go away following treatment.

“We saw some remarkable responses in patients whom we did not expect to respond,” said lead investigator Jenny Chang, M.D., director of the Houston Methodist Hospital's Neal Cancer Center.

Her study was the first to test L-NMMA in patients with cancer. To learn more about how the anti-inflammatory drug worked in the body, the researchers studied the cells, molecules, and other structures surrounding tumors (the tumor microenvironment).

Their findings suggested that, by disrupting the production of nitric oxide, the drug helped reduce inflammation around the tumors. This seems to have made it possible for tumor-targeting immune cells to penetrate the tumors and kill the cancer cells, according to the researchers.

“In some chemotherapy-resistant breast cancers, inflammation is like a fortress around the tumor,” Dr. Chang said. “The microenvironment exudes pro-inflammatory proteins that make it impossible for immune cells to penetrate.”

But L-NMMA appeared to break down those barriers, even among patients who were not responding to other treatment options, she added.

Dr. Chang and her colleagues are planning an NCI-supported phase 3 clinical trial to test the drug in more patients. The study will include people with metaplastic breast cancer , a rare and often lethal form of the disease.

"Inflammation is a critical component of metaplastic breast cancer," said Dr. Chang.

"Timing is everything"

In a normal inflammatory response, immune cells produce chemicals that can kill a pathogen. These chemicals, known as reactive oxygen species , can also damage the DNA of normal cells, which increases the risk of mutations that could lead to cancer.

"Timing is everything," said Jennifer Kay, Ph.D., of the Silent Spring Institute, who studies how healthy cells become cancerous. "If the optimal timing of biological processes related to inflammation is altered, the chances of cancer occurring increase."

For instance, in the normal inflammatory response, the production of cells to replace injured tissue is normally delayed until reactive chemicals are no longer being produced. This sequence of events reduces the chances that replacement cells will sustain DNA damage, including cancer-causing genetic mutations, caused by reactive chemicals.

But during chronic inflammation, the production of reactive chemicals can overlap with the production of cells that restore injured tissue, Dr. Kay noted. This can potentially increase the risk of cancer.

The reasons inflammation starts when it is not needed or becomes chronic are not always clear. Some recent studies have focused on the failure of mechanisms that normally shut down inflammation at the appropriate times.

"Biology is complicated, because there’s a lot that goes into keeping a body healthy," Dr. Kay said. "Evolution has produced a vast network of tightly coordinated biological processes."

Many of these biological processes are interdependent, so disruptions to one pathway can have ripple effects elsewhere, potentially leading to uncontrolled inflammation, Dr. Kay added.

Learning how to manipulate the inflammatory system

At the University of Texas MD Anderson Cancer Center, researchers are investigating the molecular mechanisms of inflammation, including a protein involved in inflammation called STAT3 .

"We are interested in learning how to manipulate components of the inflammatory system to improve the body's ability to fight tumors," said Stephanie Watowich, Ph.D., who directs the Center for Inflammation and Cancer at MD Anderson.

Abnormal levels of STAT3 activity have been linked to certain cancers , and drugs that inhibit the protein are being tested in people with cancer.

A growing body of evidence, including results from mouse studies, suggests that STAT3 inhibitors may have distinct and complementary effects: The drugs may prevent a tumor from growing while also enhancing the immune system’s ability to clear the remaining tumor cells, according to Dr. Watowich.

"That’s the hope with drugs that inhibit STAT3," Dr. Watowich said. Future research will explore whether blocking other proteins in immune cells could also improve the ability of those cells to clear tumor cells, she added.

New mouse models with functional immune systems

L-NMMA was originally developed to treat heart failure. Dr. Chang and her colleagues decided to test the drug, a nitric oxide synthetase inhibitor, in patients with cancer based in part on research in mice by NCI investigators.

A team led by David Wink, Ph.D., in NCI’s Center for Cancer Research studied drugs that inhibit nitric oxide, including L-NMMA, in new mouse models that had functional immune systems. Most mouse models used in cancer research have lacked normal immune systems.

The new models represent an important technology advance for studying cancer and inflammation, as the work on L-NMMA suggests, according to Dr. Hewitt.

"Having mice with functional immune systems allows us to dissect the molecular mechanisms involved in the interplay between the tumor and the immune system," said Dr. Hewitt.

