They reported a significant increase in the risk of mortality from colon, rectal, postmenopausal breast, ovarian, cervical, and prostate cancer and leukemia in overweight and obese individuals from this population With the prevalence of childhood obesity increasing dramatically worldwide, an important question is whether obesity in childhood leads to an increased risk of developing cancer as an adult.
The results were variable for breast cancer with some studies showing no association between BMI and risk and others showing an inverse risk. An increased risk of colon cancer mortality and kidney cancer was associated with increased BMI during adolescence.
Type 2 diabetes has also been linked to an increased risk of developing and dying from cancer in multiple studies. Early studies found an association between diabetes and cancer of the pancreas and liver. More recent studies reported an increased incidence of endometrial, breast, colorectal, bladder, and kidney cancers, as well as non-Hodgkin lymphoma The CPS II study examined the association between diabetes and cancer mortality in , men and , women in the U.
After 16 years of follow-up, they found a significantly increased risk of mortality from bladder, colon, pancreatic, and liver cancer in men and from pancreatic, colon, and breast cancer in women with diabetes After 26 years of follow-up, in addition to finding an increased risk of mortality from bladder, pancreatic, breast, liver, and colon cancers, they reported that diabetes was associated with an increased risk of oral and pharyngeal cancer, breast cancer in men, and endometrial cancer in women The association of diabetes and cancer in these studies is independent of BMI 14 , In the CPS II study, an inverse association was found between diabetes and prostate cancer mortality.
Other studies have demonstrated that men with diabetes were more likely to present with high-grade prostate cancer The inverse association between T2D and prostate cancer has previously been reported, and the reasons for it are not well understood, but it may be related to changes in hormone levels, differences in prostate-specific antigen screening, or circulating levels in those with diabetes, an effect of diabetes medications or vascular changes in the prostate. In addition to an increase in incidence and mortality, diabetes is associated with an increase in distant metastases in breast cancer patients, as well as a greater chance of cancer recurrence in breast, lung, and colorectal cancer patients 17 — Studies have demonstrated that those with diabetes who develop cancer have higher all-cause mortality.
Whether diabetes truly increases cancer-specific mortality or whether the increase in mortality observed in those with cancer and diabetes is due to the increased overall mortality associated with diabetes remains uncertain 15 , 16 , Furthermore, there may be differences in health care—seeking behavior and health screening in individuals with diabetes affecting the incidence rates of cancer and the stage of cancer at the time of diagnosis in those with diabetes.
There may be differences in cancer treatment choices made by physicians and patients with diabetes that may affect their prognosis. There may also be an effect of diabetes medications on cancer progression that could positively or negatively affect outcome.
There are fewer studies on the links between type 1 diabetes and cancer. Many of these epidemiological studies use age cutoffs or insulin use to define type 1 diabetes. The age cutoffs vary between diabetes diagnosed under the age of 18 years and diabetes diagnosed under the age of 40 years.
Therefore, many of these studies are likely to also include individuals with T2D. The results of these studies are very mixed depending on the study design cohort vs. But many other studies report no association, and individual studies with positive results report different findings.
Therefore, it remains unclear whether type 1 diabetes is associated with any increase in cancer incidence or mortality The metabolic syndrome is found in the continuum between obesity and type 2 diabetes. It has many different definitions, but most definitions include increased waist circumference, dyslipidemia high triglycerides and low HDL cholesterol , hypertension, and impaired fasting glucose in their criteria for diagnosis A number of studies have recently been published from the Metabolic Syndrome and Cancer Project Me-Can cohort in Austria, Sweden, and Norway, examining the association between the metabolic syndrome as a whole and its individual components on the risk of cancer From this cohort, the investigators have reported that higher glucose levels were associated with an increased risk of liver, gallbladder, respiratory, and thyroid cancer and multiple myeloma in men, and pancreas, bladder, endometrial, cervical, and stomach cancer in women Additionally, they have reported an increased risk of bladder cancer in men and postmenopausal breast cancer in women with a higher composite metabolic syndrome score 24 , They have reported that triglycerides are associated with an increased risk of colon, respiratory tract, kidney, and thyroid cancers and melanoma in men and respiratory, cervical, and nonmelanoma skin cancers in women Hypertension was also associated with an increased risk of multiple cancers in men and women in this cohort These factors may contribute to the development of hypertension, dyslipidemia, and hyperglycemia, as well as cancer.
Therefore, the association between elements of the metabolic syndrome and cancer may reflect common underlying etiologies between these conditions.
