Home Journals Articles Updates About
CN
image
收藏切换
Obesity–cancer axis crosstalk: Molecular insights and therapeutic approaches
收藏切换
PDF
Ahmed Rakib, Md Abdullah Al Mamun, Mousumi Mandal, Priti Sinha, Udai P. Singh*
Acta Pharmaceutica Sinica B | 2025, 15(6) : 2930 - 2944
Less
收藏切换
Acta Pharmaceutica Sinica B | 2025, 15(6): 2930-2944
• REVIEW •
Obesity–cancer axis crosstalk: Molecular insights and therapeutic approaches
Full
Ahmed Rakib, Md Abdullah Al Mamun, Mousumi Mandal, Priti Sinha, Udai P. Singh*
Affiliations
  • Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN 38103, USA
doi: 10.1016/j.apsb.2025.04.029
Outline
收藏切换

Now recognized as a global health crisis, obesity has been linked to an increased risk of many types of cancer, including those of the breast, colon, rectum, uterus, gallbladder, and ovary. Obesity and cancer share several characteristics at the cellular, molecular, and epigenetic levels. Obesity is characterized by chronic inflammation of the adipose tissue (AT), resulting in genotoxic stress that further induces metabolic complications and contributes to the initiation and progression of cancer. The excessive accumulation of AT provides adipokines and lipids to engage tumor cells with stromal and immune cells to infiltrate carcinomas and secrete a plethora of cytokines, chemokines, and growth factors within the tumor microenvironment (TME) that contribute to carcinogenesis. Obesity also alters the metabolic reprogramming of immune cells, including macrophages, neutrophils, and T cells, thereby providing a suitable environment for the growth and progression of cancer. Obesity-associated metabolic dysregulation also perturbs the gut microbiome, which produces metabolites that can further increase the risk of cancer progression. This review will discuss links between obesity and cancer progression, including several crucial pathways that bridge the crosstalk between obesity-associated changes in AT inflammation, immune cells, adipokines, chemokines, and tumor cells to support cancer progression. We will also discuss our insights into the mechanisms by which obesity-driven factors influence metabolic reprogramming and touch base on how obesity mediates microbiome dysbiosis to alter metabolite and affect cancer progression. Altogether, this review highlights the crossroads of the obesity–cancer axis, describes its salient features, and presents possible therapeutic approaches for obesity-related cancers.

Obesity  /  Adipose tissue  /  Adipokines  /  Cancer  /  Metabolic reprogramming  /  Microbiome  /  Metabolism  /  Glucagon-like peptide-1
Ahmed Rakib, Md Abdullah Al Mamun, Mousumi Mandal, Priti Sinha, Udai P. Singh. Obesity–cancer axis crosstalk: Molecular insights and therapeutic approaches[J]. Acta Pharmaceutica Sinica B, 2025 , 15 (6) : 2930 -2944 . DOI: 10.1016/j.apsb.2025.04.029
Full Text
Less
1.　Introduction
Less
The World Health Organization (WHO) has declared the worldwide prevalence of obesity to be a global pandemic. In the human body, adipose tissue (AT) functions primarily as a fat depot but it also possesses endocrine functions that regulate normal physiology by producing and secreting adipokines. AT maintains its metabolic homeostasis and fat-storing functions during obesity1,2, where it supports low-grade chronic inflammation. AT also exacerbates obesity, which is a predisposing factor for several abnormal conditions, including metabolic, autoimmune, cardiovascular, and neurological disorders3. Importantly, the inflammatory and endocrine effects of AT during obesity are a major risk for type 2 diabetes mellitus (T2DM), which has been proposed as a crucial factor that links obesity with cancer4. The US Centers for Disease Control and Prevention (CDC) documents the linkage between obesity and 13 types of cancers, including colorectal, breast, liver, and pancreatic cancers. Obesity worsens cancer conditions, ultimately leading to death5, while weight reduction decreases the incidence of colorectal and breast cancer6. Therefore, the use of animal models to explore treatment options that affect the obesity–cancer axis provides a clear understanding of the mechanisms by which fat deposition fuels several cancers and cancer-related symptoms. However, the link between obesity and the initiation of cancer, and the underlying mechanisms remain to be explored for a prudent conclusion as to whether and how obesity influences the progression of cancer.
Based on its origin, location, and function, the AT is classified as white AT (WAT), brown AT (BAT), and beige AT. WAT has been traditionally attributed a role in the storage of energy as triglycerides (TG) and releasing fuel when the expenditure of energy exceeds its intake. More recently, WAT has emerged as an important metabolic and endocrine organ that is a key mediator of AT-related inflammation7. The pathological expansion of the WAT, known as ectopic fat deposition, may cause immunological and metabolic alterations that affect DNA repair and the resultant mutagenesis and epigenetic disruption of genes, leading to altered gene function and progression toward malignant cellular transformation8,9. These epigenetic alterations, changes in adipocyte phenotypes, genetic mutations, and altered functions are key initiation factors for the development of several cancers.
The low-grade chronic inflammation associated with obesity further creates a cancer-promoting microenvironment10. Obesity-associated inflammation is marked by the infiltration of immune cells that produce pro-inflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β11. These immune cells, including macrophages, neutrophils, and T cells, also release cytokines and chemokines in the obese AT, leading to gradual DNA damage, thereby promoting the cancer cell proliferation and survival that are essential for tumorigenesis12. Obesity also negatively affects the abilities of immune cells to detect and protect against malignant cells in the body13. Obesity and AT-secreted adipokines contribute to cell proliferation, metabolic diseases, and angiogenesis, which also promote tumorigenesis6. Additionally, obese AT supports metastatic cancer cells and allows tumors to migrate to different peripheral organs14. Furthermore, obesity is strongly associated with the enteric presence of the bacterium Bacteroides fragilis, which is also abundant in cancer15. Thus, there is ample evidence to suggest that obesity promotes cancer, but the underlying mechanisms remain unknown.
The goal of this review is to discuss recent advances toward discovering the mechanisms by which crosstalk and interactions between adipocytes and the AT immune–cancer microenvironment during obesity promote cancer progression. We will discuss the common mechanisms and metabolic pathways shared by obese AT and cancer and shed light on the role of the obesity-induced gut microbiome in cancer progression. Further, we will also discuss several potential therapeutic strategies to ameliorate and/or suppress obesity-related cancers.
2.　Sex-based differences in obesity-related cancer progression
Less
Obesity generally occurs in individuals with a body mass index (BMI) of more than 30 kg/m2, a condition currently shared by approximately 40% of the US population, who are at a greater risk of developing several forms of cancer16. Approximately 24% of cancers in men and 55% of cancers in women are attributed to obesity and related disorders, which highlights the increased vulnerability of women to obesity-related cancer, relative to the incidence in men17. The rising incidence of obesity underscores the crucial need to understand sex-specific differences and to determine their role in the initiation of cancer.
Obesity is responsible for approximately 31% of endometrial cancers18, while the development of uterine cancer exhibits a significant association with an increased BMI, with a 5-unit increase in BMI being associated with 45% of uterine cancer16. Overweight individuals with an increased BMI account for 7% of postmenopausal breast cancers19. Sex-based differences were also evident in the risk of colon cancer, which is approximately 70% in obese men20. Weight gain between early and mid-adulthood is significantly associated with a higher risk of colorectal cancer in both men and women, although the male population exhibits the strongest correlation with the development of colorectal cancer21. Obesity also poses a significant threat to the development of gastrointestinal cancer in light of its association with intestinal inflammatory diseases22. In association with hormonal regulation, other factors contribute to the development of pro-inflammatory and tumor-promoting environments, including altered insulin levels, insulin-like growth factor 1 (IGF-1) signaling, and dysregulated adipokine levels, leading to cancer progression during obesity.
3.　AT as an endocrine organ
Less
As a dynamic organ, the primary function of the AT is to store and mobilize energy for the body's needs. This energy balance is regulated by the central nervous system, which receives neural and chemical input from the peripheral organs to maintain homeostasis23. Since several such signals are generated by AT-derived adipokines to regulate appetite and insulin sensitization, AT also serves as an endocrine organ to control metabolic processes such as fatty acid oxidation, insulin signaling, de novo lipogenesis, and gluconeogenesis24,25. Thus, AT can respond based on both metabolic demand and the availability of nutrients in the body, thereby influencing both local and systemic outcomes. By secreting adipokines into the systemic circulation, AT communicates with distant organs, including the liver, skeletal muscles, and heart, and regulates complex metabolic processes to maintain homeostasis.
The WAT secretes many of the AT adipokines, including TNF-α, IL-6, adiponectin, leptin, fatty acid binding protein 4 (FABP4), and plasminogen activator inhibitor-126,27. In addition to its role in maintaining thermogenesis, the BAT regulates energy homeostasis by secreting adipokines (also called batokines), including fibroblast growth factor 21, neuregulin, retinol-binding protein 4, and angiopoietin-like protein 827. Adipokines produced by the WAT and the BAT communicate with other body organs in a complex manner to regulate homeostasis. The adipokine signaling cascades and the recruitment of immune cells through adipokine–cytokine crosstalk play pivotal roles in cancer progression. Adipokines also facilitate a pro-tumorigenic environment by modulating metabolic and inflammatory signaling in the tumor microenvironment (TME).
4.　Obesity and cancer development: Uncovering the link
Less
4.1.　 Role of obesity mediators in cancer progression
One of the most important adipokines secreted by WAT adipocytes is leptin, which serves as a crucial signaling molecule in the neuronal and immune systems that links energy storage and nutritional status23. Leptin has pleiotropic effects on physiological processes, including hematopoiesis, glucose uptake, gastric emptying, and kidney function. The cognate leptin receptor expressed on the surface of the AT adipocytes as well as cells in the kidneys, brain, and muscles binds to biologically active leptin that is circulating freely in the blood28. As a key player in adipocyte hyperplasia, leptin can exert either an autocrine or a paracrine effect on the differentiation of adipocytes29. Under conditions of obesity, leptin resistance leads to the accumulation of excessive leptin (hyperleptinemia) and excess adiposity30,31. Mice lacking leptin or leptin receptors lack a satiety response feedback mechanism, leading to excessive adiposity and T2DM26, yet at higher concentrations, leptin inhibits preadipocyte proliferation32. The intricate mechanisms by which leptin regulates obesogenic factors is a key potential research field in which to ascertain the relationships between obesity and cancer.
