Obesity and Cancer: An Angiogenic and Inflammatory Link (original) (raw)

. Author manuscript; available in PMC: 2017 Apr 1.

Published in final edited form as: Microcirculation. 2016 Apr;23(3):191–206. doi: 10.1111/micc.12270

Abstract

With the current epidemic of obesity, a large number of patients diagnosed with cancer are overweight or obese. Importantly, this excess body weight is associated with tumor progression and poor prognosis. The mechanisms for this worse outcome, however, remain poorly understood. We review here the epidemiological evidence for the association between obesity and cancer, and discuss potential mechanisms focusing on angiogenesis and inflammation. In particular, we will discuss how the dysfunctional angiogenesis and inflammation occurring in adipose tissue in obesity may promote tumor progression, resistance to chemotherapy, and targeted therapies such as anti-angiogenic and immune therapies. Better understanding of how obesity fuels tumor progression and therapy resistance is essential to improve the current standard of care and the clinical outcome of cancer patients. To this end, we will discuss how an anti-diabetic drug such as metformin can overcome these adverse effects of obesity on the progression and treatment resistance of tumors.

Keywords: obesity, immune environment, desmoplasia, metformin, hypoxia, cytokines, IL-6, IL-1_β_, VEGFR-1

INTRODUCTION—THE OBESITY EPIDEMIC

Excess body weight has become a major public health problem worldwide, and its incidence is increasing at an alarming rate [176]. According to the World Health Organization, the prevalence of obesity has nearly doubled in the last three decades [176]. Excess body weight comprises overweight (25 ≥ BMI <30 kg/m2) and obesity [BMI ≥30 kg/m2]. The latest global survey shows that more than 1.4 billion adults are overweight, and more than 500 million of them are clinically obese [176]. In the United States alone, nearly 70% of the adult population are either overweight or obese [122]. The high rates of obesity and overweight are a consequence of the “western lifestyle.” The latter is mainly attributed to a positive energy balance, a combination of dietary excess energy intake along with a lack of exercise, manifesting itself as obesity. Obese adults have substantially decreased life expectancies, and with obesity-associated diseases accounting for 400,000 deaths per year in the US, we are observing the largest growth in mortality over the past decade and an explosion of medical costs [113,130]. Obesity is considered as a direct cause of the decrease in life expectancy of Americans for the first time in generations [125]. Among the reasons for obesity to associate with increased mortality, is its intimate relationship with cancer incidence and prevalence. In this review, we summarize the epidemiological and experimental evidence demonstrating an association of obesity with cancer and highlight some of the molecular mechanisms that play a pivotal role in the tumor microenvironment to initiate and propagate tumor growth, with emphasis on angiogenesis and inflammation.

THE LINK BETWEEN OBESITY AND CANCER

Based on epidemiological, clinical, and experimental data, the International Agency for Research on Cancer (IARC) in 2002 was able to evaluate the link between obesity and cancer risk [17]. IARC concluded that preventing weight gain and promoting physical activity could partially avert esophagus, colon, endometrial, and postmenopausal BC. Remarkably, a recent study found that women who gained 55 pounds or more after age 18 had almost 50% greater risk of BC after menopause compared to those who maintained their weight, making obesity the most significant risk and prognostic factor for post-menopausal BC [44]. Since the IARC report, various studies have shown that more cancers are linked to obesity than previously described. Presently, obesity and overweight are well-established major risk factors for cancer, accounting for a ~40% increase in the incidence of certain cancers [176]. In particular, an association between obesity and increased risk of gallbladder cancer, hepatocellular carcinoma, pancreatic cancer, gastric cancer, non-Hodgkin's lymphoma, cervical cancer, and prostate cancer has been described [14]. Furthermore, a number of large-scale studies have demonstrated that obesity leads to an increase in not only incidence but also cancer-related mortality [8,72,135,136]. In BC, obesity appears to be a negative prognostic factor for several cancer-related events. Obesity negatively affects disease free interval, overall survival, and outcome of second primary cancer, and is an independent predictive parameter of cancer stage [103,106]. Even if obese patients present with more advanced tumors at diagnosis, after multivariate analysis, obesity remains as an independent prognostic factor [44,103,106]. In fact, the American Cancer Society estimated that in the United States, up to 14% of all deaths from cancer in men and 20% of those in women could be caused by overweight and obesity [15]. The list of cancers associated with increased BMI and their relative mortality risk estimates as well as some potential mechanisms are shown in Tables 1 and 2.