Insulin resistance is common in obese individuals and is believed to be a key factor in the pathogenesis of the metabolic syndrome. Insulin is synthesized as proinsulin. C-peptide is cleaved from the proinsulin molecule to form mature insulin. C-peptide is commonly used as a biomarker for insulin secretion. Increased insulin secretion from the pancreas into the portal circulation may lead to increased hepatic growth hormone—mediated synthesis of IGF High-normal levels of insulin, C-peptide, and IGF-1 have been associated with an increased risk of certain cancers in epidemiological studies.
In women with early-stage breast cancer, those with insulin levels in the highest quartile of the normal range had the poorest survival, and among patients with type 2 diabetes fasting C-peptide has been associated with increased breast cancer mortality 28 , The European Prospective Investigation into Cancer and Nutrition EPIC investigators reported an increased risk of colorectal cancer in those with C-peptide levels in the highest versus lowest quartile An analysis of 12 prospective studies reported that men with serum IGF-1 levels in the highest quintile of the population range had an odds ratio of 1.
Other meta-analyses have reported a similar increase in prostate cancer risk as well as colorectal cancer and premenopausal breast cancer in those with IGF-1 levels in the highest quartile of the population range 32 , Studies have not found any association between IGF-1 levels and lung cancer 32 , and not all studies have reported positive findings.
Animal and in vitro studies have examined the role of insulin and IGF-1 as well as their respective receptors and signaling pathways in tumor growth and metastasis in isolation from other factors that may contribute to cancer risk.
In vitro, both IGF-1 and insulin stimulate the proliferation of tumor cells lines. In vivo animal studies have demonstrated that endogenous hyperinsulinemia increases the growth and metastasis of mammary tumors 35 , 36 , while increased circulating IGF-1 levels increased the growth and metastases of colon cancers in mice Subsequently, inhibitors of IGF-1 and the IGF-1R were developed to treat tumors that lack targeted therapies, such as triple-negative breast cancers and hormone therapy—resistant breast cancers.
These tumors have been shown to express high levels of the IGF-1R Recent evidence suggests that the insulin receptor IR is capable of conferring resistance to IGF-1R—targeted therapy in tumor cells and therefore may also be an important target Many tumors are known to overexpress the IR, and some studies have reported that higher expression of the IR is associated with a worse prognosis With recent developments in technology and the ability to extract and amplify RNA from formalin-fixed tissues, two studies have demonstrated that the ratio of IR-A to IR-B is higher in more aggressive breast cancers 41 , Therefore, in insulin-resistant, hyperinsulinemic individuals insulin may be signaling through the IR-A and thus lead to increased tumor growth.
Glucose is known to be a critical nutrient for proliferating cells. Many years ago, Otto Warburg proposed that cancer cells develop an increased ability to utilize glucose for anaerobic glycolysis—a phenomenon that is exploited today in detecting tumors by fluorodeoxyglucose-labeled positron emission tomography imaging for cancers 43 , The upregulation of anaerobic glycolysis shunts glycolytic intermediates into the pentose phosphate pathway, leading to the production of precursors for fatty acids, amino acids, and nucleic acids In a mouse model of hyperglycemia, more aggressive skin and mammary tumors are found compared with the normoglycemic mouse These mice also have hyperinsulinemia and increased inflammatory markers; therefore, the hyperglycemia alone may not be driving tumor growth.
In another animal model with alloxan-induced hyperglycemia and insulin deficiency, no increase in carcinogen-induced mammary tumors was observed Therefore, once tumor cells have adequate glucose to meet their demands, it is unclear that hyperglycemia alone will further stimulate their growth. Some epidemiological studies including the Vasterbotten Intervention Project of northern Sweden have reported an increased risk of pancreatic, endometrial, and urinary cancers in those with the highest quartile versus the bottom quartile of fasting glucose levels In the Me-Can project, significant increases RR 1.
However, reducing hyperglycemia in individuals with type 2 diabetes has not been clearly associated with a decreased risk of developing cancer 49 , Therefore, in obesity, diabetes, and the metabolic syndrome glucose may be playing a role in concert with hyperinsulinemia, inflammation, adipokines, and altered estrogen levels.
Endometrial cancer was one of the first cancers associated with obesity and is strongly dependent on estrogen stimulation. Similarly, increased endogenous estrogen levels have been reported to increase the risk of postmenopausal breast cancer twofold Obesity has long been known to be associated with increased circulating estrogen levels, due to increased aromatase activity in adipose tissue. In addition, insulin-resistant women have suppressed hepatic production of sex hormone—binding globulin, leading to increased levels of free estrogen AMPK is an important nutrient-sensing molecule in cells and is a negative regulator of insulin-stimulated signaling pathways.