Leptin signals via several signaling cascades, including the well-established Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. After binding to the leptin receptor, leptin eventually activates signaling through JAK2 and its downstream transcription regulators, including STAT3, which further regulates the expression of several other genes33 (Fig. 1). Leptin also induces the increased activation of the mammalian target of rapamycin (mTOR) and its signaling cascade34,35. Since leptin is expressed by tissues with high angiogenic activity, it is not surprising that leptin-related signaling pathways are involved in angiogenesis, tumorigenesis, and metastasis36. In breast cancer cells, leptin induces expression of the leptin receptor, which modulates multiple signaling pathways, including the JAK/STAT3 and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways, to promote increased levels of IL-1 signaling37. A study with mutant leptin receptors demonstrated that deficiency in the STAT3 binding site is important in stimulating the catabolic pathways by leptin signaling38. In addition, STAT3 possesses binding sites in the promoter region of programmed cell death 1 (PD-1) and is associated with increased PD-1 expression in human and murine cancers39,40. Further, knockdown of STAT3 by short hairpin RNA (shRNA) transduction inhibited the tyrosine phosphorylation of the STAT3 upstream regulator c-Src as well as downstream regulator c-Myc in breast tumors in the immunocompetent mice41. Leptin is also co-expressed with the potent angiogenic factor vascular endothelial growth factor (VEGF), which promotes the expression of VEGF and its associated receptor, VEGF receptor 2 (VEGFR2), via the JAK/STAT signaling cascade (Fig. 1)42. The association between VEGF and STAT3 was shown in a study in a cohort of 45 breast tumor specimens43. The clinicopathological characteristics from the specimens showed the correlation of STAT3 with axillary lymph node metastasis and overexpression of STAT3 was linked with elevated expression of VEGF-D, VEGF-C, and VEGFR3.
Another WAT-derived adipokine is adiponectin, which is abundant in circulating blood under normal physiological conditions but during AT inflammation or other metabolic syndrome, its levels decrease44. Adiponectin activates two specific adipokine receptors, AdipoR1 and AdipoR2, which interact with adaptor proteins such as sirtuin 1 (SIRT1), sphingosine-1-phosphate (S1P), or those containing the pleckstrin homology domains 1 (APPL1) and 2 (APPL2) to activate downstream signaling pathways45,46. Adiponectin overexpression induces the activation of peroxisome proliferator-activated receptor alpha (PPARα), which increases lipid cell metabolism and eventually leads to the generation of pancreatic β cells47. APPL1 crosstalk links the adiponectin pathway with those of other downstream targets for insulin signaling, namely the AMP-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (Akt) pathways48,49. These pathways may also be crucial for enhancing or promoting cancer, yet the mechanisms by which adiponectin shapes the TME remain unclear.
Adiponectin appears to play a dual role in the regulation of growth and proliferation in various cancers. Adiponectin suppresses the proliferation of breast cancer, colon cancer, and pancreatic cancer cells in vitro50-52, primarily facilitated by AMPK signaling. Adiponectin upregulates SIRT1, which deacetylates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), activating expression of mitochondrial genes to reprogram the metabolic pathway in cancer cells53. In an orthotopic breast cancer model of nude BALB/c mice, it has been shown that adiponectin administration upregulates SIRT1 expression and decreases the expression level of phosphorylated mTOR54. Conversely, adiponectin also facilitates angiogenesis in the process of ischemia55, perhaps via its interactions with PI3K signaling, leading to the synthesis of angiogenic growth factors. Activation of adiponectin is dependent on angiogenic factors, including VEGF and the matrix metalloproteinases (MMPs), including MMP-2 and MMP-956. In humans, adiponectin might be associated with the progression of obesity-related papillary thyroid cancer57. In a xenograft tumor-induced angiogenesis model, it has been demonstrated that knockdown of adiponectin reduced tumor-induced angiogenesis, supporting that adiponectin is associated with promoting angiogenesis and tumor growth in murine models58. Taken together, these data suggest that adiponectin possesses angiogenic properties and might induce cancer progression.
4.2.　 Immune interactions with tumor microenvironment during obesity
Obesity-related AT inflammation is caused by elevated secretion of adipokines, chemotactic factors, and pro-inflammatory cytokines to further exacerbate several metabolic and autoimmune diseases59-61. The pro-inflammatory environment in obese AT is mediated by adipokines that further increase the expression of pro-inflammatory molecules, thereby contributing to AT hypertrophy and hyperplasia62,63. The shift to expression of pro-inflammatory cytokines and chemokines attracts infiltration of immune cells into the obese AT, which further elevates the expression of chemoattractant molecules, including monocyte chemoattractant protein-1 (MCP-1)64. Under obese conditions, AT inflammation leads to the differentiation of monocytes in the WAT, generating macrophages that are predominantly of the M1 phenotype65. During chronic obesity-related inflammation, T cell subsets including CD4 and CD8 increase, the number of regulatory T cells (Tregs) decreases66,67, and neutrophils infiltrate the obese AT68. This complex interplay of AT-derived adipokines and crosstalk among different immune cells leads to chronic AT inflammation, which might initiate excessive cellular proliferation and angiogenesis, initiating or contributing to some cancers. In a cohort of 251 melanoma patients from the Cancer Genome Atlas (TCGA), obese individuals having tumors showed an elevated expression of PD-1 compared to non-obese patients, while the aged obese individuals are more prone to the expression of PD-1 and other associated markers, including T cell immunoglobulin and mucin domain-containing protein 3 (TIM3)69. Cancer cells and immune cells are in proximity in the TME and the internal networking between these two cell types is governed by secretory factors, including chemokines and cytokines. This internal complex network mutually regulates the migration of regulatory factors into the TME, where they significantly influence tumor initiation and progression70. During cancer progression, immune cells such as macrophages, myeloid-derived suppressor cells (MDSCs), and Tregs support tumor growth and dampen host immune responses71. Thus tumor-infiltrating immune cells may provide potential biomarkers for identifying the TME.
Interactions between the TME and the immune system are critical for cancer development and progression72-75. One of the key cytokines that mediate obesity-related chronic inflammation and TME is IL-6, the effects of which are mainly triggered by the IL-6 signal transducer (IL6ST or glycoprotein 130) and signaling via the STAT3 pathway76,77 (Fig. 1). IL-6 regulates chronic inflammation by increasing accumulation of macrophages in the AT during obesity78. Additionally, IL-6/STAT3 signaling has a potential effect on the tumor-infiltrating immune cells. The hyperactivation of STAT3 signaling during tumorigenesis activated immune cell infiltration in the TME, which increases the risk of tumor progression79. In a colorectal cancer mouse model, IL-6 is required for cancer occurrences, and activation of STAT3 signaling by IL-6 is required for the survival of intestinal epithelial cells and their progression through the cell cycle80. Additionally, it has been reported that knockout of STAT3 as well as inhibition of JAK2 reduced the formation of colon cancer spheroid81. In addition, in the murine model of colorectal cancer, knockout of either IL-6 or STAT3 inhibited the occurrence of colorectal cancer76. STAT3 targets two proto-oncogene serine/threonine-protein (Pim) kinases, Pim-1 and Pim-2, which are associated with cell survival and proliferation82. In conjunction with the IL-6/STAT3 axis, Pim-1 plays a role in cell growth during the progression of several cancers, including pancreatic cancer83. IL-6/STAT3 also induces expression of angiogenic factors VEGF and hypoxia-inducible factor-1α (HIF-1α) to promote angiogenesis84,85 (Fig. 1).
Nuclear factor-kappa B (NF-κB) is a master regulator of inflammatory disorders that plays a key role in the development of obesity and cancer. Activation of NF-κB signaling increases the infiltration of proinflammatory cytokines, such as IL-6, TNF-α, and IL-1β in the obese AT and TME, further worsening obesity and supporting the proliferation of the cancer cells86. In both obesity and cancer, NF-κB-mediated inflammation and immune cell infiltration are regulated by different adaptor molecules87. To this end, macrophages play a crucial role in the progression of obesity-associated AT inflammation and constitute a vast part of the immunological contribution to tumor initiation, progression, and metastasis88,89. The frequency of tumor-associated macrophages (TAMs) is strongly correlated with many tumors, such as those involved in breast, pancreatic, colorectal, and ovarian cancer90. The stimulation of TAMs by cytokines including IL-10, IL-6, and angiogenic factors such as VEGF released by tumor cells suppress the immune response, thus promoting tumor angiogenesis91,92. After activation, TAMs can produce proinflammatory cytokines, including IL-6, IL-17, and IL-23, and induce cancer progression through the NF-κB signaling or other inflammatory pathways, such as STAT393 (Fig. 1).
An important source of inflammation under conditions of obesity is the activation of inflammasomes in AT macrophages, which in turn results in the activation and secretion of pro-inflammatory cytokines IL-1β and IL-18 by caspase-1-dependent mechanisms94. In response to different stimuli, the inflammatory sensor NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) recruits and activates the NLRP3 inflammasome, which has been widely studied in the fields of obesity and cancer (Fig. 1). NLRP3 inflammasome activation and excessive IL-1β secretion are involved in obesity-related AT inflammation and other metabolic diseases, including T2DM95,96. While some studies report an anti-tumorigenic effect of the NLRP3 inflammasome, for example in colorectal cancer, this cellular complex serves as a key player in tumor development that regulates both the TME and host immune responses, thus promoting cell metastasis and proliferation in the growing tumor97,98. In a mouse model of colitis-associated colorectal cancer, high-fat diet (HFD)-induces NLRP3 inflammasomes to increase the tumor burden as well as inflammatory response99. During the development of cancer, MDSCs produce anti-inflammatory cytokines and exert immunosuppressive effects100. In mouse models, NLRP3 inflammasome activation promotes tumorigenesis by activating MDSCs and Tregs to dampen the activation of T cells and natural killer (NK) cells98. The function of IL-1 signaling in MDSCs recruitment during cancer progression is supported by a murine study, which examined that transgenic mice that overexpress human IL-1β in the stomach are associated with the development of gastric cancer101. Moreover, NLRP3 inflammasome activation induces signaling pathways such as the Toll-like receptor (TLR)-caspase signaling pathway involving TLR4/caspase-1 or TLR4/caspase-11 to promote the production of proinflammatory IL-1β, which triggers several forms of cancer102. In a mouse study, downregulation of NLRP3 by the administration of thymoquinone therapy decreased the secretion of IL-1β and IL-18, reducing the risk of metastatic melanoma103. Clearly, further experimental evidence will be needed to provide mechanistic details of the role of NLPR3 inflammasome in cancer, particularly its correlation with obesity-induced tumorigenesis.
