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The pandemic rise of obesity is alarming. The most recent data from the National Center for Health Statistics indicate that 69 percent of US adults are overweight and half of those are obese. Worldwide, an estimated 2.2 billion adults are overweight or obese, and many of these individuals exhibit the hallmarks of metabolic syndrome: elevated blood pressure and high levels of blood sugar and cholesterol. Increased circulating levels of insulin, inflammatory cytokines, and other factors are also common in obese individuals. And while these metabolic and immune changes are problems in and of themselves, they are not the only health issues faced by the obese population. Through these and other possible mediators, obesity increases the risk and/or worsens the outcome of several chronic diseases, including many types of cancer. This year, obesity overtook smoking as the top preventable cause of cancer death in the U.S., with some 20 percent of the 600,000 cancer deaths per year attributed to obesity.
A major challenge in cracking the obesity-cancer association has been distinguishing which host factors are causally linked and which are simply bystanders.
Much recent work on obesity and cancer has centered on behavioral interventions to prevent obesity. But with nearly 700 million adults worldwide already obese, coupled with the challenges associated with weight loss, more-effective strategies to reverse the increased risk and worsened prognoses in obese individuals are urgently needed. In our view, and that of organizations such as the American Society of Clinical Oncology, the World Cancer Research Fund International, and the American Cancer Society, obesity-related cancers will arguably be the most urgent issue in the cancer field in the next decade.
THE SCIENTIST STAFF
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A major challenge in understanding the complex relationship between obesity and cancer has been distinguishing which host factors are causally linked and which are simply bystanders. Obesity can induce a complex state of systemic metabolic dysregulation characterized by insulin resistance and high levels of circulating insulin and glucose; high levels of cholesterol and other lipids; impaired blood-vessel growth and clotting; altered cytokine expression and heightened inflammation; and increased circulating levels of hormones such as estradiol, leptin, and bioavailable insulin-like growth factor 1 (IGF-1). Over the last two decades, however, researchers have used genetic or pharmacologic approaches to make progress in deciphering which of these mediates the obesity-cancer link.
Intercellular signaling is undoubtedly one contributing factor. Proteins, lipid intermediates, and other molecules secreted or shed from cells—collectively referred to as the secretome—carry messages between distant organ systems and tumor cells, as well as among tumor and host cells in their microenvironment. These signaling pathways involve an increasingly large roster of obesity-related hormones, growth factors, nutrient metabolites, chemokines, and cytokines that promote tumor development and/or progression. For example, insulin resistance in obese individuals drives insulin production in the pancreas and results in excess insulin in circulation. High levels of insulin can promote cancer growth through interaction with tumor cells’ insulin receptors and/or IGF-1 receptors. Expression of the IGF-1 receptor is also necessary for the transformation of normal epithelial cells into cancer cells by numerous oncogenes, suggesting that greater IGF-1 signaling can also enhance the early stages of cancer development. In addition to the secretome, the tumor microenvironment encompasses extracellular matrix components and multiple cell types, including adipocytes and macrophages, which in obese people are highly active and capable of secreting a large number of cancer-promoting hormones and cytokines.
Another key process that likely plays a causal role in obese people’s increased risk of cancer is inflammation. In the early 2000s, physician-researcher Andrew Dannenberg of Cornell University and his colleagues demonstrated the presence of elevated inflammation in the breast tissue of overweight and obese women.1,2 In vitro experiments have revealed that elevated levels of free fatty acids released from adipocytes stimulate macrophages to produce excess amounts of proinflammatory mediators that can have direct and indirect effects on cancer progression. In addition, overweight and obese women showed increased levels of COX-2, an enzyme that catalyzes the production of proinflammatory prostaglandin E2 (PGE2).1 PGE2 is known to promote breast cancer progression via inhibition of apoptosis and stimulation of migration and invasion. (See “Fat’s Immune Sentinels,” The Scientist, December 2012.)
PGE2 also amplifies the expression of aromatase, an enzyme that converts androgens into estrogens, in adipocyte precursor cells in animal models and in cultured human adipocytes. Increased levels of aromatase in turn boost the local production of estradiol, which can promote the growth of estrogen-dependent cancers, including estrogen receptor–positive breast cancer and endometrial cancer. Other proinflammatory cytokines such as IL-1β and TNFα activate tumor cell NF-kB, a transcription factor that regulates the levels of proteins involved in proliferation, apoptosis, angiogenesis, and metastasis. TNFα also contributes to insulin resistance by suppressing insulin receptor activity and decreasing glucose transporter translocation, further spiking levels of cancer-promoting insulin.