Once the pilot study of L-NMMA had been completed, Dr. Chang’s team and the NCI researchers visualized the tumor microenvironments in the patients and the mice. In both species, prior to treatment with the drug, tumor-targeting immune cells appeared to be stuck outside the tumors, unable to infiltrate the cancers.

"The images were really remarkable," said Dr. Wink. "The way the immune cells oriented themselves relative to the tumor targets was strikingly similar between the species."

The investigators conducted additional studies to confirm their suspicions that inflammation had been preventing immune cells from killing cancer cells.

Tumor biopsies from patients who responded to L-NMMA showed increased levels of tumor-targeting immune cells and reduced levels of pro-inflammatory proteins, as did tumor biopsies from mice treated with the drug, the researchers found.

These results confirmed their view that L-NMMA helps to reduce inflammation and allow immune cells to infiltrate tumors, according to Dr. Chang.

“What we observed in the patients who responded was exactly what the mouse models had predicted would happen,” she said.

Putting knowledge to work for patients

Dr. Wink expects to see more studies testing combinations of drugs that target inflammation and other agents for treating cancer. “This is the new frontier,” he said.

More than 150 years after Rudolf Virchow’s observation, Dr. Wink continued, the time is right for a collaborative science project focused on inflammation. He envisions a comprehensive effort modeled on the Human Genome Project to describe the molecular components involved in inflammation.

“We now have the ability to map the nitty gritty of inflammation,” Dr. Wink said. “To find the Achilles’ heel of inflammation, we need to study all of the elements and the biological processes together.”

Dr. Karin agreed and issued a call to action.

“After several decades of fundamental research on inflammation and cancer, it’s time to put our knowledge to work for patients,” he said.

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• Review Article
• Published: 24 October 2013

Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms

• Eran Elinav 1   na1 ,
• Roni Nowarski 2   na1 ,
• Christoph A. Thaiss 1   na1 ,
• Bo Hu 2 , 3   na1 ,
• Chengcheng Jin 2 , 4   na1 &
• Richard A. Flavell 2 , 5  

Nature Reviews Cancer volume  13 ,  pages 759–771 ( 2013 ) Cite this article

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• Cancer microenvironment
• Gastrointestinal cancer
• Inflammation
• Tumour immunology

Inflammation is causally related to cancer development, through processes that involve genotoxicity, aberrant tissue repair, proliferative responses, invasion and metastasis.

Major inflammatory pathways that are involved in inflammation-induced carcinogenesis converge at the level of the transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB).

Tumours modulate the inflammatory environment by the secretion of soluble growth factors and chemoattractants, which render inflammatory cells suppressive against anticancer T cell responses.

In around 20% of all cases, microbial organisms are the causative agents of cancer-inducing inflammation.

In addition to bona fide pathogens, pathobionts of the commensal microbiota have recently been recognized as being involved in inflammatory processes that promote tumour growth.

A better understanding of the role of the microbiota in inflammation-induced cancer might prospectively lead to targeted antimicrobial therapies against cancer initiation or progression.

Inflammation is a fundamental innate immune response to perturbed tissue homeostasis. Chronic inflammatory processes affect all stages of tumour development as well as therapy. In this Review, we outline the principal cellular and molecular pathways that coordinate the tumour-promoting and tumour-antagonizing effects of inflammation and we discuss the crosstalk between cancer development and inflammatory processes. In addition, we discuss the recently suggested role of commensal microorganisms in inflammation-induced cancer and we propose that understanding this microbial influence will be crucial for targeted therapy in modern cancer treatment.

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Immune crosstalk in cancer progression and metastatic spread: a complex conversation

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Acknowledgements

The authors thank all members of the Elinav and Flavell laboratories for scientific suggestions and discussion. This work was supported by the Marie Curie Integration and Helmsley Charitable Foundation grants (to E.E.), by the Howard Hughes Medical Institute and a grant from the US Department of Defense 11-1-0745 (to R.A.F.) and a United States–Israel Binational Foundation grant (to E.E. and R.A.F.). C.A.T. receives a Boehinger Ingelheim Fonds Ph.D. Fellowship. R.N. is supported by a fellowship from the Jane Coffin Childs Memorial Fund, and C.J. was a recipient of a Trudeau Fellowship from Yale University, USA.

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Eran Elinav, Roni Nowarski, Christoph A. Thaiss, Bo Hu and Chengcheng Jin: These authors contributed equally to this work.