4.3.　 Insulin signaling and metabolic dysregulation are crucial for obesity-mediated cancer
The peptide hormone insulin, synthesized in and secreted by pancreatic β cells, regulates blood sugar under normal physiological conditions. However, conditions such as HFD-induced obesity trigger dysregulation of insulin signaling, leading to insulin resistance that is often associated with T2DM and other metabolic abnormalities104. It is therefore not surprising that insulin dysregulation and insulin resistance are also correlated with certain cancers105, since the mechanisms of cancer progression and insulin signaling overlap106. For example, more than 80% of patients diagnosed with pancreatic cancer have insulin resistance107. In obesity and cancer, dysregulation of multiple factors, including IGF, pro-inflammatory cytokines, adipokines, and insulin, paves the way for a complex environment that serves as a dominant contributor to cancer progression108.
PI3K/Akt signaling pathway serves as a bridge between adiposity and insulin action. This pathway is activated by signals from various receptors, including insulin receptors in AT macrophages, resulting in direct upregulation of two transcriptional factors that regulate adipogenesis, namely CCAAT/enhancer-binding protein alpha (C/EBPα) and peroxisome proliferator-activated receptor gamma (PPARγ)109,110. The production of adipokines such as adiponectin and visfatin involves signaling through the PI3K/AKT pathway109. Thus, in addition to its role in obesity-induced insulin resistance, PI3K/AKT signaling cascade plays a role in cell survival and proliferation during cancer progression. For example, PI3K/AKT signaling directly regulates the growth of proliferating tumor cells through the cell cycle inhibitor p27111, epidermal growth factor receptors (EGFRs), and IGF2112,113. Further, crosstalk between the EGFR/PI3K/Akt and NF-κB axes plays a role in regulating several types of cancer. To this end, it has been demonstrated that inhibiting insulin receptor substrate (IRS) by NT157 decreased cell proliferation in a human pancreatic adenocarcinoma cell line114. Moreover, in NP-29 pancreatic cells, IRS1 undergoes phosphorylation at multiple tyrosine sites and combined blocking of both IGF receptors and EGFR has shown potential synergistic effects in eliminating pancreatic cancer stem cells115. Signaling transduction via the type I and type 2 IGF receptors (IGF-IR and IGF-IIR, respectively) induces tyrosine kinases that promote tumor growth and metastasis. Tumors that have been depleted of cells by ionizing radiotherapy can repopulate by inducing angiogenesis, as follows: dying cells provide a signal to cleave and activate caspase-3, initiating a caspase-3/PKCδ/Akt/VEGF signaling cascade that ultimately releases VEGF to signal proliferation of the surviving cells116. In breast cancer cells, IGF promotes mitochondrial biogenesis by inducing factors like PGC-1β, and Bcl-2 interacting protein 3, thereby further promoting tumor growth117,118.
In addition to its roles in obesity and cancer, insulin is also a key player in lipid metabolism. Insulin inhibits lipid biosynthesis, which helps to reduce the proliferation of cancer cells. Lipid metabolism and biosynthesis are highly relevant to cancer, since several cancers exhibit highly abundant expression of fatty acid synthase (FASN), perhaps due to the aberrant activation of the de novo fatty acid synthesis pathway. In colorectal cancer, upregulation of FASN increases expression of the angiogenesis marker VEGF, thereby upregulating angiogenesis, and is associated with metastasis119. FASN expression also significantly decreases the overall survival of patients with pancreatic cancer120. The sphingolipid S1P serves as a crucial modulator of cancer growth and progression: the balance between the levels of S1P and ceramide plays a prominent role in cell survival and proliferation121. Finally, cancer-related stem cells utilize lipid metabolism for their functions in the TME. Thus, metabolic dysfunction primarily related to insulin and lipid metabolism provides a fundamental link between obesity-related metabolic dysregulation and cancer-associated etiologies.
5.　Metabolism of immune cells in the AT correlates with cancer progression
Less
The intricate interplay between adipokines and insulin signaling underscores the metabolic disturbances caused by obesity-related inflammation and its effect on the development of cancer. Beyond these metabolic drivers, the immune system also plays a crucial role in immune cell metabolism during obesity-related cancer progression. Specifically, metabolic dysregulation in AT macrophages and T cells and the resultant shift in cellular metabolism further accelerate the cancer risk fostered by obesity. Macrophages and monocytes undergo substantial metabolic and epigenetic reprogramming to shift toward phenotypes that facilitate cellular proliferation and the production of effector molecules122,123. There are two major subsets or phenotypes of macrophages, the M1 classically activated macrophages (proinflammatory) and the M2 alternatively activated macrophages (anti-inflammatory). The metabolism of M1 macrophages exhibits increased glycolysis and reduced Krebs cycle-related oxidative phosphorylation (OXPHOS124), while that of M2 macrophages exhibits increased OXPHOS125. T cells are also metabolically reprogrammed to proliferate and achieve effector functions126. Binding of an antigen by a T cell initiates the expression of signaling molecules and activates pathways that regulate metabolic reprogramming. The metabolic reprogramming pathways shared by macrophages and T cells reinforce the systemic nature of the intricate interplay within the obesity–cancer axis.
These shared metabolic reprogramming pathways are regulated by the HIF-1, whose α subunit is stabilized post-translationally in conditions of low oxygen availability (hypoxia), such as those found in the AT during obesity. AT macrophages and T cells maintain hypoxic conditions in the AT by inducing the production of interferon gamma (IFNγ) and NF-κB to further increase synthesis and stabilization of HIF-1α127-129. HIF-1α also regulates the expression of genes involved in angiogenesis and energy metabolism and is critical for metabolic adaptation in macrophages and T cells130. In macrophages, signaling via the TLR and AKT pathways activates NF-κB, resulting in upregulation of HIF-1α transcription131, as shown in Fig. 2. In M1 macrophages, stimulation by lipopolysaccharide and IFNγ results in a metabolic switch from OXPHOS to glycolysis via multiple transcription factors, including NF-κB and HIF-1α (Fig. 2), while blocking the glycolytic pathway in these cells decreases IFNγ-induced expression of HIF-1α132. In hypoxic T cells, the HIF-1α–glycolytic axis regulates metabolic reprogramming by upregulating IFNγ production and synthesizing several effector cytokines, including granzyme B133. HIF-1α expression is also correlated with the activation of inflammatory T helper 17 (Th17) cells and its promotion of proinflammatory conditions can lead to T cell exhaustion134-136 (Fig. 2).
TME is also hypoxic, which favors the rapid growth of tumor cells that have also undergone metabolic changes that allow them to use glycolysis and OXPHOS for energy production137. In both activated T cells and tumor cells, expression of HIF-1α induces that of angiogenic genes such as VEGF and activates the PI3K/Akt and MAPK pathways to increase expression of HIF-1α138 (Fig. 2). During the progression of breast cancer, upregulation of HIF-1α is associated with higher expression of VEGFA139. Although HIF-1α expression is also a potential risk for renal cell carcinomas and neuroblastoma, xenograft studies depicted that overexpression of HIF-1α retards tumor growth in renal cell carcinomas; however, the mechanism is not well understood140. HIF-1α also recruits growth factors, including IGF2 and transforming growth factor (TGF), to receptors on cancer cells to induce their proliferation141 (Fig. 2). Thus, it is not surprising to learn that overexpression of HIF-1α in cancer cells is associated with the failure of cancer treatments, thereby increasing the rate of mortality.
6.　The impact of obesity-associated inflammation in cancer metastasis
Less
While genetic alterations in tumor cells play a role in the progression of cancer, such progression also depends on a complex systemic process that includes the interaction with tumor cells in TME. Particularly, the interaction between the tumor cells and the associated stroma is a powerful association that impacts the initiation, progression, and metastasis of cancer142. The association of stromal cells with TME plays a critical role in the development of tumors. Mechanistic insights into stromal cell recruitment and TME reveal a unique connection between tumor biology and cancer progression that might also be directed by the body's responses to malignancy in several organs that are distant from the site of the primary tumor143. Obesity is associated with hypertrophic and hyperplasic adipocytes, which secrete adipokines to recruit immune cells into the AT and induce the production of proinflammatory cytokines, leading to insulin resistance and cancer. Further, since tumor metastasis contributes to cancer mortality, the surprising discovery of a possible link between metastatic tumor cells and the dysfunctional AT during obesity will lead to the discovery of novel therapeutics that target inflammation/obesity-induced cancers.
Cancer cell metastasis starts with the invasion of tumor cells into surrounding tissues. The chromosomal instability of cancer cells affects the segregation of chromosomes during the mitotic phase of the cell cycle144. These processes activate pathways such as DNA sensing and NF-κB signaling, leading to the dissemination of tumor cells (Fig. 1). Subsequently, epithelial–mesenchymal transition (EMT) enables tumor cells to maintain a migratory phenotype, which is caused by several factors, such as hypoxia and metabolic stress145. Obesity-related chronic inflammation not only increases the EMT but also increases interactions among tumor cells to mimic normal physiological processes, facilitating metastatic progression. Further, obesity exacerbates the pro-inflammatory microenvironment and metabolic stress, which plays a crucial role in cancer metastasis.
The metastatic cascade of tumor cells links with the obese AT via several mechanisms. In intra-abdominal cancers and gastric and ovarian cancers, adipokines are secreted by adipocytes, which metastasize into the omentum, thereby further contributing to the migration and invasion of tumor cells by interacting with leptin and adiponectin146. Tumor cells that are metabolically adapted to high lipid environments utilize fatty acids as a source of energy, mainly by FABP4. In acute myeloid leukemia (AML), increased expression of FABP4 under obesity increases tumor aggressiveness by promoting immune invasion. FABP4 is highly expressed at the adipocyte–cancer cell interface and blocking FABP4 significantly decreases lipid accumulation and omental metastasis (Fig. 1)14. In breast cancer, adipocyte-induced MMP-11 causes the dedifferentiation of adipocytes into fibroblast-like cells, corroborating the evasion of cancer cells147. Additionally, obesity-associated low-grade inflammation exacerbates the metastatic potential by disrupting the differentiation of adipocytes, further leading to hypoxia and increased expression of HIF-1148. The increased level of HIF-1 decreases the expression of adiponectin expression and elevates that of leptin (Fig. 2), a shift that is related to the increased cancer risk, particularly in triple-negative breast cancer (TNBC)149. Leptin also increases tumor cell migration and invasion via JAK/STAT signaling, promoting the cancer stem cells (CSCs) phenotype that leads to metastasis (Fig. 1)150,151.