Table 1.

Summary of cancer mortality associated with increased BMI in men.

Table 2.

Summary of cancer mortality associated with increased BMI in women.

The correlation between several types of cancer with obesity has been recapitulated in animal models [9,26,59,72,73,121]. In a spontaneous model of BC, mammary tumor incidence and tumor weight were increased in obese mice when compared to normal weighted mice. Further, the latency of mammary tumor development also decreased [39,83]. In addition, experiments using several xenograft models have shown that a HFD, which leads to an obese phenotype, induced a higher rate of primary tumor growth and metastasis [30,59,85,142,184]. In one particular study, obesity-associated changes in the hepatic microenvironment sustained metastasizing tumor cells in the liver and resulted in increased incidence of hepatic metastases after intrasplenic/portal inoculation of colon carcinoma cells [177]. Despite these findings, the mechanistic causes for the obesity–cancer association have yet to be fully elucidated. As a consequence of the obesity pandemic, the majority of cancer patients present with excess weight at diagnosis [8,95]. Thus, understanding why obesity confers worse prognosis, would lead to novel treatments and enhance the outcome of current therapies.

OBESITY AND CANCER: MOLECULAR MECHANISMS IN THE TUMOR MICROENVIRONMENT

It is widely accepted that a systemic metabolic derangement like obesity creates a supportive environment for tumor cell proliferation. The most prominently investigated mechanisms to explain the obesity–cancer link are insulin resistance with a concomitant increase in insulin and IGF-1 [134]; the production of endogenous hormones (e.g., estrogen) by adipocytes [172]; and the secretion of adipokines such as leptin [72]. Additional mechanisms comprise of angiogenesis, obesity-induced hypoxia, immune modulation, and inflammatory cytokines [72,75]. Here, we will briefly review the above-mentioned mechanisms as well as discuss the potential involvement of obesity-induced inflammation and tumor angiogenesis in therapy failure in cancer.

Established Links Between Obesity and Cancer

Insulin, insulin-like growth factor 1

Insulin and IGF-1 axis could partly explain the link between obesity and cancer. Obese subjects typically present with some degree of insulin resistance, which leads to increased systemic levels of insulin and IGF-1 [93]. In systemic insulin resistance, serum insulin levels are elevated to counteract hyperglycemic state [156]. As a consequence, hepatocytes produce excessive levels of IGF-1 via increased growth hormone receptors’ signaling. Moreover, obese individuals tend to have significantly higher levels of free (bioavailable) IGF-1 when compared to lean subjects [140]. Importantly, several clinical studies have demonstrated that patients with increased serum levels of insulin and IGF-1 have an increased risk of cancers such as breast, prostate, and colorectal cancer [133]. Insulin binds to insulin receptors and IGF-1/IGF-2 bind to specific IGF-receptors (IGF-1R/IGF-2R). Overexpression of IGF-1R in breast and pancreatic tumors was also reported [67,180]. Insulin directly promotes DNA/RNA/protein synthesis in human BC cells [128]. Insulin-IGF-1 axis inhibits apoptosis, stimulates cell proliferation, and survival through downstream signaling namely via PI3K-AKT-mTOR and Ras/Raf/MEK pathways [4,12]. Taken together, increased serum levels of insulin and IGF-1 in obesity and/or metabolic disease patients would facilitate tumorigenesis, proliferation, and survival, and appear to be a major mechanism linking obesity to cancer.

Adipokines

Research over the past decade has revealed that adipocytes are not merely inert storage deposits but also secrete variety of biologically active proteins. These secreted proteins, collectively called adipokines, play a key role in endocrine, metabolic, and inflammatory pathways that regulate cellular homeostasis [110]. More than 50 different hormone-like substances, cytokines, and chemokines are grouped in the adipokine family. Most prominent of which are adiponectin and leptin.

