Endotrophin in the tumor stroma: a new therapeutic target for breast cancer?

Tumor-stromal contribution of adipocyte towards cancer progression The molecular mechanisms underlying how obesity causes an increased risk of cancer incidence and mortality are poorly understood, although the epidemiological data are compelling [1]. Since we define obesity as a pathological expansion of adipose tissue, the adipocyte is a prime suspect as a contributor to the etiology of obesity-related cancers [2]. The adipocyte is an active endocrine cell secreting various factors, referred to as adipokines, which signal to neighboring tissues through paracrine and endocrine interactions. The endocrine aspects of adipocytes have found widespread acceptance with respect to their role in maintaining whole body energy homeostasis [3]. During the pathogenesis of obesity, the adipokine profile changes significantly; these changes include differential expression of proinflammatory cytokines, mitogenic and pro-angiogenic factors, lipid metabolites and extracellular matrix molecules (ECM). While these changes may form the underlying mechanistic basis for the tight association between obesity and cancer, the impact of dysregulated adipocytes on tumor growth remain vastly underappreciated. Nevertheless, the role of the adipocyte as a major constituent of the tumor stroma has been examined in the last few years, revealing its roles in cell proliferation, local antiapoptotic action and invasive properties of cancer cells, mediated by adipocyte-derived factors, such as leptin, adiponectin, IL-6 and IL-8. Beyond these paracrine interactions with cancer cells per se, there are additional metabolic changes originating in stromal adipocytes, creating a microenvironment more permissive for tumor progression. The altered microenvironment is further associated with chronic inflammation, lipotoxicity, fibrosis and hypoxia. All of these changes are much more likely to occur when adipocytes become dysfunctional during the processes of hypertrophy and hyperplasia, phenomena characteristically seen in the context of obesity. Furthermore, metabolically active cancer cells consume vast amounts of energy to support rapid proliferation; hence, it has been speculated that tumor-associated adipocytes may constitute a critical fuel source for cancer cells. An elegant recent report showed that lipolysis in tumor-associated adipocytes is augmented, providing critically needed fatty acids to fuel cancer cells [4]. Combined, these findings emphasize the critical need for a better understanding of the tumorassociated adipocytes, which shape the tumor microenvironment along with tumor-associated macrophages. Tumorassociated macrophages and tumor-associated adipocytes are particularly relevant for the most prominent obesity-related cancers, such as breast, ovary, colon and pancreas. We need to appreciate though that it is clearly not adipose tissue quantity that is the most critical para meter in this context, rather it is the quality of the surrounding adipose tissue that is the most significant determinant of tumor Endotrophin in the tumor stroma: a new therapeutic target for breast cancer?