Another factor that appears to be involved in the obesity-inflammation connection, but has not yet been strongly linked to cancer risk and progression, is the gut microbiome. (See “Microbesity.”) Obesity is associated with an overall reduction in gut bacterial diversity, and decreased bacterial richness has been linked to elevated systemic inflammation. Researchers have also demonstrated that high-fat diets are accompanied by impairments in gut barrier function, resulting in higher plasma levels of lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria. Increased LPS levels have been shown to induce metabolic endotoxemia, characterized by elevated adipose tissue macrophage infiltration and proinflammatory cytokine expression. Together, these studies suggest that obesity-related perturbations of the gut microbiome and barrier function associated with a high-calorie diet can induce chronic systemic and adipose tissue inflammation, which is known to play a role in the progression of several cancer types.
In addition to putting people at an increased risk for developing cancer, obesity also worsens a cancer patient’s prognosis. Research from our group and others has shown that a variety of cancers grow at faster rates in obese patients than in lean individuals. Furthermore, obesity appears to increase the chances that a patient’s cancer will metastasize. A variety of factors may underlie the obesity-metastasis link, including circulating factors such as leptin, adiponectin, and IGF-1; adipose tissue remodeling, including alterations in adipose-derived stem cells; and other changes to the tumor microenvironment. Our work in breast and pancreatic cancer, for example, has shown that obesity can drive epithelial-to-mesenchymal transition (EMT), a key mechanism in progression to metastasis.
Diminished response to chemotherapy
Another important aspect of the obesity-cancer link is obese patients’ altered responses to a variety of chemotherapies. Researchers have shown, for example, that obese patients with basal-like breast cancer (BLBC), an aggressive breast cancer subtype, have impaired responses to the chemotherapy agent carboplatin,3 while in colon cancer patients, visceral fat levels were inversely correlated with patient responses to bevacizumab-based therapy.4 Others have found that high levels of insulin, a scenario typically found in obese individuals, conferred resistance to oxaliplatin in colon cancer cell lines.5 The mechanisms underlying obesity-associated resistance to agents such as carboplatin, bevacizumab, and oxaliplatin have not been elucidated, although factors such as decreased drug uptake, increased efflux, and altered metabolism and detoxification are likely involved.
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In addition to affecting the transport and/or metabolic processes for chemotherapeutic molecules, obesity also has general effects on drug pharmacokinetics and delivery. Enhanced inflammation and the thickening and scarring of connective tissue (fibrosis) that often occurs in obese patients, for example, can act as physical barriers preventing the delivery of the therapeutic compounds to the target tissue. The metabolic dysregulation associated with obesity may also play a key role. Metabolic reprogramming can allow cells to evade stress, for example, and may contribute to cancer therapy resistance.
But there is hope. Our group has shown that nanoparticle formulations of some drugs can avoid several of these generalized and specific resistance mechanisms and improve therapeutic response.6,7 And mouse models of BLBC have revealed that treatment with the mTOR inhibitor rapamycin, which affects metabolic flux and nutrient sensing, offsets the tumor-enhancing effects of diet-induced obesity.8 Another mTOR inhibitor, called everolimus, sensitizes human breast cancer cells to carboplatin in vitro.9,10 And oxaliplatin resistance in colon cancer cell lines can be reversed by inhibiting factors such as insulin, IGF-1, and phosphatidylinositol-3-kinase (PI3K), a key upstream activator of mTOR.5 Further research should continue to unveil the reasons obese people often have reduced responses to chemotherapeutic agents, as well as more strategies to overcome such resistance.
While the rise in obesity is a major public health challenge, advances in our understanding of the obesity-cancer link in the last few decades have revealed avenues for potential cancer prevention and treatment strategies for obese cancer patients.
Reducing the risk
Despite progress in understanding how metabolic dysfunction can lead to increased cancer risk, worse prognoses, and diminished responses to therapy, there remain major knowledge gaps. First and foremost, researchers still need to answer whether weight loss alone reduces the risk of developing or dying from cancer. While most cancer-prevention guidelines rank weight loss as the number-one recommendation for reducing the burden of cancer in obese individuals, the data on its anticancer effect in chronically obese people are sparse and conflicting.
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There is emerging evidence that bariatric surgery, which often results in extreme weight loss and metabolic reprogramming, reduces the risk of several cancers. However, the effects of diet- and exercise-based weight loss interventions on the risk of developing or dying from cancer have been understudied, and preliminary results from our work on humans and mice suggest that moderate weight loss alone may not be sufficient to fully reverse the tumor-enhancing effects of chronic obesity. In obese women, for example, only those who lost at least 20 percent of their body weight showed clear changes in breast cancer–associated biomarkers.11 This may be due to epigenetic reprogramming of inflammatory and other pathways that do not readily reverse with moderate weight loss alone.