Adiponectin

Adiponectin is a collagen-like protein and a product of the APM1 gene [104]. Exclusively derived from adipocytes, adiponectin has anti-inflammatory and insulin-sensitizing effects. In obese patients, plasma concentrations of adiponectin are paradoxically reduced [5]. Several case–control studies have established an inverse relationship between adiponectin plasma levels and increased risk of BC in both pre- and post-menopause women [odds ratio (OR) OR 3.62 (1.61–8.19)] [7], endometrial cancer [OR 2.75 (1.16–6.54)] [167], and pancreatic cancer [OR 2.81 (1.04–7.59)] [155]. Although direct etiological evidence is yet to be established, the role of adiponectin in cancer appears to be protective against carcinogenesis. The anti-carcinogenic effects are mediated through AMPK/AKT system, activated mainly through two receptors, AdipoR1 and AdipoR2. Activated AMPK system plays a vital role in the regulation of energy metabolism and cellular quiescence [22]. Furthermore, independent of signaling, adiponectin decreases production of reactive oxygen species and thereby inhibits proliferation of cells [49]. A study with adipose tissue depleted mice—AZIP/F1 that are diabetic and do not have measurable levels of adiponectin—has demonstrated that this particular strain of mice is more susceptible to carcinogen-induced tumorigenesis when compared to wild-type mice [74]. Therefore, decreased plasma levels of adiponectin in obesity may contribute to increased risk of cancer among obese individuals.

Leptin

Leptin is a 16 kDa protein secreted by adipocytes, which plays a key role in tightly regulating body weight by inhibiting appetite and increasing energy consumption [162]. Defects in leptin production lead to morbid obesity in humans and rodents. Systemic leptin levels are proportional to body adiposity [54], and clinical studies have suggested an association between systemic levels of leptin and colorectal [163] as well as endometrial cancer risk [35]. Binding of leptin to LepRb—the major signaling form of the leptin receptor—leads to activation of PI3K, MAPK, and STAT signaling pathways and plays a critical role in proliferation, survival, and differentiation of cancer cells [182]. Furthermore, leptin has immunoregulatory functions that include innate immune cell activation, thymic home-ostasis, Th1 cell differentiation, and cytokine production [108].

Potential New Links Between Obesity and Cancer: Obesity is a Pro-angiogenic and Inflammatory Condition

Reciprocal regulation between adipogenesis and angiogenesis

Adipose tissue produces angiogenic factors [e.g., VEGF, PLGF] and exhibits angiogenic activity [18,33,99]. In particular, we have shown that implantation of murine preadipocytes—mesenchymal precursor cells committed to adipocyte lineage—led to vigorous angiogenesis and formed subcutaneous fat pads in a mouse dorsal skinfold chamber [52] (Figure 1). While preadipocytes differentiated into adipocytes and developed adipose tissues, new blood vessels formation also occurred. These vessels were initially immature, but subsequently remodeled/differentiated into a mature vessel network consisting of all vascular units, namely arterioles, capillaries, and venules. Importantly, inhibition of adipocyte differentiation not only abrogated fat tissue formation but also reduced angiogenesis [52]. Conversely, it has been demonstrated that established adipose tissue mass can be regulated through the vasculature [63,109,183]. In fact, we found that inhibition of angiogenesis by VEGFR-2 blocking antibody not only reduced angiogenesis and tissue growth but also inhibited differentiation of preadipocytes (Figure 2) [52]. Furthermore, we found that part of this inhibition stems from the paracrine interaction between EC and preadipocytes and that VEGF–VEGFR-2 signaling in ECs, but not in preadipocytes, mediates this process.

Figure 1.

Angiogenesis and vessel remodeling during adipogenesis in the mouse dorsal skinfold chamber after 3T3-F442A cell implantation. (A, B) Macroscopic images 9 days after implantation. (C, D) Multiphoton laser-scanning microscopy images 28 days after preadipocyte implantation. Images were obtained by maximum intensity projection of 31 optical slices, each 5 _μ_m thick: the top 150-_μ_m de novo adipose tissue layer (C) and the bottom 150-_μ_m host subcutaneous layer (D). (E through H) High-power microscopic images of fluorescence contrast-enhanced blood vessels at 7 days (E), 14 days (F), 21 days (G), and 28 days (H) after implantation. Bars indicate 5 mm (A), 0.5 mm (B), 200 _μ_m (C, D), and 100 _μ_m (E through H), respectively. This figure is reproduced from Fukumura et al., Circ Res, 2003, with permission of the publisher.

Figure 2.

Effect of VEGFR2 blockade on angiogenesis and adipogenesis. (A, B) Visualization of rhodamine–dextran contrast-enhanced blood vessels 21 days after preadipocyte implantation with control rat IgG (A) and DC101, rat monoclonal anti-mouse VEGFR2 antibody (B) treatments. (C through F) Quantitative analyzes of tissue neovascularization; C, number of vessel segments; D, vascular length density; E, vessel diameter; F, vessel volume. Filled circles represent control IgG treatment (n = 6 mice); open squares, DC101 treatment (n = 6 mice). *P<0.01 as compared with IgG by two-tailed _t_-test. This figure is reproduced from Fukumura et al., Circ Res, 2003, with permission from the publisher.