In the context of obesity-related cancer, obese adipocytes dedifferentiate into preadipocytes and are reprogrammed into cancer-associated adipocytes (CAAs) that play a critical role in tumor progression152. Compared to normal adipocytes, CAAs produce higher levels of proinflammatory mediators, such as MCP-1, RANTES, IL-6, and TNF-α, and they exhibit increased promotion of cancer invasion and metastasis153. In addition, obesity is associated with the recruitment of M1 macrophages in AT, which consistently maintain a proinflammatory microenvironment conducive to tumor progression. In cancer cells, MCP-1 induces NOTCH1 signaling, which further induces the activity of CSCs and the formation of new blood vessels154. RANTES expression in the adipocytes fosters increased motility and invasiveness of cancer cells and correlates with lymph node and other metastasis during TNBC, reducing patient rates of survival155. IL-6 that is secreted by hypertrophic obese adipocytes or CAAs serves as a major regulator for obesity-associated hepatocellular carcinoma (HCC) by increasing angiogenesis and metastasis (Fig. 1)156. M1 macrophages and adipocytes consistently produce a higher level of TNF-α as obesity progresses and an increase in TNF-α induces the production of MMPs in epithelial tumors, facilitating EMT to promote invasion and metastasis of tumor cells (Fig. 1)157. In addition, proinflammatory cytokines in the obese AT stimulate the function of CSCs and elevate the expression of CSC-related genes, further increasing tumorigenesis and migration of cancer cells14.
7.　Obesity-modulated microbiome and cancer interaction
Less
In the field of obesity and metabolism, the role of the microbiome in the regulation of these key processes is an emerging research area. Several intertwined mechanisms by which the microbiome is reprogrammed during obesity may also serve to accelerate the progression of cancer. For example, bacterial species that comprise the human microbiome are associated with various forms of cancer, with eleven entire microbiomes being directly carcinogenic to humans158. Proper maintenance of the gut microbiota is critical to regulate nutrients and energy usage and to promote the health and well-being of the host, while failure to do so correlates with disease conditions including autoimmune diseases and cancer. Any alteration or disruption in the gut microbial population potentially affects the host metabolism, meaning that the microbiota are critical players in the development of obesity and associated metabolic disturbances. These changes can initiate inflammatory and metabolic processes, cell differentiation, and abnormal multiplication, any of which might facilitate cancer progression.
The main function of the intestinal microbial flora is the extraction of energy from food ingredients such as polysaccharides and complex carbohydrates that are not digested by the host due to the absence of the appropriate enzymes. In contrast, bacterial species in the gut microbiome that express these enzymes can metabolize these substances to produce metabolites, including propionate and butyrate159. Interestingly, the differences in metabolite levels observed in obese vs lean mice can further exacerbate the conditions of obesity160, while germ-free mice that lack microbiota are protected from developing obesity on the consumption of HFD161. Thus, characterizing the intestinal microbiota, defining their relationships with obesity-associated inflammation, and subsequently identifying specific microbial targets may result in the development of potential therapeutic options for the treatment of obesity and related disorders.
Microbiota from obese individuals exhibit greater utilization of carbohydrates and more production of pro-inflammatory mediators than those from lean individuals162. For example, microbial glutamate levels are differentially affected in obese individuals relative to lean controls. In some cases, an altered microbiome can be detrimental, while in other cases, it can be helpful for gut and overall health. A decrease in microbiota-related metabolites including trimethylamine N-oxide (TMAO) and its precursors choline and carnitine is associated with significant weight loss163. Conversely, the administration of Akkermansia muciniphila reverses HFD-induced obesity and T2DM164, while B. uniformis ameliorates HFD-induced obesity in mice165. Our unpublished findings reveal that Bacteroides species are significantly downregulated in mice with HFD-induced obesity (Fig. 3), supporting the notion that these bacterial species may have potential as modulators of obesity-related metabolic disorders. Altogether, these studies suggested that interactions with the gut microbiome are critical in the regulation of obesity, but that these complex interactions depend on the intestinal environment, which may affect the incidence of obesity-associated cancer.
The association of at least 20% of cancers with various infectious agents may be related in part to the significant correlation between the gut microbiota and the progression of cancers such as those of the breast, lung, and skin166,167. In humans, obesity-driven microbial dysbiosis (modulation of microbial content) is linked with abnormal metabolism and carcinogenesis167,168, while in animal models, alteration of gut microbiota significantly increased the risk of colorectal cancer169,170. However, the mechanisms by which the gut microbiota influence the disruption of host immune responses during the progression of cancer or the association of cancer cells with the host microbiome in the context of tumorigenesis remain unclear.
Nevertheless, inflammation and dysregulation of the immune system contribute to microbiome-related carcinogenesis, further paving the way for the development of cancer. The process of inflammation is a critical regulator of the regulation and biosynthesis of microbial metabolites, primarily by modulating the TME. During tumor progression, tumor cells adopt multiple strategies to alter various signaling pathways to maintain a suitable milieu to support their growth. The role in this process of microbial metabolites is becoming clearer. For example, levels of short-chain fatty acids (SCFAs) are elevated in hepatocellular carcinomas, where they promote tumor progression in nonalcoholic fatty liver disease171, and butyrate increases Treg expression and promotes the effector function of T cells171. Given these roles, the notion that microbial metabolites may prove to be useful additions to effective anti-tumor therapies is well supported. The development of such therapies for obesity-mediated cancers will require a more thorough understanding of the microbiome and the function of its metabolites.
8.　Divergent perspectives on metabolic reprogramming and immune interactions in obesity-related cancer
Less
The TME is a complex microenvironment composed of fibroblasts, infiltrating immune cells, tumor cells, and stromal cells. It has been well established that metabolic strategies employed by cancer cells are distinctly different compared to normal cells. Cancer cells produce a variety of mediators that alter the metabolic environment to sustain their growth, thereby facilitating the progression of tumor and metastasis. The peripheral immune system and TME play crucial roles in both the progression and the prevention of cancer. The metabolic heterogeneity in the immune cell population provided by natural killer cells or cytotoxic T cells can shape immune responses and suppress tumor growth, whereas TAMs, Tregs, and MDSCs can render immunosuppressive action for the tumor's evasion of the immune system172. Within these intricate pathways of metabolism, the accumulation of lactic acid (lactate) plays a dual role in tumor progression. In an acidic environment, lactate suppresses the function of CD4 and CD8 T cells and the tumor's immune escape is facilitated by Tregs and TAMs173-175. However, in the absence of acidic conditions, lactate induces the anti-tumor activity of cytotoxic CD8 T cells176. Like lactate, succinate also delineates both anti-tumor and pro-tumor activities. Succinate produced by a tumor helps the immunosuppressive actions of TAMs, while CD8 T cell-derived succinate enhances the cytotoxicity of tumor cells177,178. Future studies will be required to reach prudent conclusions for therapeutic strategies that target the metabolic–immune interactions in cancer.
9.　Therapeutic implications and strategies for obesity-induced cancer
Less
Although patients with obesity or obesity-induced T2DM exhibit an elevated prevalence for the initiation and growth of cancer, the molecular mechanisms that link obesity-associated disorders and microbiome dysbiosis with the progression of cancer remain to be determined. The identification of the shared pathophysiology among these processes is complicated by the latent period between the initiation of cancer and its development. The question also remains whether reducing obesity can effectively reduce the risk of cancer or vice versa. We will discuss our mechanistic insights into therapeutic options for patients with obesity-associated cancers.
Radiotherapy generally provides a first-line treatment option for cancer, either alone or in combination with chemotherapy or surgery. However, obesity-associated cancer is less susceptible to radiotherapy than other cancers and the underlying mechanisms are not well understood. Although radiation effectively treats multiple tumors, resistance to radiation therapy leads to failure in therapeutic approaches and facilitates metastasis179. Triple-negative breast cancer is less sensitive to radiation therapy, while obese individuals are more prone to prostate cancer180. In breast cancer patients, obesity and larger breast size are associated with an increased risk of dermatitis after radiotherapy181. Furthermore, the serine protease inhibitor SERPINE1 correlates with the progression of obesity-related breast cancer and provides a reliable prognostic marker for patient resistance to radiotherapy.179,182
In addition to radiotherapy and chemotherapy, exercise therapy effectively mitigates obesity-related weight gain and associated breast cancer183. The American Cancer Society recommends that exercise training is safe for individuals who are undergoing cancer treatment and helps to effectively maintain a healthy body weight184. Dietary factors correlated with metabolic processes influence the risk of obesity-associated cancer progression, while dietary patterns and nutritional interventions reduce the risk of meta-inflammation and oncogenesis185. The intake of saturated fat correlates with an increased risk of cancer progression and chronic inflammation, while poly-unsaturated fatty acids (PUFA) exhibit anticancer characteristics186-188. Intake of omega 3 FAs and an increased ratio of omega 3 and omega 6 FAs correlates with a lower risk of obesity-related breast cancer189. Moreover, natural phytochemicals such as polyphenols, and stillbenes exhibit significant anti-tumorigenic effects under conditions of obesity190.
Oral antidiabetic drugs such as metformin lead to a decreased risk of breast, pancreatic, and colorectal cancers191,192. In obese mice, administration of metformin inhibits tumor growth in breast and endometrial cancers189. However, metformin shows limited or no potential benefits in randomized clinical trials when used as an adjuvant therapy193,194. Other therapeutic approaches for the treatment of these cancers may include the use of the tetrahydrolipostatin lipase inhibitor orlistat, which reduces the absorption of dietary fat and functions as an anti-obesity drug. In clinical trials, the administration of orlistat together with a low-calorie diet induced more weight loss and fewer obesity-related health complications than the diet alone195. Orlistat also significantly increases oxysterol metabolism in obese individuals196 and exhibits anti-tumorigenic activities against various solid tumors197,198. Thus, orlistat may prove beneficial for managing obesity and reducing the risk of cancers associated with metabolic disorders.
Recently, microbiota-based therapies have been used to treat metabolic disorders and associated carcinomas. Microflora-based therapy is considered a promising therapeutic strategy in the field of metabolic diseases and cancer, as it possesses fewer side effects than other therapeutic options15. Importantly, microorganisms provide a powerful source of metabolic machinery for chemotherapeutic agents199. For example, gut-microbiota-derived metabolites such as indole-3-carboxaldehyde, propionate, and kynurenic acid are protective against the adverse effects of radiotherapy200. In addition, the peptidoglycan synthesized by Enterococcus species increases the antitumor efficacy of anti-PD-L1 antibodies by improving the immunocompetence of cancer patients. Dietary fiber produced by the gut microbiota produces SCFAs, which have the potential to manage obesity and cancer. Moreover, SCFAs increase the efficacy of CD8+ T cells, leading to successive immune checkpoint therapy201.
