Basic Science Newsbrief September 2011


How Does Obesity Amplify the Risks of Certain Cancers?

by: Gerald V. Denis

Cancer is among the serious diseases associated with obesity and metabolic syndrome. Initially, epidemiological work established that elevated BMI is associated with an increased risk of cancer mortality, although the relative risk has been observed to vary by type of cancer, with strong associations for colorectal cancer, hepatocellular carcinoma (HCC), renal, endometrial and post-meno-pausal breast cancer. The relationship does not hold for all malignancies. Pre-menopausal breast cancer and prostate cancer appear to be among the exceptions and the jury is still out on ovarian and pancreatic cancer. It has been proposed that the molecular pathways involved include elevated insulin-like growth factor (IGF)-1 and leptin signaling through Stat3, which govern important growth-regulatory and cytokine signaling networks; increased levels of sex steroid hormones or pro-inflammatory cytokines; and reduced levels of adiponectin, interleukin-10 and other anti-inflammatory cytokines.


Several investigators have been using mouse models to test specific interactions between obesity and cancer models based on genetic lesions or carcinogens. For example, the Mittelman group at USC reported recently that a high fat diet accelerated the onset of acute leukemia in the Heisterkamp Bcr/Abl transgenic and AKR/J mouse models (Yun et al 2010 Cancer Prev Res 3:1259–1264). Indeed, obesity appears to be a risk factor for Bcr/Abl+ human chronic myelogenous leukemia (Strom et al 2009 Cancer Epidemiol Biomarkers Prev 18:1501–1506). Likewise, the Karin group at UCSD showed that HCC, a common form of liver cancer originating from chronic hepatic inflammation, and that can be induced in mice with the carcinogen diethyl nitrosamine, is significantly exacerbated in diet-induced obesity or in genetic models of obesity (Park et al 2010 Cell 140:197–208). Nitrosamines are found in beer, pickles and other preserved foods, but the relationships among nitrosamine consumption, obesity and cancer rates has not been measured in humans. In HCC as well as certain other cancers with an inflammatory component, Stat3 is implicated in signal transduction from receptors for cytokines, such as interleukin (IL)-6 and TNF-α, culminating with activation of NF-κB, and exacerbating persistent, chronic inflammation in the relevant tissue. Failure to resolve inflammation is thus a risk factor for multiple dangerous diseases.

An interesting intellectual shift has been occurring in this area of investigation with the development of the idea that insulin resistant adipose tissue itself can function as a carcinogen or as a tumor promoter. Thus, ‘obesity’ constitutes an ‘exposure’. The inflammatory characteristics of metabolically dysfunctional fat depots are well appreciated, including elevated serum markers of systemic inflammation (TNF-α, C-reactive protein, serum amyloid, IL-6), local production in fat of these same pro-inflammatory cytokines, recruitment of pro-inflammatory macrophages to adipose tissue to deal with dead or dying adipocytes, a decline in ‘alternatively’ activated macrophages that might be able to reduce the inflammatory environment, increased infiltration of adipose tissue with pathogenic T-cells and a corresponding change in the local balance among Th1- and Th17-polarized (pro-inflammatory) and T-regulatory (Treg; anti-inflammatory) T-cells. These mechanisms underpin the hypothesis that chronic inflammation is both carcinogenic and diabetogenic.

The cancer chemoprevention field has deeply investigated dietary components (e.g., polyphenols and anti-oxidants: curcumin, capsaicin, resveratrol and (-)-epigallocatechin gallate; EGCG) that are chemoprotective against specific cancers. Likewise, obesity investigators have focused attention on the how the caloric content of foods, their availability in the built environment, their interactions with genetics and family history or culturally defined diets; and the presence of obesogenic compounds or pollutants (such as tributyltin) contribute to metabolic syndrome. However, insufficient work has been done to connect these areas as a tripartite problem, with obesity and cancer linked through dietary exposures. I suspect that patients with unresolved inflammation are more likely to be both insulin resistant and at elevated risk for obesity-associated cancers, mediated in part by these inflammatory pathways. Thus, a hypothesis follows: dietary components with anti-inflammatory/anti-oxidant properties will simultaneously reduce the risk of cancer and preserve insulin sensitivity in obesity. Anti-inflammatory drugs such as aspirin are known to be effective chemopreventive agents, and we are much closer to a comprehensive understanding of the relevant mechanisms, including the specific cancers, cytokine signaling pathways, transcriptional networks and immunological mediating variables

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