These findings revealed a reciprocal regulation between adipogenesis and angiogenesis, and suggested that blockade of angiogenesis with inhibitors of VEGF signaling can interfere with in adipose tissue formation in vivo. Indeed, we subsequently demonstrated that VEGFR-2 blockade significantly reduced body weight gain in diet-induced obese mice as compared to the control animals (Figure 3) [161]. Importantly, a recent study has shown that the consequences of modulation of angiogenic activity could be context dependent [159]. In agreement with the long-term inhibition of VEGFR2 in HFD, anti-VEGF treatment significantly reduced body weight gain in genetically engineered obesity model (ob/ob)—an effect likely mediated by the ablation of dysfunctional pro-inflammatory adipocytes [159]. However, during early stages of HFD, VEGF overexpression improved adipose tissue metabolism and resulted in reduced body weight gain, whereas anti-VEGF treatment induced adverse effects.

Figure 3.

Effects of VEGFR1 (MF1) and VEGFR2 (DC101) blockade in mice with DIO. (A) Body weight gain relative to weight at day 0 for mice given different diets and treatments. Male C57BL6 mice, 10–12 weeks old at time 0, were used for all groups. All diets and treatments began at day 0, at dosages and schedules as described in the Methods section. DC101 + HFD, DC101 treatment, white triangles (n = 5). MF1 + HFD, MF1 treatment, black squares (n = 5). HFD controls, no treatment (n = 4) or PBS treatment (n = 4), white circles. LFD: standard diet controls, crosses (n = 4). All data reported as mean ± SEM. Asterisks denote significant difference between DC101 + HFD and HFD groups (p, 0.05). This figure is reproduced from Tam et al., PLOS one, 2009, with permission from the publisher.

Dysfunctional adipose tissue angiogenesis in obesity causes inflammation

A widely accepted notion is that obesity is an inflammatory condition [73,81,157], and hypoxia is one of the most plausible causes. Adipose tissues often have inadequate vascularization, perfusion, and oxygen delivery presumably because angiogenesis cannot catch up with tissue expansion rate [62,75]. In addition, the excessive uptake of lipids by adipocytes in obesity leads to cellular hypertrophy, to the point where oxygen diffusion is no longer effective [62,75]. All of these result in a hypoxic microenvironment and eventually necrosis [72,75]. The former induces local production of angiogenic factors and inflammatory cytokines such as interleukin-1_β_, TNF-α, and MCP-1, which in turn increase infiltration of macrophages responding to the distress signals of enlarged adipocytes [33,52,53,70,72,73,99,165].

Abnormal angiogenesis in obesity and cancer

As mentioned above, angiogenesis, inflammation, and immune cell infiltration are signature features of expanding adipose tissues in obesity [33,70,73,75,117,150,174,179]. Interestingly, it was recently suggested that obesity promotes these processes also in the tumor microenvironment to facilitate tumor progression [27,123]. Another experimental study concluded that hypercholesterolemia in mice after HFD also induces angiogenesis and accelerates growth of orthotopically implanted breast tumor [131]. VEGF family such as VEGF and PlGF that have been associated with tumor progression may mediate this process. In fact, pre-clinical and clinical evidence suggests a relationship between these angiogenic factors and obesity [92,100,132,169]. Furthermore, leptin secreted by adipocytes induces activation, proliferation, and migration of EC by upregulating VEGF and VEGFR-2, and transactivates VEGFR-2 independently of VEGF [57]. Similarly, it has been shown that adipose CD34+ progenitor cells promote angiogenesis and cancer growth [107,126]. In addition, VEGFR-1 expressed in ECs and macrophages, binds to VEGF and PlGF, and has been shown to promote tumor angiogenesis, and recruitment and activation (e.g., cytokine production) of macrophages [48,68,96,115,116,148]. On the other hand, PlGF/VEGFR-1 signaling may regulate energy metabolism. Indeed, mice genetically deficient in PlGF, a ligand of VEGFR-1 and NRP-1, gained less weight during HFD-feeding than wild-type animals [100], but presented with insulin resistance and hyperinsulinemia [65]. Overall, VEGFR-1 appears to be involved in key processes both in the tumor microenvironment and adipose tissues, which suggests that, it can be a new link in the obesity–cancer connection.

