Current mechanisms in obesity and tumor progression

Abstract

Purpose of review: Hyperadiposity, as present in obesity, is a substantial threat to cancer risk and prognosis. Studies that have investigated the link between obesity and tumor progression have proposed several mechanistic frameworks, yet, these mechanisms are not fully defined. Further, a comprehensive understanding of how these various mechanisms may interact to create a dynamic disease state is lacking in the current literature.

Recent findings: Recent work has begun to explore not only discrete mechanisms by which obesity may promote tumor growth (for instance, metabolic and growth factor functions of insulin; inflammatory cytokines; adipokines; and others), but also how these putative tumor-promoting factors may interact.

Summary: This review will highlight the present understanding of obesity, as it relates to tumor development and progression. First, we will introduce the impact of obesity in cancer within the dynamic tumor microenvironment, which will serve as a theme to frame this review. The core of this review will discuss recently proposed mechanisms that implicate obesity in tumor progression, including chronic inflammation and the role of pro-inflammatory cytokines, adipokines, hormones, and genetic approaches. Furthermore, we intend to offer current insight in targeting adipose tissue during the development of cancer prevention and treatment strategies.

FIGURE 1.

Obesity and adipose tissue inflammation. Obesity-induced inflammation in adipose tissue leads to dysfunction of several processes in adipose tissue. Obesity-induced inflammation increases in both the size and number of adipocytes, leading structural and functional damage, hypoxia, oxidative stress and increased cancer risk. Increase in hormone signaling leads to upregulation of metabolic pathways like JAK/STAT3 and AMPK. Inflamed adipose tissue incites abnormal adipokine secretion, including leptin and adiponectin. In a state of chronic injury, inflamed adipose tissue is infiltrated by pro-inflammatory factors, such as macrophages, IL-6 and TNFα. Systemic changes in obesity such as increased insulin resistance and cancer risk are mediated by this altered adipose tissue state. IL-6, interleukin-6; TNFα, tumor necrosis factor-α.

FIGURE 2.

Adipose tissue inflammation and the tumor microenvironment. In the presence of the tumor microenvironment, the obesity-induced altered adipose tissue state becomes a source of energy substrates and structural support for the growing tumor. Tumor tissue induce a transformation from adipocytes to CAAs where resources are shuttled to the tumor. Various mechanisms support tumor sustenance and metastasis, including increased adipocyte lipolysis, secretion of inflammatory cytokines, and metabolic reprogramming. The inflamed adipose tissue creates a pro-tumor environment where the tumor can adopt a more aggressive and invasive phenotype. AT, adipose tissue; CAA, cancer-associated adipocyte.

FIGURE 3.

Mechanisms by which adipocyte dysfunction may promote tumor growth. In obesity, the hyperplastic, hypertrophic adipocytes – including CAAs – promote inflammation, ECM remodeling, and oxidative stress. These phenomena promote a variety of pathologic properties, including increases in adipokine and cytokine secretion, increased circulating insulin, leptin, and estrogen concentrations, and long noncoding RNAs. Together, each of these perturbations has been proposed to promote tumor pathogenesis. CAA, cancer-associated adipocyte; ECM, extracellular matrix; FFA, free fatty acids; lncRNAs, long noncoding RNAs.