Obesity and cancer: the role of adipose tissue and adipo-cytokines-induced chronic inflammation

Abstract

Adipose tissue in addition to its ability to keep lipids is now recognized as a real organ with both metabolic and endocrine functions. Recent studies demonstrated that in obese animals is established a status of adipocyte hypoxia and in this hypoxic state interaction between adipocytes and stromal vascular cells contribute to tumor development and progression. In several tumors such as breast, colon, liver and prostate, obesity represents a poor predictor of clinical outcomes. Dysfunctional adipose tissue in obesity releases a disturbed profile of adipokines with elevated levels of pro-inflammatory factors and a consequent alteration of key signaling mediators which may be an active local player in establishing the peritumoral environment promoting tumor growth and progression. Therefore, adipose tissue hypoxia might contribute to cancer risk in the obese population. To date the precise mechanisms behind this obesity-cancer link is not yet fully understood. In the light of information provided in this review that aims to identify the key mechanisms underlying the link between obesity and cancer we support that inflammatory state specific of obesity may be important in obesity-cancer link.

Keywords: adipocytes inflammation; adipocytokine; cancer.; obesity.

Figure 1

Schematic representation of adipose tissue.

Figure 2

Adipocyte hypertrophy and hyperplasia induces an inflammatory cascade and accumulation of immune cells, activation of leukocytes, endothelial cells coupled with angiogenesis, adipogenesis and death of adipocytes.

Figure 3

The different mechanisms linking obesity and cancer. Excessive adipose tissue is related to the changes of the lipids concentrations in the circulation, levels of species reactive oxygen as well as to secretion of adipokines and circulating hormones. The hypertrophy and hypoxia of adipose tissue cause chronic inflammation. Thus, cytokines secreted by inflamed adipose tissue, production of angiogenic factors, infiltration of macrophages M1 and insulin resistance associated with obesity may favor stimulation of a favorable microenvironment for tumorigenesis.

Figure 4

Dysfunctional adipose tissue in obesity is associated with disturbed profile of mediators released from this tissue establishing a state of chronic inflammation. An increase of pro-inflammatory cytokines and leptin causes a down regulation of adiponectin. This results in a reduction of anti-inflammatory and anti-tumor activity explicated by adiponectin. In obesity high levels of pro-inflammatory cytokines such as TNF-α and IL-6 act systematically and could induce oncogenic effects in distant sites such as colon, liver, breast.

Figure 5

Summary of the various proteins secreted by white adipocytes both in conditions of normal volume and in hypertrophic adipocytes. Adipose tissue play an active role in controlling the physiological and pathological process through various adipokines. Dysfunctional adipose tissue in obesity releases a disturbed profile of adipokines with elevated levels of pro-inflammatory factors like leptin, IL-6 and TNF-alfa and reduced adiponectin that is protective against tumourigenesis. These adipokines have been implicated in cancer development and progression through their effects on insulin resistance, lipolysis and various inflammatory pathways. In the context of obesity, the hypertrophic expansion of adipose tissue induces local hypoxia, inflammatory activation and reactive angiogenesis, changes which favour tumourigenesis.

Figure 6

In obese subjects lower adiponectin levels lead to a reduction of the anti-inflammatory antidiabetic and antitumor power explicate by adiponectin. Decreased levels of adiponectin leads to a state of insulin resistance by cytokine-mediated inflammation contributing to the tumor permissive microenvironment that facilitates tumourigenesis.

Figure 7

Leptin plays important action in regulating glucose metabolism, in the satiety signal and increase insulin sensitivity. Under conditions of obesity can develop a state of leptin resistance and therefore the actions ensured by this hormone cannot be exercised. In obese subjects an increase of adipocytes is related to an increase in leptin levels that activates inflammatory cell response and induces pro-inflammatory cytokine production maintaining the obesity-associated state of chronic inflammation. In this context increased leptin levels lead to increased expression of anti-apoptotic, pro-inflammatory and angiogenic factors that promote proliferation and migration of cancer cells.

Figure 8

Actions of inflammatory triad. Obesity causes chronic silent inflammation with subsequent increased secretion of inflammatory triad cytokines and decreased production of adiponectin that make unable adipose tissue to store the surplus of free fatty acids contributing to a development of insulin resistance, type 2 diabetes, and obesity-related cardiovascular disease. The mitogenic and anti-apoptotic environment caused by elevated levels of insulin in obesity accelerates the stepwise accumulation of mutations and, hence, favor carcinogenesis. TNF-a, IL-6 and IL-1 signaling, enhancing carcinogenesis by increasing cell proliferation and neoangiogenic cell properties. In addition, the inflammatory enhancing expression of VEGF, ICAM-1 and VCAM-1 by endothelial cells.