Obesity-associated inflammation causes tumor progression and therapeutic failure

Similar to angiogenesis, it is well established that chronic inflammation is important for cancer initiation and progression. In fact, many of the adipocyte-produced inflammatory factors mentioned above have been shown to associate with worse prognosis in cancer patients, and to promote cancer initiation and progression in pre-clinical models [6,8,72]. In addition, obesity-associated inflammation may also affect response to chemotherapeutic agents as well as targeted therapy. For instance, in pancreatic cancer, the limited effectiveness of therapy may be attributed to the fibro-inflammatory microenvironment, which causes vessel compression that limits perfusion and directly hinders drug penetration [2,23,24,37,66,120,124]. Indeed, PDACs—the most common type of pancreatic cancer—are hypovascularized, poorly perfused, and hypoxic [71,88,124], which contributes to poor outcome of chemotherapy [25,66]. Importantly, obesity induces a pro-inflammatory state not only in adipose tissue as described above but also in visceral organs. In the normal pancreas, obesity induces pancreatic steatosis—abnormal cellular lipid retention—leading to increased expression of pro-inflammatory cytokines such as IL-1_β_ and IL-6 [72,151]. The inflammatory state leads to immune cell infiltration, ECM remodeling, and eventually fibrosis in the pancreas [73,136]. This is consistent with increased AngII production and AT1 signaling in obesity, which can be promoted by inflammatory mediators [124]. Whether these changes extend to the microenvironment of PDAC is currently unknown. In addition, PDACs in obese mice and patients also have increased adipocyte content [69,184]. Of clinical relevance, the interaction of cancer cells with adipocytes—both in the form of accumulation of fat in pancreas (pancreatic steatosis) and as invasion of cancer cells into local adipose tissue at the expanding edge of the tumor—is associated with worse outcomes in PDAC patients [64,151]. Further, the pro-inflammatory effects of adipokines (e.g., leptin) may also facilitate inflammation and immunosuppression [108]. Although the precise role of intratumor adipocytes during obesity-induced tumor progression is still unclear, it seems plausible that obesity-induced adipocyte infiltration induces tumor inflammation and aggravates desmoplasia to worsen the treatment response in PDACs and other desmoplastic tumors.

Obesity-induced resistance to anti-angiogenic therapy

Hypoxia, immune cell infiltration and the upregulation of inflammatory and angiogenic pathways, e.g., IL-6 and GF-2, have been proposed as mechanisms of resistance to anti-VEGF therapy, since they can sustain angiogenesis and tumor progression despite VEGF blockade [19,20,42,43,50,79]. In metastatic kidney or colon cancer, obesity is associated with reduced survival, specifically in patients receiving bevacizumab, an anti-VEGF antibody [53,60,78,80,91]. The effect of obesity on response to anti-VEGF therapy in BC is currently unknown. In this particular case, breast adipose tissue is the second major depot of fat in the body particularly in obese individuals and tends to be invaded by BC [10,171]. Since adipose tissue is a large component of BC, it is plausible that obesity-induced inflammation in the BC microenvironment may promote resistance to anti-VEGF therapies via these mechanisms.

It has been shown that macrophages and IL-6 expression are typically found in close proximity to dead adipocytes in breast adipose tissue [166]. Furthermore, adipocytes located near tumor cells upregulate IL-6 production in patients [10,38,158]. Indeed, adipose tissue produces 35% of the circulating levels of IL-6 [84] and IL-6 levels correlate with multiple parameters of obesity [11,129]. It is noteworthy that IL-6 can influence all stages of tumor development and metastasis [87]. In addition, IL-6 can also regulate trafficking and recruitment of inflammatory cells, which are a significant source of pro-inflammatory and pro-tumorigenic cytokines [137,138]. Not surprisingly, high levels of plasma IL-6 have also been associated with poor outcomes in cancer patients (kidney and liver cancer) treated with anti-angiogenic agents [42,43,87]. Importantly, IL-6 inhibition improved response to anti-VEGF therapy in a glioma mouse model [145]. Besides IL-6, other studies have shown that FGF2 is increased in cancer patients following anti-VEGF or VEGFR tyrosine kinase inhibitors therapy [21,61,98]. Furthermore, the FGF pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. FGF-2 is also produced abundantly by adipocytes, and not surprisingly plasma levels of FGF-2 correlate with BMI [55,98]. Hence, it is possible that obesity can interfere with the response to targeted therapy such as anti-angiogenic agents by overproduction of alternative angiogenic and inflammatory factors.