These mechanisms are thought to tie together the increased estrogen-stimulated breast cancer growth that occurs in obesity. The estrogen receptor ER and IGF-1R are known to have significant cross-talk in the normal mammary gland and breast cancer. Additionally, in ER-positive human breast cancer cells IGF-1R has been shown to mediate resistance to antiestrogen therapies In one such study, despite the successful lowering of IGF-1 levels, using the somatostatin analog octreotide, no improvement in survival was found in the octreotide- and tamoxifen-treated group compared with tamoxifen treatment alone As hormone-resistant tumors have been shown to express higher levels of the IR, particularly IR-A, blocking both the IR and IGF-1R using a tyrosine kinase inhibitor may be beneficial in treating tamoxifen-resistant breast cancers Some cross-talk between the ER and IR also occur.
However, there is still much to be learned about the interactions between insulin, aromatase, and estrogen in cancer development and growth. Two of the defining criteria for the metabolic syndrome are low HDL cholesterol and increased triglycerides; these lipid abnormalities are commonly seen in insulin-resistant patients and those with type 2 diabetes.
The Me-Can study has reported that men and women with elevated triglycerides have an increased risk of overall cancer RR 1. Low HDL cholesterol has also been associated with an increased risk of breast cancer. Women with a high LDL—to—HDL cholesterol ratio have higher free estradiol levels, which may be a mechanism through which this lipid profile increases the risk of breast cancer Some studies suggest that statins may reduce the risk of developing cancer.
However, they did report a decrease in the risk of melanoma, endometrial cancer, and non-Hodgkin lymphoma The mechanisms that may link cholesterol to cancer growth have been most extensively studied in prostate cancer. Prostate cells are capable of synthesizing cholesterol, while most of the cholesterol located in the cell membrane is derived from circulating cholesterol Such short-term feeding regiments do not affect tumor initiation of orthotopically implanted mouse breast cancer cells [ 20 ].
This was evident even though the HFD exposure was maintained for seven weeks until the end of the experiment [ 20 ]. Thus, an established state of obesity and obesity-induced physiological changes are required for affecting tumor outcomes.
Short feeding periods should thus be avoided [ 20 , 21 ], and the establishment of obesity-induced clinical and biochemical features should be verified before tumor challenge. A key question in the field is to what degree reversing the obese phenotype affects tumor outcomes. With the DIO models, a number of studies have utilized dietary switch experiments.
Five weeks low-fat diet LFD feeding after established DIO was enough to reverse obesity-induced inflammation and breast tumor formation [ 20 ]. A comparison between a short-term and a long-term dietary switch demonstrated that exposing the DIO mice to LFD for seven days was not sufficient to affect the obesity-induced effects on intestinal stem cells, while the phenotype was reversed after four weeks LFD [ 12 ].
Taken together, these observations indicate that obesity-induced effects on tumor outcomes are reversible. The interaction between obesity and cancer could be governed by genetic as well as non-genetic alterations. Currently there is limited evidence for a genetic component linking obesity to cancer initiation. This likely reflects the difficulty of obtaining body mass index BMI measures as well as incorporation of potential cachexia-induced weight loss in large consortia databanks containing patient genomic status.
Instead, an expanding number of cellular processes have been suggested to govern obesity effects in malignancies. Adipose tissue is an active endocrine organ which secretes adipokines, chemokines and constituents of the extracellular matrix ECM [ 22 ]. In response to increased demand of triglyceride storage, adipose tissue undergoes hyperplasia and hypertrophy in the transition from a lean to an obese state.
These architectural adjustments induce changes in the adipocyte secretome and released metabolites which contribute to an altered micro- and macroenvironment in the obese compared to the lean setting [ 22 ]. Adipokines have long been hypothesized to provide a mechanistic link between cancer and obesity.
Leptin is secreted in proportion to adipose volume and total fat mass [ 23 , 24 ]. By signaling through leptin receptors in the central nervous system CNS , leptin regulates energy balance by functioning as a satiety signal, which reduces food intake and increases energy expenditure. In obese individuals, however, the satiety-promoting effects of leptin are impaired by the induction of cellular leptin resistance [ 25 ]. Along with decreasing energy expenditure and promoting obesity, hyperleptinemia has pronounced peripheral effects on cancer cells discussed below and the tumor microenvironment including immune cells — particularly the T-helper 1 cells [ 26 , 27 ].
Leptin and the leptin receptors have been identified in malignant cells of various origins including hepatocellular cancer, colorectal cancer, thyroid cancer and breast cancer [ 28 ]. Overall, leptin has been assigned a pro-tumorigenic function.