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Department of Immunology, Weizmann Institute of Science, 100 Herzl Street, Rehovot, 76100, Israel

Eran Elinav & Christoph A. Thaiss

Department of Immunobiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

Roni Nowarski, Bo Hu, Chengcheng Jin & Richard A. Flavell

Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

Department of Cell Biology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

Chengcheng Jin

Howard Hughes Medical Institute, New Haven, 06520, Connecticut, USA

Richard A. Flavell

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Powerpoint slide for fig. 1, powerpoint slide for fig. 2, powerpoint slide for fig. 3, powerpoint slide for fig. 4, powerpoint slide for table 1.

Cellular and non-cellular components of the tissue that surrounds and influences tumour growth. Crucial components of the tumour microenvironment are immune cells, blood vessels, fibroblasts, extracellular matrix and other stromal cells.

An intracellular multiprotein complex of the innate immune system, consisting of sensor proteins of the NOD-like receptor (NLR) family, adaptor proteins and the pro-inflammatory serine protease caspase 1. The function of the inflammasome is to cleave the cytokines pro-interleukin-1β and pro-interleukin-18 into their biologically active forms.

(SASP). A common profile of secreted factors, induced during cellular senescence. These factors include pro-inflammatory cytokines, such as interleukin-1 and interleukin-6, and chemoattractants, such as CXC-chemokine ligand 8.

A genomic island in bacteria that encodes proteins with potentially genotoxic — that is, genome-damaging — properties.

Pertaining to microbial species that are introduced into the intestinal microbial ecosystem to exert beneficial effects on the host.

Interventions (not live microorganisms) that function to stabilize a particular microbial community with a beneficial effect.

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Elinav, E., Nowarski, R., Thaiss, C. et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer 13 , 759–771 (2013). https://doi.org/10.1038/nrc3611

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Inflammation and Cancer

Nitin singh.

Department of Pedodontics and Preventive Dentistry, Chandra Dental College and Hospital, Safedabad, Barabanki, Uttar Pradesh, India

Deepak Baby

1 Department of Conservative and Endodontics, P.S.M Dental College and Research Centre, Akkikavu, Thrissur, Kerala, India

Jagadish Prasad Rajguru

2 Department of Oral Pathology and Microbiology, Hi-Tech Dental College and Hospital, Bhubaneswar, Odisha, India

Pankaj B Patil

3 Department of Oral and Maxillofacial Surgery, School of Dental Sciences, Krishna Institute of Health Sciences Deemed to be University, Karad, Maharashtra, India

Savita S Thakkannavar

4 Department of Oral Pathology and Microbiology, Tatyasaheb Kore Dental College and Research Centre, New Pargaon, Kolhapur, Maharashtra, India

Veena Bhojaraj Pujari

5 Department of Oral Medicine and Radiology, Tatyasaheb Kore Dental College and Research Centre, New Pargaon, Kolhapur, Maharashtra, India

Inflammation is often associated with the development and progression of cancer. The cells responsible for cancer-associated inflammation are genetically stable and thus are not subjected to rapid emergence of drug resistance; therefore, the targeting of inflammation represents an attractive strategy both for cancer prevention and for cancer therapy. Tumor-extrinsic inflammation is caused by many factors, including bacterial and viral infections, autoimmune diseases, obesity, tobacco smoking, asbestos exposure, and excessive alcohol consumption, all of which increase cancer risk and stimulate malignant progression. In contrast, cancer-intrinsic or cancer-elicited inflammation can be triggered by cancer-initiating mutations and can contribute to malignant progression through the recruitment and activation of inflammatory cells. Both extrinsic and intrinsic inflammations can result in immunosuppression, thereby providing a preferred background for tumor development. The current review provides a link between inflammation and cancer development.

Résumé

L’inflammation est souvent associée au développement et à la progression du cancer. Les cellules responsables de l’inflammation associée au cancer sont génétiquement stables et ne subissent donc pas l’émergence rapide d’une pharmacorésistance; par conséquent, le ciblage de l’inflammation représente une stratégie attrayante à la fois pour la prévention du cancer et pour le traitement du cancer. L’inflammation tumorale extrinsèque est causée par de nombreux facteurs, notamment: infections bactériennes et virales, maladies auto-immunes, obésité, tabagisme, exposition à l’amiante et consommation excessive d’alcool, le tout qui augmentent le risque de cancer et stimulent la progression maligne. En revanche, l’inflammation intrinsèque au cancer ou provoquée par le cancer peut être déclenchée par des mutations initiant un cancer et peuvent contribuer à la progression maligne par le recrutement et l’activation de cellules inflammatoires. Tous les deux les inflammations extrinsèques et intrinsèques peuvent entraîner une immunosuppression, fournissant ainsi un fond préféré pour le développement de la tumeur. le l’examen actuel établit un lien entre l’inflammation et le développement du cancer.