Overcoming obesity-associated tumor progression: repurposing metformin

It would be ideal if we could develop a strategy to curb the effects of obesity on tumor progression using drugs that are accessible in the clinic—that are used to interfere with obesity-related disorders. One such agent, currently under intense clinical investigation, is metformin, the most widely prescribed anti-diabetic generic drug that is also frequently administered to diabetic PDAC patients [47]. Metformin can improve treatment outcomes in preclinical models of cancer, particularly in the obese setting [1,3,58,86,112,118,127,152,164,170,178,181]. In addition, it reduces the incidence of cancer in diabetic patients as well as improves survival in newly diagnosed cases [28,94,97,102,144,152]. Metformin has been shown to target cancer cells, transcription factors, microRNAs, DNA damage, cancer stem cells, and metabolism [29,40,56,77,119,160]. In addition, we recently performed a study in our laboratory establishing novel effects of metformin on pancreatic cancer. Using samples from pancreatic cancer patients, complemented with mouse models of pancreatic cancer and in vitro studies, we found that in overweight/obese condition, metformin reprograms the fibro-inflammatory tumor microenvironment and ultimately reduces metastasis in pancreatic cancer models [76]. We found that metformin at clinically relevant doses directly reduced ANG II receptor 1 expression and PDGF-β/TGF-β signaling and ECM production by PSCs—preferentially hyaluronan. It should be noted that ANG II signaling is also associated with coagulopathy [146]. Therefore, metformin treatment may produce an additional beneficial effect through prevention of thrombotic events that frequently occur in pancreatic cancer patients and contribute to the poor prognosis [153]. Furthermore, metformin treatment can restore EC function and production of NO [31,36,147,168]. NO is a potent vasodilator and has been shown to maintain/improve tumor perfusion and enhance drug delivery [51,105]. These preventative effects of metformin against vascular and thrombotic events could collectively improve tumor perfusion, even though anti-angiogenic effects of metformin on ECs have been reported [36,46,82,154,168]. Indeed, we found that metformin increases tumor perfusion while not affecting vessel density (unpublished).

Metformin also reduces inflammation—another key element of desmoplasia—through reduction of cytokine production, and recruitment and M2-polarization of TAMs. This was associated with AMPK activation and STAT3 signaling inhibition in macrophages. Finally, the alleviation of desmoplasia by metformin was associated with reduced ECM remodeling, EMT, and systemic metastasis (Figure 4). Importantly, the effects on desmoplasia observed in human samples seem restricted to an overweight/obese population, which appear to have tumors with increased content of ECM components. Indeed, a recent retrospective [141] and the first two prospective studies [89,90,139] indicated that metformin might not be beneficial to an unstratified patient population. The benefit in some but not all studies suggests that a subset of patients may respond better to metformin and that careful selection of patients may be required for metformin to be effective. We found that metformin's effect on desmoplasia in patients only occurred when their BMI was higher than 25 (overweight and obese patients), which supports the enhanced anti-cancer effects in obese compared to normal weight mice. This indicates that metformin may not be beneficial in normal weight patients, and suggests that BMI should be explored as a potential biomarker of response to this drug. With nearly 200 trials ongoing to address the effect of metformin on diabetic and non-diabetic cancer patients, understanding the yet elusive mechanisms of action of metformin may provide an opportunity to uncover potential biomarkers of response and define strategies of patient stratification for the judicious use of this highly promising yet generic drug.

Figure 4.