In breast cancer, leptin and the leptin receptor are overexpressed in primary and metastatic lesions compared to non-cancer tissues [ 29 , 30 ]. In cell culture, leptin acts as a growth-stimulating agent for breast cancer cells, promoting proliferation and repressing apoptotic pathways [ 31 ]. A similar role has been reported in colon cancer, where leptin acts as a growth factor at stages correlating with tumor initiation in a murine model [ 32 ]. Moreover, leptin treatment of cancer cells modulates processes such as metabolic reprogramming [ 33 ] and reactive oxygen species production [ 34 , 35 ].
In females, higher leptin concentrations are associated with increased risk, as well as grade, stage and recurrence of breast cancer [ 36 , 37 ]. In the obese context, leptin has been linked to tumor-initiating cell survival and obesity-associated triple negative breast cancer development by promoting cancer stem cell enrichment and epithelial-to-mesenchymal transition EMT [ 38 , 39 ].
Leptin governs the stem cell phenotype through epigenetic mechanisms controlled by a leptin-STAT3-G9a histone methyltransferase signaling axis [ 40 ]. In sum, several studies support a role of leptin in tumorigenesis which favors cell growth and survival by increasing proliferation and decreasing apoptosis, regulating inflammatory processes, modulating cancer stem cell properties as well as metabolic activity.
This suggests that peripheral cancer cell leptin signaling is required for obesity-dependent effects of MMTV-Wnt1 cells. Taken together, these experiments illustrate that leptin does not solely account for obesity-accelerated tumor progression for all cancer types.
In addition to leptin, deregulation of the adipokine adiponectin has been implicated in driving tumor progression in several obesity-associated cancer types, including colon, liver, breast, renal, gastric, esophageal, pancreatic and endometrial cancer [ 46 ].
Circulating adiponectin levels negatively correlate with body fat mass and adiposity. This hormone acts as an insulin sensitizer of tissues such as liver and muscle, as well as balancing glucose and lipid metabolism [ 47 , 48 ]. Adiponectin mediates its effects through its classical and ubiquitously expressed receptors AdipoR1 and AdipoR2, and the non-classical receptor T-Cadherin [ 49 , 50 ].
In addition, adiponectin also potently stimulates ceramidase activity through AdipoR1 and AdipoR2, and thereby enhance pro-apoptotic ceramide catabolism leading to formation of its downstream anti-apoptotic metabolite sphingosinephosphate S1P [ 52 ].
Epidemiological studies have linked low serum adiponectin levels to an increased risk of colon cancer [ 54 ]. This is consistent with in vivo studies that have demonstrated promotion of intestinal carcinogenesis by lack of adiponectin in both genetic and chemically induced cancer models [ 55 ].
Another study also found a repressing role on colonic epithelial proliferation in a chemically induced cancer model. However, this effect was specific to adiponectin-deficient mice fed an HFD. No effect was observed for adiponectin-deficient mice fed a basal diet compared with wild-type mice [ 56 ]. Likewise, adiponectin protects against liver tumorigenesis in nude mice, and its reduced expression is associated with poor prognosis in obese patients with hepatocellular carcinoma [ 57 ].
These findings were supported by studies using an orthotopic liver tumor nude mouse model, which showed inhibited tumor growth and lower incidence of lung metastasis in adiponectin treated mice [ 58 ]. Furthermore, adiponectin treatment suppressed hepatic stellate cell activation and macrophage infiltration [ 58 ]. In addition to anti-inflammatory and growth-suppressing effects, adiponectin has been shown to constrain tumor growth by inhibiting tumor vasculature [ 58 , 59 ].
Thus, a general role of adiponectin in tumor angiogenesis remains to be defined. Resistin is mainly expressed in adipocytes and immune cells [ 63 ] and has been reported to promote breast tumorigenesis in vitro and in vivo [ 64 ].
In a DIO mouse model, its expression and secretion are significantly increased in mammary adipose tissue. Adipose tissue is a major component of the breast. The cytokine secretion from adipocytes is affected by menopausal status, which could link to the paradoxical association of obesity and pre- and post-menopausal breast cancer risk.
After menopause, a high estrone E1 : estradiol E2 ratio in tissue and circulation was observed in both mouse models and human patients. In summary, accumulating evidence obtained by a variation of model systems supports an important role of adipokines in tumor progression.
The fatless mouse model mimics generalized lipodystrophy and is characterized by the majority of the comorbidities associated with obesity including insulin resistance and ectopic lipid accumulation but lack the secretion of adipokines. Overall, more model-specific research is needed to fully understand the link between obesity, cancer and adipokines.