I NTRODUCTION

The presence of leukocytes within tumors, observed in the 19 th century by Rudolf Virchow, provided the first indication of a possible link between inflammation and cancer. Yet, it is only during the past decade that clear evidence has been obtained that inflammation plays a critical role in tumorigenesis.[ 1 ]

However, when inflammation becomes chronic or lasts too long, it can prove harmful and may lead to disease. The role of pro-inflammatory cytokines, chemokines, adhesion molecules, and inflammatory enzymes has been linked with chronic inflammation [ Figure 1 ].[ 2 ]

Different faces of inflammation and its role in tumorigenesis

Chronic inflammation has been found to mediate a wide variety of diseases, including cardiovascular diseases, cancer, diabetes, arthritis, Alzheimer's disease, pulmonary diseases, and autoimmune diseases.[ 3 ]

The current review, however, will be restricted to the role of chronic inflammation in cancer. Chronic inflammation has been linked to various steps involved in tumorgenesis, including cellular transformation, promotion, survival, proliferation, invasion, angiogenesis, and metastasis.[ 4 ]

Only a minority of all cancers are caused by germline mutations, whereas the vast majority (90%) are linked to somatic mutations and environmental factors. Many environmental causes of cancer and risk factors are associated with some form of chronic inflammation. Up to 20% of cancers are linked to chronic infections, 30% can be attributed to tobacco smoking and inhaled pollutants (such as silica and asbestos), and 35% can be attributed to dietary factors (20% of cancer burden is linked to obesity).[ 5 ]

Recent efforts have shed new light on molecular and cellular circuits linking inflammation and cancer. Two pathways have been schematically identified: in the intrinsic pathway, genetic events causing neoplasia initiate the expression of inflammation-related programs that guide the construction of an inflammatory microenvironment, and in the extrinsic pathway, inflammatory conditions facilitate cancer development.[ 6 ]

The triggers of chronic inflammation that increase cancer risk or progression include infections (e.g., Helicobacter pylori for gastric cancer and mucosal lymphoma; papillomavirus and hepatitis viruses for cervical and liver carcinomas, respectively), autoimmune diseases (e.g., inflammatory bowel disease for colon cancer), and inflammatory conditions of uncertain origin (e.g., prostatitis for prostate cancer). Cancer-related inflammation, the seventh hallmark of cancer, links to genetic instability.[ 7 ]

It was in 1863 that Rudolf Virchow noted leukocytes in neoplastic tissues and made a connection between inflammation and cancer. He suggested that the “lymphoreticular infiltrate” reflected the origin of cancer at sites of chronic inflammation. Over the past 10 years, our understanding of the inflammatory microenvironment of malignant tissues has supported Virchow's hypothesis, and the links between cancer and inflammation are starting to have implications for prevention and treatment.[ 8 ]

I NFLAMMATION AND C AUSES

Inflammation is the body's response to tissue damage, caused by physical injury, ischemic injury (caused by an insufficient supply of blood to an organ), infection, exposure to toxins, or other types of trauma. The body's inflammatory response causes cellular changes and immune responses that result in repair of the damaged tissue and cellular proliferation (growth) at the site of the injured tissue. Inflammation can become chronic if the cause of the inflammation persists or certain control mechanisms in charge of shutting down the process fail. When these inflammatory responses become chronic, cell mutation and proliferation can result, often creating an environment that is conducive to the development of cancer. The so-called “perfect storm” is an extreme challenge that cancer patients face. This is true for the onset of cancer but also even more important for the advancement of the disease. Various signaling pathways are key contributors in creating epigenetic changes on the outside of the cell, switching on these internal mutations. Therefore, treating the inflammatory causes is always important.

Chronic inflammation has been linked to various steps involved in tumorigenesis, including cellular transformation, promotion, survival, proliferation, invasion, angiogenesis, and metastasis.