(A) Metformin treatment associates with reduced hyaluronan levels in human pancreatic cancers in overweight/obese patients. (i) Representative histology images showing the effect of metformin on tumor hyaluronan levels in normal weight or overweight/obese patients (n = 22 controls, 7 metformin). (ii) Immunohistochemical analysis of total tumor hyaluronan levels. Metformin decreases the hyaluronan-positive area fraction (%) in patients with BMI >25. Data are presented as the mean ± standard error. *p < 0.05 vs. control in patients with BMI >25. (B) Metformin reduces hyaluronan production by PSC. (i) PSCs were incubated in vitro with metformin (1 mM) for 48 hours. Representative immunocytochemistry images showing the effect of metformin on tumor hyaluronan and COL-I levels in human PSCs in vitro (n = 2). (ii) Quantification of hyaluronan expression in PSCs. Metformin decreases the expression of hyaluronan on PSCs. _α_SMA denotes activated PSCs. (C) Metformin inactivates PSCs and TAMs, alleviates the fibroinflammatory tumor microenvironment and reduces metastasis. Metformin treatment reduces COL-I and HA production by PSCs, leading to decreased fibrosis in PDACs. Metformin treatment also reduces cytokine production, infiltration, and M2 polarization of TAMs, leading to decreased inflammation. These lead to improved desmoplasia and reduced ECM remodeling, EMT, and metastasis. This figure is reproduced from Incio et al., PLOS One, 2015, with permission from the publisher.

CONCLUSION

Epidemiological studies clearly indicate that obesity is associated with increased risk of cancer and worsened treatment outcome [17,176]. Given the prevalence of obesity, understanding the mechanisms that underlie the poorer prognosis of obese pancreatic cancer patients is of paramount importance. A combination of hampered metabolic state and concurrent insulin resistance with factors produced by adipocytes (i.e., hormones, adipokines) in the obese setting may contribute to a tumor microenvironment that facilitates tumor proliferation, evades host immune response, and induces resistance to therapy [72,75,134,172]. In addition, obesity is a pro-angiogenic condition, as evidenced in previous work from our laboratory and others [52,63,109,183]. Despite that, the vasculature in expanding adipose tissues is insufficient and dysfunctional, leading to hypoxia and inflammation [73,81,157]. This induces production of multiple angiogenic and inflammatory factors that may abrogate the efficacy of anti-angiogenic treatment as a cancer agent. Furthermore, the local and systemic inflammation in obesity may also promote cancer progression via inflammatory cytokine signaling as well as the consequence of increased fibrosis, and may reduce the efficacy of chemotherapeutic agents. Today, for several cancer types including of breast and pancreas, majority of the patients are overweight or obese at diagnosis. We therefore should incorporate the important parameter of body weight in the design of pre-clinical studies in order to better recapitulate the clinical reality of (lack of) response to novel targeted therapies such as anti-VEGF as well as conventional therapies (e.g., chemotherapy) (Figure 5). Most importantly, by better understanding the mechanisms by which obesity promotes tumor progression and resistance to therapy, we will be able to improve the current standard of care for cancer patients. To this end, targeting fibrosis, inflammation, and metabolic pathways holds the promise to improve the clinical outcome of the major subset of cancer patients (Figure 6).

Figure 5.

The evolution of the mouse tumor model. For preclinical cancer study, we have observed an evolution of mouse models to better represent the clinical setting: It evolves from a heterotopic to an orthotopic xenograft, from xenograft tumors in immunodeficient mice to syngeneic models, from transplantation model to genetic mouse models that better reflect the initial stages of tumor development or patient-derived xenografts to accurately represent tumor heterogeneity. Finally, we need to incorporate the obese mouse model as another dimension of improvement of the mouse model to better mimic patient population.

Figure 6.

Obesity-tailored rethinking the approach to pre-clinical cancer research in light of the current obesity epidemics. Obesity patients may respond differently to a treatment or need additional therapy in order to make the treatment effective. The development of such strategy requires the use of animal models that better mimic biology and microenvironment of obese patients.

PERSPECTIVE.

Obesity is associated with inflammatory and angiogenic alterations in tumors that may affect response to conventional and targeted therapies in cancer patients.

ACKNOWLEDGMENTS

We thank Shan Min Chin for help with illustrations.

SOURCES OF FUNDING

The authors’ work was supported by a fellowship from the Foundation for Science and Technology (http://www.fct.pt/; Portugal, POPH/FSE funding program) (JI) and funds from the National Institutes of Health (http://nih.gov/; CA080124, CA085140, CA096915, CA115767, CA126642, CA197743), the US Department of Defense (W81XWH-10-1-0016), and the Lustgarten Foundation.