Increased serum concentrations of insulin and IGF-1 are frequently detected in obese individuals. Both factors have been proposed to serve as key hormonal mediators mechanistically linking obesity and cancer [ 67 ]. Expression of the respective receptors is detected on cancer cells of different origins and several cancers are driven by insulin and IGF-1 in vitro [ 69 — 73 ].
A positive association is also detected between insulin and obesity-prone cancers in terms of tumor growth in rodents as well as stage at diagnosis and death in humans reviewed in [ 74 ].
Moreover, case-control and cohort studies have demonstrated that individuals with higher levels of insulin or C-peptide indirect insulin measure are at higher risk for developing obesity-related cancers including breast, endometrial, colorectal, pancreatic, liver, ovarian and gastric cancers compared to individuals with low levels of these factors reviewed in [ 75 ].
In addition to a mitogenic function in carcinogenesis, insulin has been suggested to effect metabolic processes in cancer cells. Insulin increases mitochondrial glucose oxidation and augments cell division in cells derived from obesity-associated tumors, including colon, breast and prostate cancer. In contrast, no alteration of substrate preference is observed in obesity-independent cell lines melanoma, lymphoma and small cell lung cancer [ 76 ].
In studies using an insulin lowering agent, dapagliflozin, a sodium-glucose cotransporter-2 SGLT2 inhibitor, reduction in insulin levels slowed obesity-accelerated tumor growth of both syngeneic breast and colon cancer models. The authors concluded that this effect is not due to increases in ketosis or to a direct effect on tumor cell division, but rather is mediated by the reversal of hyperinsulinemia, resulting in diminished tumor glucose uptake and oxidation [ 77 ].
At present, several human clinical trials are investigating insulin-lowering treatments as adjuvants to cancer treatments reviewed in [ 74 ]. Tumors are composed of cancer cells along with their connected stromal compartment. The tumor stroma consists of vasculature, non-transformed cell types including fibroblasts and immune cells, as well as structural elements such as the basement membrane and ECM.
The stromal compartment is an integral part of cancer initiation, growth and progression reviewed in [ 78 ] and a number of studies have begun to delineate how obesity-induced stromal alterations influence tumor growth.
Adipose tissue in obese individuals is among others characterized by an altered biochemical as well as biophysical microenvironment [ 79 ]. For instance, adipocytes in expanding adipose tissue deposit altered amounts of ECM components causing ECM remodeling and changes in tissue stiffness. Furthermore, obese tissue ECM contains more aligned fibers and higher interstitial pressure reviewed in [ 80 ]. These changes are not restricted to subcutaneous and visceral fat but occur also in other fat depots.
For instance, the homeostasis of mammary fat is disrupted in obese mouse models, as this tissue is enriched in myofibroblasts and stiffness-promoting ECM components [ 81 ]. These alterations, which are characteristic features of desmoplasia and fibrosis, can promote the tumorigenic potential of premalignant human breast epithelial cells [ 81 ].
Interestingly, it was suggested that the exacerbated desmoplasia and augmented tumor growth was a result of crosstalk between adipocytes, tumor-associated neutrophils and pancreatic stellate cells [ 42 ]. Grohmann et al. Moreover, single ECM components that are deregulated in the obese state have been demonstrated to promote tumorigenesis. One example is collagen VI, which is abundantly produced and secreted by adipocytes. A recent study applying proteomic analysis of ECM isolated by in vitro decellularization methods identified collagen VI to be up-regulated in murine obese mammary gland and breast tumor tissues relative to lean tissues [ 83 ].
Adipocyte-derived collagen VI has previously been demonstrated to be important for early mammary tumor progression, as collagen knockout mice in the background of the MMTV-PyMT mammary cancer model have reduced rates of early hyperplasia and primary tumor growth [ 84 ]. In vitro studies point to that full-length collagen VI is a driver of triple negative breast cancer cell adhesion, migration and invasion [ 83 ].
Furthermore, obesity-associated ECM remodeling has been shown to regulate the properties of immune cells. Culturing of bone-marrow-derived macrophages on ECM isolated from obese mice induce proliferation, changes the morphology, impact polarization as well as promote angiogenic traits compared to cells cultured on top of ECM derived from lean mice [ 85 ].
Hermano et al. In the obese environment, they showed that heparanase stimulates macrophage production of inflammatory mediators that induce aromatase, a rate-limiting enzyme in estrogen synthesis [ 86 ]. Metabolic reprogramming is commonly observed in cancer cells during tumor progression. Given the multiple local and systemic metabolic abnormalities in obese individuals, the obese state provides an interesting case for new discoveries in the interface between systemic and tumor metabolism.
