Obesity, metabolism and the microenvironment: Links to cancer

Abstract

Historically, cancer research has focused on identifying mutations or amplification of genes within the tumor, which informed the development of targeted therapies against affected pathways. This work often considers tumor cells in isolation; however, it is becoming increasingly apparent that the microenvironment surrounding tumor cells strongly influences tumor onset and progression. This is the so-called "seed and soil" hypothesis wherein the seed (cancer cell) is fed and molded by the metabolites, growth factors, modifications of the extracellular matrix or angiogenic factors provided by the soil (or stroma). Currently, 65% of the US population is obese or overweight; similarly staggering figures are reported in US children and globally. Obesity mediates and can exacerbate, both normal and tumor microenvironment dysfunction. Many obesity-associated endocrine, metabolic and inflammatory mediators are suspected to play a role in oncogenesis by modifying systemic nutrient metabolism and the nutrient substrates available locally in the stroma. It is vitally important to understand the biological processes linking obesity and cancer to develop better intervention strategies aimed at curbing the carcinogenic events associated with obesity. In this review, obesity-driven changes in both the normal and tumor microenvironment, alterations in metabolism, and release of signaling molecules such as endocrine, growth, and inflammatory mediators will be highlighted. In addition, we will discuss the effects of the timing of obesity onset or particular "windows of susceptibility," with a focus on breast cancer etiology.

Keywords: Basal-like breast cancer; health disparities; inflammation; macrophage; tumor subtype; window of susceptibility.

Figure 1

Obesity mediated alterations in nutrient sensitive pathways. Overnutrition in obesity leads to an increase in insulin and glucose. Insulin, insulin-like growth factor-1 and downstream pathways are activated increasing fuel metabolism and cell growth through Akt-dependent pathways. Energy sensing pathways such as AMP-activated protein kinase and mammalian target of rapamycin are potential targets to blunt cell growth either through caloric restriction or pharmacologically.

Figure 2

Recruitment of inflammatory cells in the tumor microenvironment mediated by obesity. (a) Obese adipose tissue is characterized by hypertrophy and hyperplasia of adipocytes, apoptosis and a shift in the stroma from less inflammatory eosinophils and M2-polarized cells (promoting insulin sensitivity), to an environment rich in pro-inflammatory M1-polarized macrophages, crown-like structures and activated fibroblasts. The mammary gland displays many of the same phenotypic changes with obesity. This low-level chronic inflammation in the tissue is known to induce oncogenesis, with an interesting shift in polarized macrophages from less M1 tumoricidal macrophages to more M2 tumor-promoting macrophages (b).