Promising new therapies under development target the insulin, adipokine, and inflammatory signaling pathways for the treatment of obesity-related cancer. Therapies that target glucagon-like peptide-1 (GLP-1) may prove effective for the treatment of obesity and T2DM. In addition to controlling weight gain and glucose homeostasis, therapies based on long-acting GLP-1 agonists appear to decrease the incidence of cardiovascular diseases such as stroke and myocardial infarction202, while cells that overexpress the GLP-1 receptor (GLP-1R) contribute significant therapeutic benefits in hepatic diseases. In colorectal cancer, GLP-1R agonists block cell cycle progression, decrease cell proliferation, and block PI3K/Akt/mTOR signaling to promote tumor cell apoptosis203. GLP-1R agonists also attenuate the growth of prostate cancer by inhibiting ERK signaling204 and exhibit anti-proliferative effects on breast cancer cells treated with conditioned media from obese AT-derived stem cells, which promotes cancer growth and proliferation205. Although GLP-1 therapy shows promising results for the treatment of obesity, diabetes, and cancer, careful selection of GLP-1R agonists and long-term safety monitoring will be required before the potential adoption of such agents for the treatment of obesity-related cancers.
Chimeric antigen receptor (CAR) T-cell therapy represents a revolutionary breakthrough in cancer treatment in murine and human models206,207. CAR-T cells primarily target the B cell lineage antigen CD19 and provide a significant treatment option for treating patients with B cell non-Hodgkin lymphomas and acute B cell lymphoblastic leukemia208. These results have opened the door to using CAR-T cells against other inflammatory diseases, including nonalcoholic steatohepatitis and heart failure209,210. A novel and exciting offshoot of CAR-T cell therapy is the engineering of autologous T cells to acquire the thermogenic metabolic profile of brown fat, which might increase their resting energy expenditure without the risk of mitochondrial uncoupling. Thus, researchers are investigating the effect of thermogenic T cells that target BAT as a potential therapeutic option for the treatment of obesity211. However, the development and delivery of thermogenic T cells remain a promising experimental model that needs more work.
10.　Concluding remarks
Less
Obesity is accompanied by metabolic disorders and increased risks of various cancers, highlighting the critical importance of understanding the interwinding mechanisms that link obesity and cancer. Dysregulation of adipocytes and infiltrating immune cells in the AT results in chronic inflammation, which plays a crucial role in the progression of obesity-associated cancers. However, the underlying mechanisms for the progression of obesity-associated cancers remain unclear. Obesity is a multifactorial condition in which the complex interplay between AT immune cells and cancer cells, and the adipokines and cytokines they produce, provides a suitable milieu for cancer growth that is further exacerbated by the pro-tumorigenic effects of obesity-related metabolic dysregulation. In the future, a critical understanding of the pathogenesis of obesity, metabolic syndrome, and cancer progression will be required for the development of effective therapeutics to treat these conditions. Several approaches, including improved insulin signaling, reprogramming and modulating immune cell metabolism, and the use of recent therapeutic options like CAR-T cell and GLP-1 therapies offer a promising roadmap for intervention in obesity-induced cancer. Amid the growing prevalence of obesity, prioritizing these strategies and the development of combination therapies will prove fruitful as preventive options for the treatment and prevention of obesity-related cancers.
References
Less
1.
García-López MÁ, Mora A, Corrales P, Pons T, Sánchez de Diego A, Talavera Gutiérrez A, et al. DIDO is necessary for the adipogenesis that promotes diet-induced obesity. Proc Natl Acad Sci U S A 2024;121:e2300096121.
2.
Choe SS, Huh JY, Hwang IJ, Kim JI, Kim JB. Adipose tissue remodeling: its role in energy metabolism and metabolic disorders. Front Endocrinol 2016;7:30.
3.
Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature 2017;542:177—85.
4.
Lega IC, Lipscombe LL. Diabetes, obesity, and cancer—pathophysiology and clinical implications. Endocr Rev 2020;41:33—52.
5.
Williams SC. Link between obesity and cancer. Proc Natl Acad Sci U S A 2013;110:8753—4.
6.
Avgerinos KI, Spyrou N, Mantzoros CS, Dalamaga M. Obesity and cancer risk: emerging biological mechanisms and perspectives. Metabolism 2019;92:121—35.
7.
Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 2005;115:911—9.
8.
Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358:1148—59.
9.
Vázquez-Vela MEF, Torres N, Tovar AR. White adipose tissue as endocrine organ and its role in obesity. Arch Med Res 2008;39:715—28.
10.
Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct Target Ther 2021;6:263.
11.
Rakib A, Kiran S, Mandal M, Singh UP. MicroRNAs: a crossroad that connects obesity to immunity and aging. Immun Ageing 2022;19:64.
12.
Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860—7.
13.
Andersen CJ, Murphy KE, Fernandez ML. Impact of obesity and metabolic syndrome on immunity. Adv Nutr 2016;7:66—75.
14.
Annett S, Moore G, Robson T. Obesity and cancer metastasis: molecular and translational perspectives. Cancers 2020;12:3798.
15.
Parida S, Siddharth S, Gatla HR, Wu S, Wang G, Gabrielson K, et al. Gut colonization with an obesity-associated enteropathogenic microbe modulates the premetastatic niches to promote breast cancer lung and liver metastasis. Front Immunol 2023;14:1194931.
16.
Murtha JA, Liu N, Birstler J, Hanlon BM, Venkatesh M, Hanrahan LP, et al. Obesity and “obesity-related” cancers: are there body mass index cut-points?. Int J Obes 2022;46:1770—7.
17.
Argyrakopoulou G, Dalamaga M, Spyrou N, Kokkinos A. Gender differences in obesity-related cancers. Curr Obes Rep 2021;10:100—15.
18.
Sung H, Siegel RL, Torre LA, Pearson-Stuttard J, Islami F, Fedewa SA, et al. Global patterns in excess body weight and the associated cancer burden. CA Cancer J Clin 2019;69:88—112.
19.
Chan DS, Abar L, Cariolou M, Nanu N, Greenwood DC, Bandera EV, et al. World Cancer Research Fund International: continuous Update Project—systematic literature review and meta-analysis of observational cohort studies on physical activity, sedentary behavior, adiposity, and weight change and breast cancer risk. Cancer Causes Control 2019;30:1183—200.
20.
Bardou M, Barkun AN, Martel M. Obesity and colorectal cancer. Gut 2013;62:933—47.
21.
Song M, Hu FB, Spiegelman D, Chan AT, Wu K, Ogino S, et al. Adulthood weight change and risk of colorectal cancer in the nurses’ health study and health professionals follow-up study. Cancer Prev Res 2015;8:620—7.
22.
Donohoe CL, O’Farrell NJ, Doyle SL, Reynolds JV. The role of obesity in gastrointestinal cancer: evidence and opinion. Therap Adv Gastroenterol 2014;7:38—50.
23.
Martínez-Sánchez N. There and back again: leptin actions in white adipose tissue. Int J Mol Sci 2020;21:6039.
24.
Heinonen S, Jokinen R, Rissanen A, Pietiläinen KH. White adipose tissue mitochondrial metabolism in health and in obesity. Obes Rev 2020;21:e12958.
25.
AlZaim I, de Rooij LP, Sheikh BN, Börgeson E, Kalucka J. The evolving functions of the vasculature in regulating adipose tissue biology in health and obesity. Nat Rev Endocrinol 2023;19:691—707.
26.
Zhu Q, Scherer PE. Immunologic and endocrine functions of adipose tissue: implications for kidney disease. Nat Rev Nephrol 2018;14:105—20.
27.
Villarroya F, Cereijo R, Villarroya J, Giralt M. Brown adipose tissue as a secretory organ. Nat Rev Endocrinol 2017;13:26—35.
28.
Casado ME, Collado-Pérez R, Frago LM, Barrios V. Recent advances in the knowledge of the mechanisms of leptin physiology and actions in neurological and metabolic pathologies. Int J Mol Sci 2023;24:1422.
29.
Horwitz A, Birk R. Adipose tissue hyperplasia and hypertrophy in common and syndromic obesity—the case of BBS obesity. Nutrients 2023;15:3445.
30.
Vilariño-García T, Polonio-González ML, Pérez-Pérez A, Ribalta J, Arrieta F, Aguilar M, et al. Role of leptin in obesity, cardiovascular disease, and type 2 diabetes. Int J Mol Sci 2024;25:2338.
31.
Arch J, Stock M, Trayhurn P. Leptin resistance in obese humans: does it exist and what does it mean?. Int J Obes 1998;22:1159—63.
32.
Wagoner B, Hausman DB, Harris RB. Direct and indirect effects of leptin on preadipocyte proliferation and differentiation. Am J Physiol Regul Integr Comp Physiol 2006;290:R1557—64.
33.
Bocian-Jastrzębska A, Malczewska-Herman A, Kos-Kudła B. Role of leptin and adiponectin in carcinogenesis. Cancers 2023;15:4250.
34.
Dempsey LA. Leptin and mToR. Nat Immunol 2012;13:939.
35.
Liu Z, Xiao T, Liu H. Leptin signaling and its central role in energy homeostasis. Front Neurosci 2023;17:1238528.
36.
Lin T-C, Hsiao M. Leptin and cancer: updated functional roles in carcinogenesis, therapeutic niches, and developments. Int J Mol Sci 2021;22:2870.
37.
Zhou W, Guo S, Gonzalez-Perez R. Leptin pro-angiogenic signature in breast cancer is linked to IL-1 signalling. Br J Cancer 2011;104:128—37.
38.
Thornton JE, Cheung CC, Clifton DK, Steiner RA. Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology 1997;138:5063—6.
39.
Bally AP, Austin JW, Boss JM. Genetic and epigenetic regulation of PD-1 expression. J Immunol 2016;196:2431—7.
40.
Bu L, Yu G, Wu L, Mao L, Deng W, Liu J, et al. STAT3 induces immunosuppression by upregulating PD-1/PD-L1 in HNSCC. J Dent Res 2017;96:1027—34.
41.
Ling X, Arlinghaus RB. Knockdown of STAT3 expression by RNA interference inhibits the induction of breast tumors in immunocompetent mice. Cancer Res 2005;65:2532—6.
42.