In mouse models of BLBC, we compared tumor growth; levels of circulating hormones, growth factors, and cytokines; mammary epithelial cell signaling; and global methylation in control-fed mice, obese mice, or formerly obese mice whose weight normalized after switching from a long-term obesity-inducing diet to a control diet for 12 weeks. Although most metabolic factors normalized in the formerly obese mice after the weight loss, circulating IGF-1 and inflammatory cytokines remained elevated.12 Moreover, several inflammation-related genes in tumors from obese mice displayed hypermethylation, and nearly all of these genes remained hypermethylated in tumors from formerly obese mice (unpublished data).
This work has helped reframe the discussion, shifting the focus from adiposity per se as a factor in cancer risk and progression to the metabolic perturbations that typically accompany obesity. Indeed, inhibiting key mediators such as insulin and IGF-1 decreases mammary, skin, pancreatic, and colon cancer development and/or progression in obese mice, without reducing weight or adiposity levels. Additionally, we found that mice lacking white adipose tissue but having increased levels of insulin, IGF-1, and cytokines are highly susceptible to cancer despite being essentially fatless.13 The idea that preventing obesity-related cancers depends on targeting the obesity-associated metabolic dysregulation rather than weight is further reinforced by the recent recognition that some 20 percent of normal-weight people are metabolically unhealthy and at increased risk for cancer,14 while approximately 10 percent of obese individuals are metabolically healthy and show no elevated cancer risk.15 (See “A Weighty Anomaly.”)
Thus, while weight normalization in a significant number of the obese adults worldwide will likely never be a realistic goal, it is also unclear whether this simple reversal of obesity would markedly reduce the cancer burden. A precision-medicine approach that targets key processes dysregulated by obesity may be needed to break the obesity-cancer link. In addition, combination approaches that simultaneously target growth factor, inflammatory, or other key signals will likely have better success than single agents or interventions.
Stephen D. Hursting is a professor at the University of North Carolina at Chapel Hill and the Nutrition Research Institute in Kannapolis, North Carolina. Ciara H. O’Flanagan and Laura W. Bowers are postdoctoral fellows in his laboratory at Chapel Hill.
- K. Subbaramaiah et al., “Increased levels of COX-2 and prostaglandin E2 contribute to elevated aromatase expression in inflamed breast tissue of obese women,” Cancer Discov, 2:356-65, 2012.
- P.G. Morris et al., “Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer,” Cancer Prev Res, 4:1021-29, 2011.
- S. Chen et al., “Obesity or overweight is associated with worse pathological response to neoadjuvant chemotherapy among Chinese women with breast cancer,” PLOS ONE, 7:e41380, 2012.
- B. Guiu et al., “Visceral fat area is an independent predictive biomarker of outcome after first-line bevacizumab-based treatment in metastatic colorectal cancer,” Gut, 59:341-47, 2010.
- J. Chen et al., “Insulin caused drug resistance to oxaliplatin in colon cancer cell line HT29,” J Gastrointest Oncol, 2:27-33, 2011
- R.E. De Angel et al., “Stearoyl gemcitabine nanoparticles overcome obesity-induced resistance to gemcitabine in a mouse model of breast cancer,” Cancer Biol Ther, 14:357-64, 2013.
- Y. Naguib et al., “Solid lipid nanoparticle formulations of docetaxel prepared with high-melting point triglycerides: In vitro and in vivo evaluation,” Mol Pharm, 11:1239-49, 2014.
- L.M. Nogueira et al., “Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity,” Endocr Relat Cancer, 19:57-68, 2012.
- H. Liu et al., “Metformin and the mTOR inhibitor everolimus (RAD001) sensitize breast cancer cells to the cytotoxic effect of chemotherapeutic drugs in vitro,” Anticancer Res, 32:1627-37, 2012.
- H. Liu et al., “The mTOR inhibitor RAD001 sensitizes tumor cells to the cytotoxic effect of carboplatin in breast cancer in vitro,” Anticancer Res, 31:2713-22, 2011.
- C.J. Fabian et al., “Favorable modulation of benign breast tissue and serum risk biomarkers is associated with >10% weight loss in postmenopausal women,” Breast Cancer Res Treat, 142:119-32, 2013.
- R.E. De Angel et al., “The enhancing effects of obesity on mammary tumor growth and Akt/mTOR pathway activation persist after weight loss and are reversed by Rad001,” Mol Carcinog, 52:446-58, 2013.
- S.D. Hursting et al., “The obesity-cancer link: Lessons learned from a fatless mouse,” Cancer Res, 67:2391-93, 2007.
- K. Aung et al., “Risk of developing diabetes and cardiovascular disease in metabolically unhealthy normal-wight and metabolically healthy obese individuals,” J Clin Endocrinol, 99:462-68, 2014.
- P. Pajunen et al., “Metabolically healthy and unhealthy obesity phenotypes in the general population,” BMC Public Health, 11:754, 2011.