C ANCER D EVELOPMENT : A N O VERVIEW

Cancer defines malignant neoplasms characterized by metastatic growth. It may occur in almost every organ and tissue relating to a variety of etiologic factors, such as genomic instability and environmental stress.[ 9 ]

However, cancer development is still accepted as a multistep process, during which genetic alterations confer specific types of growth advantages; therefore, it drives the progressive transformation from normal cells to malignant cancer cells. Malignant growth is characterized by several key changes: self-sufficiency of growth signals, insensitivity to antigrowth signals, escaping from apoptosis, unregulated proliferation potential, enhanced angiogenesis, and metastasis. Each of these shifts is complicated and accomplished by combined efforts of various signaling processes. In later discussion, we will find that inflammation may contribute to the formation of these cancer phenotypes.[ 10 ]

M ECHANISMS FOR THE A SSOCIATION BETWEEN I NFLAMMATION AND C ANCER

Chronic inflammation is characterized by sustained tissue damage, damage-induced cellular proliferation, and tissue repair. Cell proliferation in this context is usually correlated with “metaplasia,” a reversible change in cell type. “Dysplasia,” a disorder of cellular proliferation leading to atypical cell production, follows and is regarded as the previous event of carcinoma because it was usually found adjacent to the site of neoplasm.[ 11 ]

M UTAGENIC P OTENTIAL OF I NFLAMMATION

The chronic inflammatory microenvironment is predominated by macrophages. Those macrophages, together with other leukocytes, generate high levels of reactive oxygen and nitrogen species to fight infection.[ 12 ] However, in a setting of continuous tissue damage and cellular proliferation, the persistence of these infection-fighting agents is deleterious. They may produce mutagenic agents, such as peroxynitrite, which react with DNA and cause mutations in proliferating epithelial and stroma cells. Macrophages and T-lymphocytes may release tumor necrosis factor-alpha (TNF-α) and macrophage migration inhibitory factor to exacerbate DNA damage.[ 13 ]

Migration inhibitory factor impairs p53-dependent protective responses, thus causing the accumulation of oncogenic mutations. Migration inhibitory factor also contributes to tumorigenesis by interfering Rb-E2F pathway.

H ELICOBACTER P YLORIAND AND C ANCER R ISK

The bacterium H. pylori is known to colonize the human stomach and induce chronic atrophic gastritis, intestinal metaplasia, and gastric cancer. H. pylori infection is a major risk factor for gastric cancer development, which is one of the most challenging malignant diseases worldwide with limited treatments.[ 14 ]

The multistep pathogenesis of gastric cancer is the best highlighted by Correa sequence that explains the progressive pathway to gastric cancer characterized by distinct histological changes. This model predicts that infection with H. pylori triggers an inflammatory response resulting in chronic, and then, atrophic, gastritis. This is followed by intestinal metaplasia which can be further classified into complete and incomplete subtypes. At this point, some patients will then proceed to gastric cancer via the intermediate stage of dysplasia [ Figure 2 ].[ 15 ]

Correa sequence

The improvement or elimination of atrophy and intestinal metaplasia with H. pylori eradication could potentially inhibit gastric carcinogenesis. It is noteworthy to mention that gastric cancer can still develop even after successful eradication therapy. H. pylori eradication does not result in the regression of all precancerous lesions, which may depend on the degree and extent of preneoplastic changes at the time of eradication.[ 14 ]

I NFLAMMATORY C ELLS IN T UMOR M ICROENVIRONMENT

The inflammatory microenvironment of tumors is characterized by the presence of host leukocytes both in the supporting stroma and in tumor areas.[ 16 ] Tumor-infiltrating lymphocytes may contribute to cancer growth and spread and to the immunosuppression associated with malignant disease.

Macrophages

Tumor-associated macrophages (TAM) are a major component of the infiltrate of most, if not all tumors. TAM derives from circulating monocytic precursors and is directed into the tumor by chemoattractant cytokines called chemokines. Many tumor cells also produce cytokines called colony-stimulating factors that prolong the survival of TAM. When appropriately activated, TAM can kill tumor cells or elicit tissue destructive reactions centered on the vascular endothelium. However, TAM also produces growth and angiogenic factors as well as protease enzymes which degrade the extracellular matrix. Hence, TAM can stimulate tumor cell proliferation, promote angiogenesis, and favor invasion and metastasis.[ 17 ]

Dendritic cells

Dendritic cells have a crucial role in both the activation of antigen-specific immunity and the maintenance of tolerance, providing a link between innate and adaptive immunity. Tumor-associated dendritic cells (TADCs) usually have an immature phenotype with defective ability to stimulate T-cells.[ 18 ]

This distribution of TADC is clearly different from that of TAM, which is evenly scattered in tumor tissue. The immaturity of TADC may reflect lack of effective maturation signals, prompt migration of mature cells to lymph nodes, or the presence of maturation inhibitors. TADC is likely to be poor inducers of effective responses to tumor antigens.