Gonzalez RR, Cherfils S, Escobar M, Yoo JH, Carino C, Styer AK, et al. Leptin signaling promotes the growth of mammary tumors and increases the expression of vascular endothelial growth factor (VEGF) and its receptor type two (VEGF-R2). J Biol Chem 2006;281:26320—8.
43.
Chen Y, Liu Y, Wang Y, Li W, Wang X, Liu X, et al. Quantification of STAT3 and VEGF expression for molecular diagnosis of lymph node metastasis in breast cancer. Medicine (Baltim) 2017;96:e8488.
44.
Di Zazzo E, Polito R, Bartollino S, Nigro E, Porcile C, Bianco A, et al. Adiponectin as link factor between adipose tissue and cancer. Int J Mol Sci 2019;20:839.
45.
Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003;423:762—9.
46.
Ruan H, Dong LQ. Adiponectin signaling and function in insulin target tissues. J Mol Cell Biol 2016;8:101—9.
47.
Ye R, Wang M, Wang QA, Scherer PE. Adiponectin-mediated anti-lipotoxic effects in regenerating pancreatic islets. Endocrinology 2015;156:2019—28.
48.
Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 2007;13:332—9.
49.
Ryu J, Galan AK, Xin X, Dong F, Abdul-Ghani MA, Zhou L, et al. APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. Cell Rep 2014;7:1227—38.
50.
Nigro E, Schettino P, Polito R, Scudiero O, Monaco M, De Palma GD, et al. Adiponectin and colon cancer: evidence for inhibitory effects on viability and migration of human colorectal cell lines. Mol Cell Biochem 2018;448:125—35.
51.
Chung SJ, Nagaraju GP, Nagalingam A, Muniraj N, Kuppusamy P, Walker A, et al. ADIPOQ/adiponectin induces cytotoxic autophagy in breast cancer cells through STK11/LKB1-mediated activation of the AMPK—ULK1 axis. Autophagy 2017;13:1386—403.
52.
Kato M, Watabe K, Tsujii M, Funahashi T, Shimomura I, Takehara T. Adiponectin inhibits murine pancreatic cancer growth. Dig Dis Sci 2014;59:1192—6.
53.
Huang B, Cheng X, Wang D, Peng M, Xue Z, Da Y, et al. Adiponectin promotes pancreatic cancer progression by inhibiting apoptosis via the activation of AMPK/Sirt1/PGC-1α signaling. Oncotarget 2014;5:4732.
54.
Pham D-V, Park P-H. Adiponectin triggers breast cancer cell death via fatty acid metabolic reprogramming. J Exp Clin Cancer Res 2022;41:1—20.
55.
Shibata R, Ouchi N, Kihara S, Sato K, Funahashi T, Walsh K. Adiponectin stimulates angiogenesis in response to tissue ischemia through stimulation of amp-activated protein kinase signaling. J Biol Chem 2004;279:28670—4.
56.
Chakraborty D, Jin W, Wang J. The bifurcated role of adiponectin in colorectal cancer. Life Sci 2021;278:119524.
57.
Li C, Zhang J, Dionigi G, Liang N, Guan H, Sun H. Uncovering the connection between obesity and thyroid cancer: the therapeutic potential of adiponectin receptor agonist in the AdipoR2—ULK axis. Cell Death Dis 2024;15:708.
58.
Lee HP, Lin CY, Shih JS, Fong YC, Wang SW, Li TM, et al. Adiponectin promotes VEGF-A-dependent angiogenesis in human chondrosarcoma through PI3K, Akt, mTOR, and HIF-α pathway. Oncotarget 2015;6:36746.
59.
Varra FN, Varras M, Varra VK, Theodosis-Nobelos P. Molecular and pathophysiological relationship between obesity and chronic inflammation in the manifestation of metabolic dysfunctions and their inflammation-mediating treatment options. Mol Med Rep 2024;29:95.
60.
Kiran S, Mandal M, Rakib A, Bajwa A, Singh UP. miR-10a-3p modulates adiposity and suppresses adipose inflammation through TGF-β1/Smad3 signaling pathway. Front Immunol 2023;14:1213415.
61.
Khanna D, Khanna S, Khanna P, Kahar P, Patel BM. Obesity: a chronic low-grade inflammation and its markers. Cureus 2022;14:e22711.
62.
Mancuso P. The role of adipokines in chronic inflammation. ImmunoTargets Ther 2016;5:47—56.
63.
Maury E, Ehala-Aleksejev K, Guiot Y, Detry R, Vandenhooft A, Brichard SM. Adipokines oversecreted by omental adipose tissue in human obesity. Am J Physiol Endocrinol Metab 2007;293:E656—65.
64.
Lee D-K, Kim T, Byeon J, Park M, Kim S, Kim J, et al. REDD1 promotes obesity-induced metabolic dysfunction via atypical NF-κB activation. Nat Commun 2022;13:6303.
65.
Balistreri CR, Caruso C, Candore G. The role of adipose tissue and adipokines in obesity-related inflammatory diseases. Mediat Inflamm 2010;2010:802078.
66.
Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 2009;15:930—9.
67.
Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 2009;15:914—20.
68.
Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J, McNelis J, et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med 2012;18:1407—12.
69.
Wang Z, Aguilar EG, Luna JI, Dunai C, Khuat LT, Le CT, et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat Med 2019;25:141—51.
70.
Du W, Nair P, Johnston A, Wu P-H, Wirtz D. Cell trafficking at the intersection of the tumor—immune compartments. Annu Rev Biomed Eng 2022;24:275—305.
71.
Ino Y, Yamazaki-Itoh R, Shimada K, Iwasaki M, Kosuge T, Kanai Y, et al. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer 2013;108:914—23.
72.
Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow?. Lancet 2001;357:539—45.
73.
Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436—44.
74.
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140:883—99.
75.
Chen DS, Mellman I. Oncology meets immunology: the cancer—immunity cycle. Immunity 2013;39:1—10.
76.
Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 2009;15:103—13.
77.
Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol 2015;16:448—57.
78.
Han MS, White A, Perry RJ, Camporez JP, Hidalgo J, Shulman GI, et al. Regulation of adipose tissue inflammation by interleukin 6. Proc Natl Acad Sci U S A 2020;117:2751—60.
79.
Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 2007;7:41—51.
80.
Bollrath J, Phesse TJ, von Burstin VA, Putoczki T, Bennecke M, Bateman T, et al. GP130-mediated STAT3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 2009;15:91—102.
81.
Zhu L, Cheng X, Ding Y, Shi J, Jin H, Wang H, et al. Bone marrow-derived myofibroblasts promote colon tumorigenesis through the IL-6/JAK2/STAT3 pathway. Cancer Lett 2014;343:80—9.
82.
Hirano T. IL-6 in inflammation, autoimmunity and cancer. Int Immunol 2021;33:127—48.
83.
Xu J, Xiong G, Cao Z, Huang H, Wang T, You L, et al. PIM-1 contributes to the malignancy of pancreatic cancer and displays diagnostic and prognostic value. J Exp Clin Cancer Res 2016;35:1—12.
84.
Wei LH, Kuo ML, Chen CA, Chou CH, Lai KB, Lee CN, et al. Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene 2003;22:1517—27.
85.
Xu Q, Briggs J, Park S, Niu G, Kortylewski M, Zhang S, et al. Targeting STAT3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene 2005;24:5552—60.
86.
Xia Y, Shen S, Verma IM. NF-κB, an active player in human cancers. Cancer Immunol Res 2014;2:823—30.
87.
Wolfsberger J, Sakil HA, Zhou L, van Bree N, Baldisseri E, de Souza Ferreira S, et al. TAp73 represses NF-κB—mediated recruitment of tumor-associated macrophages in breast cancer. Proc Natl Acad Sci U S A 2021;118:e2017089118.
88.
Cao S, Pan Y, Tang J, Terker AS, Arroyo Ornelas JP, Jin GN, et al. EGFR-mediated activation of adipose tissue macrophages promotes obesity and insulin resistance. Nat Commun 2022;13:4684.
89.
Xu Y, Wang X, Liu L, Wang J, Wu J, Sun C. Role of macrophages in tumor progression and therapy. Int J Oncol 2022;60:1—19.
90.
Balkwill F. Cancer and the chemokine network. Nat Rev Cancer 2004;4:540—50.
91.
Yang C, He L, He P, Liu Y, Wang W, He Y, et al. Increased drug resistance in breast cancer by tumor-associated macrophages through IL-10/STAT3/BCL-2 signaling pathway. Med Oncol 2015;32:1—8.
92.
Mauer J, Chaurasia B, Goldau J, Vogt MC, Ruud J, Nguyen KD, et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol 2014;15:423—30.
93.
Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol 2017;10:1—12.
94.
Swanson KV, Deng M, Ting JP-Y. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 2019;19:477—89.
95.
Stienstra R, Joosten LA, Koenen T, Van Tits B, Van Diepen JA, van den Berg SA, et al. The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab 2010;12:593—605.
96.
Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 2011;17:179—88.
97.
Zaki MH, Boyd KL, Vogel P, Kastan MB, Lamkanfi M, Kanneganti TD. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 2010;32:379—91.
98.
Deng Z, Lu L, Li B, Shi X, Jin H, Hu W. The roles of inflammasomes in cancer. Front Immunol 2023;14:1195572.
99.
Pandey A, Shen C, Man SM. Inflammasomes in colitis and colorectal cancer: mechanism of action and therapies. Yale J Biol Med 2019;92:481.
100.
Lasser SA, Ozbay Kurt FG, Arkhypov I, Utikal J, Umansky V. Myeloid-derived suppressor cells in cancer and cancer therapy. Nat Rev Clin Oncol 2024;21:147—64.
101.
Tu S, Bhagat G, Cui G, Takaishi S, Kurt-Jones EA, Rickman B, et al. Overexpression of interleukin-1β induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 2008;14:408—19.
102.
Terlizzi M, Colarusso C, Popolo A, Pinto A, Sorrentino R. IL-1α and IL-1β-producing macrophages populate lung tumor lesions in mice. Oncotarget 2016;7:58181.
103.
Ahmad I, Muneer KM, Tamimi IA, Chang ME, Ata MO, Yusuf N. Thymoquinone suppresses metastasis of melanoma cells by inhibition of NLRP3 inflammasome. Toxicol Appl Pharmacol 2013;270:70—6.
104.
Kumar A, Sundaram K, Mu J, Dryden GW, Sriwastva MK, Lei C, et al. High-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance. Nat Commun 2021;12:213.
105.
Chiefari E, Mirabelli M, La Vignera S, Tanyolaç S, Foti DP, Aversa A, et al. Insulin resistance and cancer: in search for a causal link. Int J Mol Sci 2021;22:11137.