Recent studies have proposed that lipid metabolism and fatty acid oxidation contribute to cancer stemness. A subpopulation of human carcinoma cells that expressed high levels of the fatty acid transporter CD36 and lipid metabolism genes was identified to possess cancer stemness features and to contribute to a poor prognosis in human cancer patients [ 87 , 88 ].
In addition to direct cancer cell-autonomous effects, obesity-induced elevated levels of saturated fatty acid drive the accumulation of metabolically activated macrophages in adipose tissue. Such macrophages were shown to enhance stem-like properties in triple negative breast cancer cells and promote tumor initiation in obese mouse models [ 20 ]. Overall, there is compelling evidence that fatty acids could be a critical link between obesity and tumor initiation. In addition to enhanced tumor initiation, emerging evidence indicates that the elevated circulating FFA and fatty acid binding proteins in the obese state are associated with cancer progression.
In ovarian cancer, the rapid growth and metastatic colonization of cancer cells were suggested to be directly fueled by fatty acids delivered by fatty acid binding protein 4 FABP4 , also known as adipocyte FABP A-FABP , from adipocytes [ 89 ]. Hao et al. They demonstrated that increased circulating levels of A-FABP enhanced breast cancer stemness and aggressiveness in both in vitro and in vivo models [ 90 ].
Consistently, Madak-Erdogan et al. Also, these findings suggested that fatty acids activate a mTOR and MAPK dependent signaling network to facilitate increased glycolytic and aerobic respiration in breast cancer cells. Finally, cancer cells and immune cells display distinct metabolic adaptations in the obesogenic tumor microenvironment [ 92 ]. For example, HFD represses PHD3 expression specifically in cancer cells, which rewire their metabolism to accelerate fatty acid uptake and oxidation.
This in turn impacts the fatty acid availability for T cells in the same microenvironment and thereby impairs T cells infiltration and function [ 92 ]. In addition to fatty acid-related adaptations, modifications in other metabolic pathways have been identified in tumors evolving in obese environments, including glucose handling, nitrogen metabolism and pyruvate-dependent mitochondrial respiration. For example, in a genetic model for pancreas cancer, HFD feeding heightened aerobic glycolysis through hyperactivation of oncogenic KRAS [ 93 ].
Moreover, transcriptomic analysis of an orthotopic xenograft PDAC model revealed an enrichment of nitrogen metabolism pathways [ 94 ]. The authors identified the mitochondrial enzyme arginase 2 ARG2 , which catabolizes arginine into ornithine and urea, to be induced in obese mouse tumors and that its expression level correlated with patient BMI.
As an important enzyme at the final step of the urea cycle, the obesity-induced upregulated ARG2 enhances nitrogen flux into the urea cycle. In a search for mechanisms underlying the increased cancer risk that is associated with the combination of metabolic deregulation and circadian disruption, Ramos et al.
BMAL1, a key circadian transcription factor, suppresses the flexibility of mitochondrial substrate usage and pyruvate-dependent mitochondrial respiration induced by chronic insulin treatment in vitro.
Interestingly, orthotopic transplantation of E breast cancer cells depleted for BMAL1 revealed that BMAL1 functions as a tumor suppressor in obese, but not in lean mice. In humans, down-regulation of BMAL1 is associated with higher risk of metastasis [ 95 ]. Obesity is associated with local and systemic immune system dysregulation characterized by increased secretion of inflammatory cytokines and phenotypic conversions in immune cells [ 96 ].
Recently, a growing number of studies have suggested that obesity-associated inflammatory alterations might promote progression of multiple cancer types through diverse mechanisms. A fundamental question is whether obesity-induced chronic inflammation alters immune cell infiltration in tumors. At the histological level, HFD-feeding increases infiltration of tumor-associated macrophages in both transplant and some autochthonous PDAC models [ 97 — 99 ] as well as in transplant models of breast cancer [ 53 , 86 ] and in chemically induced hepatocarcinoma [ , ].
In kidney cancer, increased numbers of inhibitory dendritic cells DC infiltrate tumors of DIO mice [ ]. This is in line with our own preliminary findings. We interrogated the immune-infiltrating cells in tumors grown in obese and non-obese mouse models using a marker immune-focused mass cytometry panel [ ].
Immunotyping of three syngeneic breast cancer models and two pancreas cancer models revealed that tumor immune infiltrate composition is highly model- and cancer type-specific. While no major immune cell alterations were observed in the pancreas cancer models and in two of the breast cancer models, HFD-feeding increased two T cell suppressive cell types and decreased CD8 T-cells in the E breast cancer model [ ].
In addition to affecting the overall infiltration of immune cells, accumulating evidence indicates that obesity affects immune function through modulating immune cell phenotypes. The immune subset that has so far received the most attention is macrophages. In several cancer models, obesity has been proposed to regulate recruitment, polarization and signaling of macrophages, thereby contributing to accelerated tumor progression.
