Molecular pathways: adipose inflammation as a mediator of obesity-associated cancer

Abstract

The increasing rate of obesity worldwide is predicted to be associated with a surge in diseases. Notably, obesity has been linked to approximately 20% of cancer cases in the United States; obesity is associated with both increased risk and worse outcomes after diagnosis. Altered levels of circulating factors are strongly implicated, including insulin, insulin-like growth factor 1, leptin, adiponectin, and interleukin-6 (IL-6). In addition, increasing attention has focused on the consequences of local adipose inflammation. Inflammatory foci characterized by crown-like structures consisting of dead adipocytes encircled by macrophages occur in white adipose depots, including the breast tissue, of most overweight and obese women. Saturated fatty acids, released as a consequence of obesity-associated lipolysis, induce macrophage activation via Toll-like receptor 4, thereby stimulating NF-κB signaling. This, in turn, activates transcription of proinflammatory genes including COX-2, IL-6, IL-1β, and TNFα. Elevated levels of proinflammatory mediators cause both local and systemic effects. Of particular relevance with regard to breast cancer is increased transcription of the CYP19 gene encoding aromatase, the rate-limiting enzyme for estrogen synthesis. Notably, this obesity-inflammation-aromatase axis provides a plausible explanation for increased rates of postmenopausal, hormone receptor-positive breast cancer associated with obesity and hence may offer targets for interventions to attenuate risk or improve prognosis. Potential approaches include weight reduction, exercise, and suppression of obesity-driven signaling pathways using pharmaceutical or dietary agents. A key future goal is to identify biomarkers that accurately report adipose inflammation, both for identification of at-risk individuals and to assess the efficacy of interventions. Clin Cancer Res; 19(22); 6074-83. ©2013 AACR.

Figure 1. Paracrine interactions between macrophages and other cell types establish an inflammatory milieu in obese breast adipose tissue, resulting in activation of estrogen receptor-α-dependent gene expression

Saturated fatty acids, released from adipocytes as a result of obesity-associated lipolysis, complex with Fetuin A (FetA) and activate Toll-like receptor 4 (TLR4) signaling resulting in enhanced NFκB activity in macrophages. Additionally, bacterial endotoxin (lipopolysaccharide; LPS) entering systemic circulation as a consequence of obesity-induced impairment of gut mucosal integrity may also elicit NFκB activation through TLR4 ligation. NFκB induces expression of proinflammatory genes including COX-2, IL-1β and TNFα in macrophages. n-3 polyunsaturated fatty acids (PUFAs) signal via GPR120 and can suppress TLR4 signaling. Cytokines and COX-2-derived PGE₂ activate transcription of the CYP19 gene encoding aromatase in neighboring cells, including preadipocytes, leading to elevated expression and activity of aromatase. Consequently, estrogen biosynthesis is enhanced, which manifests as increased expression of ER target genes, including the progesterone receptor. Systemic consequences of adipose inflammation include increased circulating levels of cytokines as well as accumulation of the PGE₂ metabolite PGE-M in urine. Urinary PGE-M levels may therefore provide a valuable biomarker of obesity-related white adipose tissue inflammation.