106.
Park JB, Moon GH, Cho A, Kwon M, Park J-W, Yi EC, et al. Neddylation of insulin receptor substrate acts as a bona fide regulator of insulin signaling and its implications for cancer cell migration. Cancer Gene Ther 2024;31:599—611.
107.
Liu J, Knezetic JA, Strömmer L, Permert J, Larsson Jr, Adrian TE. The intracellular mechanism of insulin resistance in pancreatic cancer patients. J Clin Endocrinol Metab 2000;85:1232—8.
108.
Kim D-S, Scherer PE. Obesity, diabetes, and increased cancer progression. Diabetes Metab J 2021;45:799—812.
109.
Savova MS, Mihaylova LV, Tews D, Wabitsch M, Georgiev MI. Targeting PI3K/AKT signaling pathway in obesity. Biomed Pharmacother 2023;159:114244.
110.
Acosta-Martinez M, Cabail MZ. The PI3K/Akt pathway in meta-inflammation. Int J Mol Sci 2022;23:15330.
111.
Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, et al. PKB/Akt mediates cell-cycle progression by phosphorylation of p27Kip1 at threonine 157 and modulation of its cellular localization. Nat Med 2002;8:1145—52.
112.
He Y, Sun MM, Zhang GG, Yang J, Chen KS, Xu WW, et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther 2021;6:425.
113.
Xu WW, Li B, Zhao JF, Yang JG, Li JQ, Tsao SW, et al. IGF2 induces CD133 expression in esophageal cancer cells to promote cancer stemness. Cancer Lett 2018;425:88—100.
114.
Takács T, László L, Tilajka Á, Novák J, Buday L, Vas V. Insulin receptor substrate 1 is a novel member of EGFR signaling in pancreatic cells. Eur J Cell Biol 2024;103:151457.
115.
Urtasun N, Vidal-Pla A, Pérez-Torras S, Mazo A. Human pancreatic cancer stem cells are sensitive to dual inhibition of IGF-IR and ErbB receptors. BMC Cancer 2015;15:1—8.
116.
Cheng J, He S, Wang M, Zhou L, Zhang Z, Feng X, et al. The caspase-3/PKCδ/Akt/VEGF-A signaling pathway mediates tumor repopulation during radiotherapy. Clin Cancer Res 2019;25:3732—43.
117.
Zhang G, Xu Z, Yu M, Gao H. Bcl-2 interacting protein 3 (BNIP3) promotes tumor growth in breast cancer under hypoxic conditions through an autophagy-dependent pathway. Bioengineered 2022;13:6280—92.
118.
Hua H, Kong Q, Yin J, Zhang J, Jiang Y. Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy. J Hematol Oncol 2020;13:1—17.
119.
Zaytseva YY, Elliott VA, Rychahou P, Mustain WC, Kim JT, Valentino J, et al. Cancer cell-associated fatty acid synthase activates endothelial cells and promotes angiogenesis in colorectal cancer. Carcinogenesis 2014;35:1341—51.
120.
Tadros S, Shukla SK, King RJ, Gunda V, Vernucci E, Abrego J, et al. De novo lipid synthesis facilitates gemcitabine resistance through endoplasmic reticulum stress in pancreatic cancer. Cancer Res 2017;77:5503—17.
121.
Fu Y, Zou T, Shen X, Nelson PJ, Li J, Wu C, et al. Lipid metabolism in cancer progression and therapeutic strategies. MedComm 2021;2:27—59.
122.
Hata M, Andriessen EM, Hata M, Diaz-Marin R, Fournier F, Crespo-Garcia S, et al. Past history of obesity triggers persistent epigenetic changes in innate immunity and exacerbates neuroinflammation. Science 2023;379:45—62.
123.
Phan AT, Goldrath AW, Glass CK. Metabolic and epigenetic coordination of T cell and macrophage immunity. Immunity 2017;46:714—29.
124.
Galván-Peña S, O’Neill LA. Metabolic reprograming in macrophage polarization. Front Immunol 2014;5:420.
125.
Jing C, Castro-Dopico T, Richoz N, Tuong ZK, Ferdinand JR, Lok LS, et al. Macrophage metabolic reprogramming presents a therapeutic target in lupus nephritis. Proc Natl Acad Sci U S A 2020;117:15160—71.
126.
Lim AR, Rathmell WK, Rathmell JC. The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy. Elife 2020;9:e55185.
127.
Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int J Obes 2009;33:54—66.
128.
He Q, Gao Z, Yin J, Zhang J, Yun Z, Ye J. Regulation of HIF-1α activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia. Am J Physiol Endocrinol Metab 2011;300:E877—85.
129.
Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, et al. NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 2008;453:807—11.
130.
Phan AT, Goldrath AW. Hypoxia-inducible factors regulate T cell metabolism and function. Mol Immunol 2015;68:527—35.
131.
Viola A, Munari F, Sánchez-Rodríguez R, Scolaro T, Castegna A. The metabolic signature of macrophage responses. Front Immunol 2019;10:1462.
132.
Wang F, Zhang S, Jeon R, Vuckovic I, Jiang X, Lerman A, et al. Interferon gamma induces reversible metabolic reprogramming of M1 macrophages to sustain cell viability and pro-inflammatory activity. EBioMedicine 2018;30:303—16.
133.
Shen H, Ojo OA, Ding H, Mullen LJ, Xing C, Hossain MI, et al. HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells. Nat Commun 2024;15:9394.
134.
Li F, Liu H, Zhang D, Ma Y, Zhu B. Metabolic plasticity and regulation of T cell exhaustion. Immunology 2022;167:482—94.
135.
Liao HJ, Chu CL, Wang SC, Lee HY, Wu CS. Increased HIF-1α expression in T cells and associated with enhanced Th17 pathway in systemic lupus erythematosus. J Formos Med Assoc 2022;121:2446—56.
136.
Wu H, Zhao X, Hochrein SM, Eckstein M, Gubert GF, Knöpper K, et al. Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming. Nat Commun 2023;14:6858.
137.
Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Investig 2013;123:3664—71.
138.
Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu M, et al. Modulation of HIF-1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 2000;60:1541—5.
139.
Farooq M, Bhat GR, Besina S, Thakur N, Zahoor S, Rather RA, et al. Expression of HIF-1α and markers of angiogenesis and metabolic adaptation in molecular subtypes of breast cancer. Transl Med Commun 2023;8:2.
140.
Denise Tiburcio P, Choi H, Eric Huang L. Complex role of HIF in cancer: the known, the unknown, and the unexpected. Hypoxia 2014;2:59—70.
141.
Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003;3:721—32.
142.
Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013;19:1423—37.
143.
McAllister SS, Weinberg RA. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol 2014;16:717—27.
144.
Bakhoum SF, Ngo B, Laughney AM, Cavallo JA, Murphy CJ, Ly P, et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 2018;553:467—72.
145.
Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther 2020;5:28.
146.
Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 2011;17:1498—503.
147.
Andarawewa KL, Motrescu ER, Chenard M-P, Gansmuller A, Stoll I, Tomasetto C, et al. Stromelysin-3 is a potent negative regulator of adipogenesis participating to cancer cell—adipocyte interaction/crosstalk at the tumor invasive front. Cancer Res 2005;65:10862—71.
148.
Trayhurn P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev 2013;93:1—21.
149.
Sultana R, Kataki AC, Borthakur BB, Basumatary TK, Bose S. Imbalance in leptin-adiponectin levels and leptin receptor expression as chief contributors to triple negative breast cancer progression in Northeast India. Gene 2017;621:51—8.
150.
Barone I, Giordano C, Bonofiglio D, Andò S, Catalano S. The weight of obesity in breast cancer progression and metastasis: clinical and molecular perspectives. Semin Cancer Biol 2020;60:274—84.
151.
Alshaker H, Krell J, Frampton AE, Waxman J, Blyuss O, Zaikin A, et al. Leptin induces upregulation of sphingosine kinase 1 in oestrogen receptor-negative breast cancer via Src family kinase-mediated, janus kinase 2-independent pathway. Breast Cancer Res 2014;16:1—15.
152.
Wu Q, Li B, Li Z, Li J, Sun S, Sun S. Cancer-associated adipocytes: key players in breast cancer progression. J Hematol Oncol 2019;12:1—15.
153.
Arendt LM, McCready J, Keller PJ, Baker DD, Naber SP, Seewaldt V, et al. Obesity promotes breast cancer by CCL2-mediated macrophage recruitment and angiogenesis. Cancer Res 2013;73:6080—93.
154.
Tsuyada A, Chow A, Wu J, Somlo G, Chu P, Loera S, et al. CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer Res 2012;72:2768—79.
155.
D’Esposito V, Liguoro D, Ambrosio MR, Collina F, Cantile M, Spinelli R, et al. Adipose microenvironment promotes triple negative breast cancer cell invasiveness and dissemination by producing CCL5. Oncotarget 2016;7:24495.
156.
Bergmann J, Müller M, Baumann N, Reichert M, Heneweer C, Bolik J, et al. IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice. Hepatology 2017;65:89—103.
157.
Hagemann T, Wilson J, Kulbe H, Li NF, Leinster DA, Charles K, et al. Macrophages induce invasiveness of epithelial cancer cells via NF-κB and JNK. J Immunol 2005;175:1197—205.
158.
de Martel C, Georges D, Bray F, Ferlay J, Clifford GM. Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis. Lancet Global Health 2020;8:e180—90.
159.
Davis CD. The gut microbiome and its role in obesity. Nutr Today 2016;51:167—74.
160.
Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027—31.
161.
DiBaise JK, Zhang H, Crowell MD, Krajmalnik-Brown R, Decker GA, Rittmann BE. Gut microbiota and its possible relationship with obesity. Mayo Clin Proc 2008;83:460—9.
162.
Liu R, Hong J, Xu X, Feng Q, Zhang D, Gu Y, et al. Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention. Nat Med 2017;23:859—68.
163.
Heianza Y, Sun D, Smith SR, Bray GA, Sacks FM, Qi L. Changes in gut microbiota—related metabolites and long-term successful weight loss in response to weight-loss diets: the POUNDS Lost trial. Diabetes Care 2018;41:413—9.
164.
Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A 2013;110:9066—71.
165.
Gauffin Cano P, Santacruz A, Moya Á, Sanz Y. Bacteroides uniformis CECT 7771 ameliorates metabolic and immunological dysfunction in mice with high-fat-diet induced obesity. PLoS One 2012;7:e41079.