In breast and pancreatic cancer models, obesity induces recruitment of tumor-associated macrophage TAM with an M2-like cytokine profile. Furthermore, the elevated level of fatty acids during obesity drives polarization of adipose tissue macrophages towards a metabolically activated phenotype.
In colitis-associated colorectal cancer, signaling through obesity-induced IL-6 was reported to shift macrophage polarization towards a tumor-promoting phenotype that produced the chemokine CC-chemokine-ligand CCL in the tumor microenvironment.
Interestingly, these effects could specifically be blocked in HFD-fed mice by inhibition of the IL-6 receptor [ ]. In a liver cancer model, HFD induced liver endoplasmic reticulum ER stress boosted macrophages-mediated production of inflammatory cytokines.
The importance of macrophages in the connection between obesity and breast cancer has however been challenged. Bousquenaud et al. Hence, the authors concluded that macrophages do not contribute to promote obesity accelerated tumor progression [ ]. Tumoral T cell function is of great interest, especially since the T cell is the critical mediator of immunotherapies, including adoptive T cell therapy and immune checkpoint therapy.
Obese cancer patients have been reported to display increased levels of dysfunctional and exhausted T cells [ 92 , ], suggesting that immunotherapy could be a promising treatment option for obese cancer patients. Indeed, in both human patients and preclinical animal models, obesity associates with better response to anti-PD1 and anti-CD8 immune checkpoint therapy [ 92 , , ].
To address whether inflammatory processes are required for obesity-induced tumor initiation and progression, several studies have obstructed inflammatory signaling pathways, through genetic depletion of key cytokines or pharmacological inhibition of specific immune cell populations in animal models.
Although these studies are limited by the systemic depletion, they indicate a required role of the immune system in obesity-induced cancers. Experimental evidence across cancer types supports a pivotal role of cyclooxygenase-2 COX-2 -mediated inflammatory pathways in obesity promoted cancer progression [ 98 , ].
In contrast, treatment with aspirin, a nonsteroidal anti-inflammatory agent NSAID that blocks the cyclooxygenase enzymes, did not impact tumor progression, immune cell infiltration or fibrosis in an obese genetic model of PDAC [ 7 ]. An integrated part of the obese phenotype is alterations in the microbiota composition [ , ]. As a natural part of the tumor microenvironment of gastrointestinal malignancies, the altered microbiota can directly participate in the regulation of gastrointestinal cancer progression.
In addition to such local effects, microbiota-mediated metabolites display both systemic metabolic and inflammatory changes [ , ]. Gut microbiota are the major producers of short-chain fatty acids SCFAs , which can be the utilized as an energy source and as key signaling molecules. Feeding mice with an HFD results in the decreased production of multiple SCFAs including acetate, propionate and butyrate and were demonstrated to promote G12D mutant Kras-driven intestinal carcinogenesis [ ].
Interestingly, butyrate supplement through feeding successfully reversed the cancer progression effect of the high-fat feeding. Also, fecal-transplantation from HFD-fed to normal diet fed Kras mutant mice was sufficient to induce tumorigenesis [ ].
These findings suggest that an HFD-induced microbiota shift synergizes with the Kras mutation during tumorigenesis and that such effects could act independently of obesity. In chemically-induced HCC, obesity-dependent alterations of the gut microbiota promote tumorigenesis through deoxycholic acid - a secondary bile acid [ 11 , ].
In addition to bile acids, the altered gut microbiota provided lipoteichoic acid to the liver, and this compound synergistically promoted the SASP in hepatic stellate cells. Bromberg, J. Stat3 as an oncogene. Cell 98 , — Vaisse, C. Nature Genet. Dano, K. Plasminogen activation and cancer. Ferrara, N. Binding to the extracellular matrix and proteolytic processing: two key mechanisms regulating vascular endothelial growth factor action.
Cell 21 , — Egeblad, M. Tumors as organs: complex tissues that interface with the entire organism. Cell 18 , — Foekens, J. Plasminogen activator inhibitor-1 and prognosis in primary breast cancer. Mutoh, M. Plasminogen activator inhibitor-1 Pai-1 blockers suppress intestinal polyp formation in Min. Carcinogenesis 29 , — Bajou, K. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization.
Plasminogen activator inhibitor-1 protects endothelial cells from FasL-mediated apoptosis. Cancer Cell 14 , — Zhang, Y. Positional cloning of the mouse obese gene and its human homologue. Cohen, P. Selective deletion of leptin receptor in neurons leads to obesity. Snoussi, K. Leptin and leptin receptor polymorphisms are associated with increased risk and poor prognosis of breast carcinoma.