Abbrevations used

AdipoR1

adiponectin-receptor 1

AKT

protein kinase B

AMPK

adenosine mono phosphate kinase

ANG II

angiotensin II

APM1

adipose-most-abundant-gene-transcript 1

AT1

angiotensin II type-1 receptor

AZIP/F1

transgenic lipoatrophic diabetic mouse model

BC

breast cancer

BMI

body mass index

COL-I

collagen-I

DC101

anti VEGFR-2 antibody

DIO

diet-induced obesity

EC

endothelial cell

ECM

extracellular matrix

EMT

epithelial to mesenchymal transition

FGF-2

fibroblast growth factor 2

GEMM

genetically engineered mouse model

HA

hyaluronan

HFD

high-fat diet

HM

humanized mouse model

IGF-1

insulin growth factor 1

IgG

immunoglobulin

IL-6

interleukin 6

LepRb

leptin receptor long isoform

MCP-1

monocyte chemoattractant protein 1

MF1

anti VEGFR-1 antibody

mTOR

mammalian target of rapamycin

NO

nitric oxide

NRP-1

neuropilin 1

ob/ob

leptin-deficient mouse model

PBS

phosphate-buffered saline

PDAC

pancreatic ductal adenocarcinoma

PDX

patient-derived xenographt model

PI3K

phosphatidylinositol 3-kinase

PlGF

placental growth factor

PDGF

platelet-derived growth factor

PSC

pancreatic stellate cell

RR

relative risk

STAT3

signal transducer and activator of transcription 3

TAM

tumor associated macrophage

TGF

transforming growth factor

TNF-α

tumor necrosis factor α

VEGFR-1

vascular endothelial growth factor receptor 1

VEGFR-2

vascular endothelial growth factor receptor 2

VEGF

vascular endothelial growth factor

_α_SMA

alpha smooth muscle antigen

AUTHOR BIOGRAPHIES

Dai Fukumura, MD, PhD, is an Associate Professor and the Deputy Director of the Edwin L. Steele Laboratories Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School. He is an internationally recognized expert in imaging, angiogenesis, vascular and tumor biology. Dr. Fukumura and his colleagues have developed various innovative intravital optical imaging techniques and sophisticated animal models—which more faithfully represent the clinical behavior of tumors—in collaboration with world-renowned experts. Dr. Fukumura's research areas include (i) role of host–tumor interaction (microenvironment) in angiogenesis, tumor growth, metastasis and treatment response; (ii) role of nitric oxide in vessel formation, function, and normalization; (iii) probing and exploiting tumor microenvironment using nanotechnology; (iv) role of obesity in angiogenesis and tumor progression; and (v) tissue-engineered blood vessels. For more information, go to <http://steele.mgh.harvard.edu/dai_fukumura/pi_bio>.

Joao Incio obtained his MD degree in 2007 from Porto Medical School, Porto University, in the foggy yet beautiful city in the north of Portugal where Port wine comes from. He initiated his clinical training in internal medicine in Porto, and in 2010 he joined the Edwin L. Steele Laboratories as a PhD student under the supervision of Professors Dai Fukumura and Rakesh K. Jain. He has been studying the mechanisms of action of the anti-diabetic drug metformin in cancer. In addition, he has been deciphering the impact of inflammation and immunosuppression on cancer progression and therapy resistance using the inflammation-augmented obese mouse model.

Ram C. Shankaraiah is a PhD student in the laboratory of Prof. Massimo Negrini at Department of Morphology, Surgery and Experimental Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy. He obtained his Master in Oncology in August 2014 at Vrije University, Amsterdam. In the past, he worked with Professor Dai Fukumura and Professor Rakesh Jain at the Edwin L. Steele Laboratories at the Department of Radiation Oncology, Massachusetts General Hospital, Boston, in the field of breast cancer and brain metastases. His current research focus is to investigate the role of non-coding RNAs in hepatocellular cancer.

Rakesh K. Jain is Andrew Werk Cook Professor of Tumor Biology and director of the Edwin L. Steele Laboratories for Tumor Biology in the radiation oncology department of Massachusetts General Hospital and Harvard Medical School. He is a member of the National Academy of Sciences, the National Academy of Engineering and the National Academy of Medicine, and a recipient of the US National Medal of Science. Dr. Jain is regarded as a pioneer in the area of tumor microenvironment and widely recognized for his seminal discoveries in tumor biology, drug delivery, in vivo imaging, bioengineering, and bench-to-bedside translation. These include uncovering the barriers to the delivery and efficacy of molecular and nano-medicines in tumors; developing new strategies to overcome these barriers; and then translating these strategies from bench to bedside.

Footnotes

CONFLICT OF INTEREST

MGH has filed a patent application on the work presented here on metformin.

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