166.
Zur Hausen H. The search for infectious causes of human cancers: where and why. Virology 2009;392:1—10.
167.
Raza MH, Gul K, Arshad A, Riaz N, Waheed U, Rauf A, et al. Microbiota in cancer development and treatment. J Cancer Res Clin Oncol 2019;145:49—63.
168.
Sheflin AM, Whitney AK, Weir TL. Cancer-promoting effects of microbial dysbiosis. Curr Oncol Rep 2014;16:1—9.
169.
Arthur JC, Perez-Chanona E, Mühlbauer M, Tomkovich S, Uronis JM, Fan TJ, et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 2012;338:120—3.
170.
Bonnet M, Buc E, Sauvanet P, Darcha C, Dubois D, Pereira B, et al. Colonization of the human gut by E. coli and colorectal cancer risk. Clin Cancer Res 2014;20:859—67.
171.
Behary J, Amorim N, Jiang X-T, Raposo A, Gong L, McGovern E, et al. Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma. Nat Commun 2021;12:187.
172.
Dyck L, Lynch L. Cancer, obesity and immunometabolism—Connecting the dots. Cancer Lett 2018;417:11—20.
173.
Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 2014;513:559—63.
174.
Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 2007;109:3812—9.
175.
Gu J, Zhou J, Chen Q, Xu X, Gao J, Li X, et al. Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells. Cell Rep 2022;39:110986.
176.
Feng Q, Liu Z, Yu X, Huang T, Chen J, Wang J, et al. Lactate increases stemness of CD8+ T cells to augment anti-tumor immunity. Nat Commun 2022;13:4981.
177.
Wu JY, Huang TW, Hsieh YT, Wang YF, Yen CC, Lee GL, et al. Cancer-derived succinate promotes macrophage polarization and cancer metastasis via succinate receptor. Mol Cell 2020;77:213—27.e5.
178.
Elia I, Rowe JH, Johnson S, Joshi S, Notarangelo G, Kurmi K, et al. Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8+ T cells. Cell Metab 2022;34:1137—50.e6.
179.
Su YH, Wu YZ, Ann DK, Chen JL, Kuo CY. Obesity promotes radioresistance through SERPINE1-mediated aggressiveness and DNA repair of triple-negative breast cancer. Cell Death Dis 2023;14:53.
180.
Wang LS, Murphy CT, Ruth K, Zaorsky NG, Smaldone MC, Sobczak ML, et al. Impact of obesity on outcomes after definitive dose-escalated intensity-modulated radiotherapy for localized prostate cancer. Cancer 2015;121:3010—7.
181.
Ross KH, Gogineni K, Subhedar PD, Lin JY, McCullough LE. Obesity and cancer treatment efficacy: existing challenges and opportunities. Cancer 2019;125:1588—92.
182.
Harbeck N, Schmitt M, Kates RE, Kiechle M, Zemzoum I, Jänicke F, et al. Clinical utility of urokinase-type plasminogen activator and plasminogen activator inhibitor—1 determination in primary breast cancer tissue for individualized therapy concepts. Clin Breast Cancer 2002;3:196—200.
183.
Harrigan M, Cartmel B, Loftfield E, Sanft T, Chagpar AB, Zhou Y, et al. Randomized trial comparing telephone versus in-person weight loss counseling on body composition and circulating biomarkers in women treated for breast cancer: the lifestyle, exercise, and nutrition (LEAN) study. J Clin Oncol 2016;34:669—76.
184.
Campbell KL, Winters-Stone K, Wiskemann J, May AM, Schwartz AL, Courneya KS, et al. Exercise guidelines for cancer survivors: consensus statement from international multidisciplinary roundtable. Med Sci Sports Exerc 2019;51:2375.
185.
Huang P, Fan X, Yu H, Zhang K, Li H, Wang Y, et al. Glucose metabolic reprogramming and its therapeutic potential in obesity-associated endometrial cancer. J Transl Med 2023;21:94.
186.
Saadatian-Elahi M, Norat T, Goudable J, Riboli E. Biomarkers of dietary fatty acid intake and the risk of breast cancer: a meta-analysis. Int J Cancer 2004;111:584—91.
187.
Zheng JS, Hu XJ, Zhao YM, Yang J, Li D. Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies. BMJ 2013;346:f3706.
188.
Boyd N, Stone J, Vogt K, Connelly B, Martin L, Minkin S. Dietary fat and breast cancer risk revisited: a meta-analysis of the published literature. Br J Cancer 2003;89:1672—85.
189.
Lee-Rueckert M, Canyelles M, Tondo M, Rotllan N, Kovanen PT, Llorente-Cortes V, et al. Obesity-induced changes in cancer cells and their microenvironment: mechanisms and therapeutic perspectives to manage dysregulated lipid metabolism. InSemin Cancer Biol 2023;93:36—51.
190.
Fernández LP, Gomez de Cedron M, Ramirez de Molina A. Alterations of lipid metabolism in cancer: implications in prognosis and treatment. Front Oncol 2020;10:577420.
191.
Cejuela M, Martin-Castillo B, Menendez JA, Pernas S. Metformin and breast cancer: where are we now?. Int J Mol Sci 2022;23:2705.
192.
Zhang K, Bai P, Dai H, Deng Z. Metformin and risk of cancer among patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Prim Care Diabetes 2021;15:52—8.
193.
El-Attar AA, Ibrahim OM, Alhassanin SA, Essa ES, Mostafa TM. Effect of metformin as an adjuvant therapy to letrozole on estradiol and other biomarkers involved in the pathogenesis of breast cancer in overweight and obese postmenopausal women: a pilot study. Eur J Clin Pharmacol 2023;79:299—309.
194.
Bayraktar S, Hernadez-Aya LF, Lei X, Meric-Bernstam F, Litton JK, Hsu L, et al. Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer. Cancer 2012;118:1202—11.
195.
Ballinger A. Orlistat in the treatment of obesity. Expet Opin Pharmacother 2000;1:841—7.
196.
Kwon YJ, Kwon GE, Lee HS, Choi MH, Lee JW. The effect of orlistat on sterol metabolism in obese patients. Front Endocrinol 2022;13:824269.
197.
Carvalho MA, Zecchin KG, Seguin F, Bastos DC, Agostini M, Rangel ALC, et al. Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model. Int J Cancer 2008;123:2557—65.
198.
Schcolnik-Cabrera A, Chávez-Blanco A, Domínguez-Gómez G, Taja-Chayeb L, Morales-Barcenas R, Trejo-Becerril C, et al. Orlistat as a FASN inhibitor and multitargeted agent for cancer therapy. Expet Opin Invest Drugs 2018;27:475—89.
199.
Koppel N, Maini Rekdal V, Balskus EP. Chemical transformation of xenobiotics by the human gut microbiota. Science 2017;356:eaag2770.
200.
Yang Q, Wang B, Zheng Q, Li H, Meng X, Zhou F, et al. A review of gut microbiota-derived metabolites in tumor progression and cancer therapy. Adv Sci (Weinh) 2023;10:2207366.
201.
Spencer CN, McQuade JL, Gopalakrishnan V, McCulloch JA, Vetizou M, Cogdill AP, et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science 2021;374:1632—40.
202.
Drucker DJ. The benefits of GLP-1 drugs beyond obesity. Science 2024;385:258—60.
203.
Tong G, Peng T, Chen Y, Sha L, Dai H, Xiang Y, et al. Effects of GLP-1 receptor agonists on biological behavior of colorectal cancer cells by regulating PI3K/AKT/mTOR signaling pathway. Front Pharmacol 2022;13:901559.
204.
Nomiyama T, Kawanami T, Irie S, Hamaguchi Y, Terawaki Y, Murase K, et al. Exendin-4, a GLP-1 receptor agonist, attenuates prostate cancer growth. Diabetes 2014;63:3891—905.
205.
Alanteet AA, Attia HA, Shaheen S, Alfayez M, Alshanawani B. Anti-proliferative activity of glucagon-like peptide-1 receptor agonist on obesity-associated breast cancer: the impact on modulating adi-pokines’ expression in adipocytes and cancer cells. Dose Response 2021;19:1559325821995651.
206.
MacKay M, Afshinnekoo E, Rub J, Hassan C, Khunte M, Baskaran N, et al. The therapeutic landscape for cells engineered with chimeric antigen receptors. Nat Biotechnol 2020;38:233—44.
207.
Elsallab M, Levine BL, Wayne AS, Abou-El-Enein M. CAR T-cell product performance in haematological malignancies before and after marketing authorisation. Lancet Oncol 2020;21:e104—16.
208.
Wagner DL, Fritsche E, Pulsipher MA, Ahmed N, Hamieh M, Hegde M, et al. Immunogenicity of CAR T cells in cancer therapy. Nat Rev Clin Oncol 2021;18:379—93.
209.
Aghajanian H, Kimura T, Rurik JG, Hancock AS, Leibowitz MS, Li L, et al. Targeting cardiac fibrosis with engineered T cells. Nature 2019;573:430—3.
210.
Amor C, Feucht J, Leibold J, Ho Y-J, Zhu C, Alonso-Curbelo D, et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature 2020;583:127—32.
211.
Beier UH, Baker DJ, Baur JA. Thermogenic T cells: a cell therapy for obesity?. Am J Physiol Cell Physiol 2022;322:C1085—94.
Appendix
Less
Year 2025 volume 15 Issue 6
PDF
66
38
Cite this Article
BibTeX
Article Info
doi: 10.1016/j.apsb.2025.04.029
  • Receive Date：2025-02-03
  • Online Date：2026-04-03
Article Data
Affiliations
History
  • Received：2025-02-03
  • Revised：2025-04-24
  • Accepted：2025-04-28
Affiliations
    Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN 38103, USA

Corresponding:

* Corresponding author.
References
Share
https://castjournals.cast.org.cn/joweb/apsb/EN/10.1016/j.apsb.2025.04.029
Share to
QR

Scan QR to access full text

Cite this article
BibTeX
Citations
表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
关闭全屏
  • BibTeX
  • EndNote
  • RefWorks
  • TxT
Links
Articles
Latest Articles
Most Read
Collections
Updates
Events
News
Multimedia
About
About Us
Contact
No. 86 Xueyuan South Road, Haidian District, Beijing
100081
010-62199257
qkjq@cast.org.cn

Copyright © 2025 China Association for Science and Technology. All rights reserved. For all open access content, the relevant licensing terms apply.
Sponsored by the Office of the Leading Group for Cybersecurity and Informatization of CAST, and supported by Science and Technology Review Publishing House