Lymphocytes

Natural killer cells are rare in the tumor microenvironment. The predominant T-cell population has a “memory” phenotype. The cytokine profile of these tumor-infiltrating T-cells has not been studied systematically, but in some tumors (e.g. Kaposi's sarcoma, Hodgkin's disease, bronchial carcinoma, and cervical carcinoma), they produce mainly interleukins (ILs) 4 and 5 and not interferon. IL-4 and 5 are cytokines associated with the T-helper type 2 (Th2) cells, whereas interferon is associated with Th1 responses.[ 19 ]

K EY M OLECULAR P LAYERS IN L INKING I NFLAMMATION TO C ANCER

To address the details of transition from inflammation to cancers and the further development of inflammation-associated cancers, it is necessary to investigate specific roles of key regulatory molecules involved in this process.

Pro-inflammatory cytokines

The cytokine network of several common tumors is rich in inflammatory cytokines, growth factors, and chemokines but generally lacks cytokines involved in specific and sustained immune responses.[ 20 ]

There is now evidence that inflammatory cytokines and chemokines, which can be produced by the tumor cells and/or tumor-associated leukocytes and platelets, may contribute directly to malignant progression. Many cytokines and chemokines are inducible by hypoxia, which is a major physiological difference between tumor and normal tissue. Examples are TNF, IL-1 and 6, and chemokines.

The immune response to tumors is constituted by cytokines produced by tumor cells as well as host stromal cells. Tumor-derived cytokines, such as Fas ligand, vascular endothelial growth factor (VEGF), and transforming growth factor-h, may facilitate the suppression of immune response to tumors. Moreover, inflammatory cytokines have also been reported to facilitate the spectrum of tumor development.[ 21 ]

Tumor necrosis factor

TNF is a multifunctional cytokine that plays important roles in diverse cellular events such as cell survival, proliferation, differentiation, and death. As a pro-inflammatory cytokine, TNF is secreted by inflammatory cells, which may be involved in inflammation-associated carcinogenesis. TNF exerts its biological functions through activating distinct signaling pathways such as nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK). NF-κB is a major cell survival signal that is antiapoptotic while sustained JNK activation contributes to cell death. The crosstalk between the NF-κB and JNK is involved in determining cellular outcomes in response to TNF. TNF is a double-edged sword that could be either pro- or antitumorigenic. On one hand, TNF could be an endogenous tumor promoter because TNF stimulates cancer cells' growth, proliferation, invasion and metastasis, and tumor angiogenesis. On the other hand, TNF could be a cancer killer. The property of TNF in inducing cancer cell death renders it a potential cancer therapeutic.[ 22 ]

TNF can be detected in malignant and/or stromal cells in human ovarian, breast, prostate, bladder, and colorectal cancer, lymphomas, and leukemias, often in association with ILs-1 and 6 and macrophage colony-stimulating factor.[ 23 ]

Interleukins 1 and 6 in cancer regulation

IL-6 is a pleiotropic cytokine that plays important roles in immune response, inflammation, and hematopoiesis. It is produced by a variety of normal cells including monocytes and macrophages but is also expressed by multiple tumor tissue types, such as breast, prostate, colorectal, and ovarian cancer. IL-6 may also play an important role in various aspects of tumor behavior, including apoptosis, tumor growth cell proliferation, migration and invasion, angiogenesis, and metastasis.[ 24 ]

IL-10, initially termed “cytokine synthesis inhibitor” or “cytokine inhibitory factor” due to its inhibitory action on cytokine production by T helper cells, is produced by almost all leukocytes, as well as numerous human tumor cells including breast, kidney, colon, pancreas, malignant melanomas, and neuroblastomas. IL-10 is essential to suppress tumor-promoting inflammation mediators, thereby facilitating tumor growth and metastasis. Specifically, TAMs produce IL-10 and are also associated with in-tumor immunosuppression, thereby providing a suitable microenvironment for cancer growth.[ 25 ]

In mouse models of metastasis, treatment with an IL-1 receptor antagonist (which inhibits the action of IL-1) significantly decreased tumor development, suggesting that local production of this cytokine aids the development of metastasis. Moreover, mice deficient in IL-1 were resistant to the development of experimental metastasis.[ 26 ]

Inflammatory cytokines are major inducers of a family of chemoattractant cytokines called chemokines that play a central role in leukocyte recruitment to sites of inflammation. Most tumors produce chemokines of the two major groups α (or CXC) and β.

