Mechanisms linking excess adiposity and carcinogenesis promotion

Abstract

Obesity constitutes one of the most important metabolic diseases being associated to insulin resistance development and increased cardiovascular risk. Association between obesity and cancer has also been well established for several tumor types, such as breast cancer in post-menopausal women, colorectal, and prostate cancer. Cancer is the first death cause in developed countries and the second one in developing countries, with high incidence rates around the world. Furthermore, it has been estimated that 15-20% of all cancer deaths may be attributable to obesity. Tumor growth is regulated by interactions between tumor cells and their tissue microenvironment. In this sense, obesity may lead to cancer development through dysfunctional adipose tissue and altered signaling pathways. In this review, three main pathways relating obesity and cancer development are examined: (i) inflammatory changes leading to macrophage polarization and altered adipokine profile; (ii) insulin resistance development; and (iii) adipose tissue hypoxia. Since obesity and cancer present a high prevalence, the association between these conditions is of great public health significance and studies showing mechanisms by which obesity lead to cancer development and progression are needed to improve prevention and management of these diseases.

Keywords: adipokine; adipose tissue; carcinogenesis; hypoxia; inflammation; insulin resistance; obesity.

Figure 1

Macrophages are representative of the innate immune system and represent a large proportion of the stromovascular cell fraction in adipose tissue. The phenotype of macrophages depends on the subset of monocytes upon arrival at target tissues being probably determined by the local microenvironment. Based on their cytokine profile secretion and cell surface markers, macrophages are classified into two main types: the “classical” macrophages named M1 in contrast to the “alternatively activated” M2. M1 macrophages are the first line of defense against intracellular pathogens and are classically stimulated by interferon (IFN)-γ or by lipopolysaccharide (LPS). M1 induce the secretion of inflammatory cytokines [interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, or monocyte chemoattractant protein (MCP)-1]. Alternative activation, resulting from induction by the Th2 cytokines interleukin IL-4 and IL-13, is associated with tissue repair and humoral immunity producing immunosuppressive factors, including IL-10, IL-1Ra, and arginase. Obesity and initial tumor stages induce a phenotypic switch from an anti-inflammatory M2-polarized state to a pro-inflammatory M1 state.

Figure 2

Proposed mechanisms linking obesity and cancer. The excess of adipose tissue, especially abdominal obesity, is related to changes in circulating lipid concentrations, reactive oxygen species levels as well as adipokine and hormone secretion profile. Obesity is also linked to adipocyte hypertrophy and hypoxia, aggravating the inflammatory state. Therefore, the adipose tissue-derived inflammatory cytokines, the production of angiogenic factors by adipocytes, or infiltrating M1 macrophages that take place in obesity together with the obesity-associated insulin resistance may promote the stimulation of a microenvironment favorable for tumorigenesis. CRP, C-reactive protein; HIF-1α, hypoxia-inducible factor-1α; IGF, insulin growth factor; IGFBP, insulin-like growth factor-binding protein; IL, interleukin; MCP-1, monocyte chemoattractant protein 1; MMP, matrix metalloproteinase; OPN, osteopontin; PAI-1, plasminogen activator inhibitor-1; TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor α; YKL-40, chitinase-3-like protein.