BMC Cancer 6 , 38 Howard, J. Leptin and gastro-intestinal malignancies. Obes Rev. Jarde, T. Molecular mechanisms of leptin and adiponectin in breast cancer. Cancer 47 , 33—43 Maffei, M. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects.
Lagiou, P. Leptin in relation to prostate cancer and benign prostatic hyperplasia. Cancer 76 , 25—28 Stattin, P. Leptin is associated with increased prostate cancer risk: a nested case-referent study. Mantzoros, C. Leptin in relation to carcinoma in situ of the breast: a study of pre-menopausal cases and controls. Cancer 80 , — Tamakoshi, K. Leptin is associated with an increased female colorectal cancer risk: a nested case-control study in Japan. Oncology 68 , — Banks, A.
Activation of downstream signals by the long form of the leptin receptor. Hardwick, J. Leptin is a growth factor for colonic epithelial cells. Gastroenterology , 79—90 Dieudonne, M.
Leptin mediates a proliferative response in human MCF7 breast cancer cells. Onuma, M. Prostate cancer cell-adipocyte interaction: leptin mediates androgen-independent prostate cancer cell proliferation through c-Jun NH2-terminal kinase. Choi, J. Expression of leptin receptors and potential effects of leptin on the cell growth and activation of mitogen-activated protein kinases in ovarian cancer cells.
Amemori, S. Adipocytes and preadipocytes promote the proliferation of colon cancer cells in vitro. Gastrointest Liver Physiol. Catalano, S. Teraoka, N. High susceptibility to azoxymethane-induced colorectal carcinogenesis in obese KK-A y mice. Aparicio, T. Leptin reduces the development of the initial precancerous lesions induced by azoxymethane in the rat colonic mucosa.
Gastroenterology , — Park, J. Leptin receptor signaling supports cancer cell metabolism through suppression of mitochondrial respiration in vivo. Scherer, P. A novel serum protein similar to C1q, produced exclusively in adipocytes. Hu, E. AdipoQ is a novel adipose-specific gene dysregulated in obesity. Barb, D. Adiponectin in relation to malignancies: a review of existing basic research and clinical evidence. Tworoger, S. Plasma adiponectin concentrations and risk of incident breast cancer.
Dal Maso, L. Circulating adiponectin and endometrial cancer risk. Cust, A. Plasma adiponectin levels and endometrial cancer risk in pre- and postmenopausal women. Soliman, P. Circulating adiponectin levels and risk of endometrial cancer: the prospective Nurses' Health Study. Kaklamani, V. Bub, J. Adiponectin as a growth inhibitor in prostate cancer cells.
Kim, A. Lam, J. Adiponectin haploinsufficiency promotes mammary tumor development in MMTV-PyVT mice by modulation of phosphatase and tensin homolog activities.
PLoS One 4 , e Fogarty, S. Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer. Acta , — Sharma, D. Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis.
Hepatology 52 , — Sun, Y. Adiponectin deficiency promotes tumor growth in mice by reducing macrophage infiltration. PLoS One 5 , e Holland, W.
Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Ogretmen, B. Biologically active sphingolipids in cancer pathogenesis and treatment. Nature Rev. Cancer 4 , — Grossmann, M. Role of the adiponectin leptin ratio in prostate cancer. Rabe, K. Adipokines and insulin resistance. Sood, A. Obesity, adipokines, and lung disease. Sun, K. Adipose tissue remodeling and obesity. Adipose tissue-derived progenitor cells and cancer. World J. Stem Cells 2 , — White adipose tissue cells are recruited by experimental tumors and promote cancer progression in mouse models.
Pasqualini, R. Tang, W. White fat progenitor cells reside in the adipose vasculature. Cinti, S. A morphological study of the adipocyte precursor. Submicrosc Cytol.
McLean, K. Human ovarian carcinoma-associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production. Karnoub, A. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Xu, H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.
Kosteli, A. Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. Lumeng, C. Obesity induces a phenotypic switch in adipose tissue macrophage polarization.
Ehses, J. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56 , — Varma, V. Muscle inflammatory response and insulin resistance: synergistic interaction between macrophages and fatty acids leads to impaired insulin action.
Pollard, J. Tumour-educated macrophages promote tumour progression and metastasis. Cancer 4 , 71—78 Coussens, L. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis.
Murdoch, C. The role of myeloid cells in the promotion of tumour angiogenesis. Cancer 8 , — Qian, B. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis.
Ueno, T. Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer.
CAS Google Scholar. Campbell, M. Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. Breast Cancer Res. Treat , —
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