Typically, CXC chemokines are active on neutrophils and lymphocytes, whereas CC chemokines act on several leukocyte subsets including monocytes, eosinophils, dendritic cells, lymphocytes, and natural killer cells but not neutrophils.[ 27 ]

Human and murine tumors also frequently secrete CXC chemokines such as IL-8. These chemokines are potent neutrophil attractants, yet neutrophils are rare in tumors. However, both IL-8 and a related chemokine called “gro” induce proliferation and migration of melanoma cell.

I MPLICATIONS FOR P REVENTION AND T REATMENT

Tumor necrosis factor blockade.

TNF antagonists (etanercept [Enbrel] and infliximab [Remicade]) have been licensed for a clinical trial in the treatment of rheumatoid arthritis and Crohn's disease, with over 70,000 patients now treated. Thalidomide inhibits the processing of mRNA for TNF and VEGF, and continuous low-dose thalidomide has shown activity in patients with advanced myeloma. The role of etanercept in ameliorating the adverse effects of other cancer therapies is also being evaluated. There are also ongoing and planned clinical trials with infliximab. As with other “biological” approaches to cancer treatment, anti-TNF therapy may be optimal in an adjuvant setting with minimal disease.[ 28 ]

Chemokine antagonism

Chemokine receptors belong to a family of receptors (transmembrane G-protein-coupled receptors) which is already a target of pharmacological interest. Tumors driven by chemokines and those where chemokines are implicated in metastasis (e.g. seeding to lymph nodes) may be an appropriate target for chemokine antagonists now under development.[ 29 ]

IL-6 is a major growth factor for myeloma cells. In advanced disease, there is an excess of IL-6 production, and raised serum concentrations are associated with plasmablastic proliferative activity and short survival.

Nonsteroidal anti-inflammatory agents

Nonsteroidal anti-inflammatory drugs (NSAIDs) are nonselective or selective COX-1/2 inhibitors, which are wildly prescribed for pain killing, fever reduction, and even anti-inflammation.

Patients on NSAIDs are at reduced risk of colon cancer. This may also be true for cancers of the esophagus, stomach, and rectum, and in rodents experimental bladder, breast, and colon cancer. Colon cancer is reduced when NSAIDs are administered concurrently with carcinogens. NSAIDs inhibit cyclooxygenase enzymes and angiogenesis.[ 30 ]

The mechanisms involved in the association between NSAIDs and distant metastasis inhibition remain incompletely investigated. One possible explanation is that NSAIDs inhibit COX2. Abnormally high COX2 expression is observed in multicancers. Disordered COX2/PGE pathway is involved in multicancer processes, including carcinogenesis, proliferation, and metastatic spread; in addition, inhibition of COX2/PGE pathway with NSAIDs can restrain cancer cell lines.

Mutual promotion relationship between cancer metastasis and cancer-associated thrombosis is possibly another one of the underlying mechanisms. Abnormally high constitutive level of tissue factor (TF), one key regulator of hemostasis, is expressed by metastatic cancer cells, cancer microparticles, and cancer-associated monocytes and macrophages. TF can promote thrombosis formation by activating the extrinsic pathway of coagulation cascade. Furthermore, inflammation induced by thrombosis could result in endothelial damage that results in the vascular leak, facilitating the escape of cancer cells from blood vessels. Consequently, NSAIDs may disrupt the relationship between cancer metastasis and cancer-associated thrombosis via the suppression of platelet function, which is detrimental for the disseminated cancer cells in the bloodstream.[ 31 ]

C ONCLUSION

Overall, this review provides evidence for a strong link between chronic inflammation and cancer. Thus, inflammatory biomarkers as described here can be used to monitor the progression of the disease. These biomarkers can also be exploited to develop new anti-inflammatory drugs to prevent and treat cancer. These drugs can also be used as an adjuvant to the currently available chemotherapy and radiotherapy, which by themselves activate NF-κB and mediate resistance. Numerous anti-inflammatory agents including those identified from natural sources have been shown to exhibit chemopreventive activities.

Financial support and sponsorship

Conflicts of interest.

There are no conflicts of interest.

R EFERENCES