Role of Obesity in Tumor Microenvironment

Abstract

Obesity is a serious social problem in the world and has been known to contribute the high risk of several chronic diseases including cancer. Epidemiologic studies have demonstrated that increased circulating levels of insulin, insulin-like growth factor (IGF)-1, leptin, inflammatory factors, vascular endothelial growth factor (VEGF) and plasminogen activator inhibitor (PAI)-1, are typically observed in obese individuals. Therefore, obesity is considered as an chronic inflammatory response, which is characterized by production of abnormal cytokine which trigger the proinflammatory signaling and modulate cellular differentiation, apoptosis, proliferation, and angiogenesis. Adipose tissue is an active endocrine organ and secrets variety of hormones, bioactive peptides, and cytokines, termed adipokines, such as leptin, TNF-α, IL-6 and insulin & insulin like growth factor. Elevated levels of proinflammatory cytokines have been noted in the serum of asymptomatic obese individuals corresponding to the degree of obesity, including leptin, TNF-a, IL-6 and insulin & insulin like growth factor. These cytokines are regulated by the transcription factor NF-κB. NF-κB controls the expression of the genes linked with proliferation, invasion, angiogenesis, and metastasis of cancer. Tumor microenvironment is the cellular environment in which the tumor exists, including surrounding blood vessels, immune cells, fibroblasts, other cells, signaling molecules, and the extracellular matrix (ECM). The tumor microenvironment contributes to every aspect of carcinogenesis including malignant transformation, tumor growth, metastasis, and drug resistance. In chronic inflammation, proinflammatory cytokines such as TNF-? can induce DNA damage through generation of reactive oxygen/nitrogen species (ROS/RNS), which leads to tumor initiation. Growth factors, ROS, RNS, and cytokines released from inflammatory cells lead to genomic alterations in the epithelium and subsequent cancer initiation. Thease cytokines can promote malignant transformation through epithelial-mesenchymal transition (EMT). Tumor growth and invasion are also favored by proinflammatory cytokines that stimulate cell proliferation, reduce apoptosis, and enhance EMT and angiogenesis. Dietary fat also associated with tumor microenvironment. Dietary fat increases solid tumor growth and could prolong mortality. Several studies reported that HFD diet (60% kcal fat) induces tumor growth and progression through EMT and inflammatory response in a mouse xenograft tumor model. Dietary fatty acid, such as arachidonic acid and oleic acid present esterified form in cell membrane phospholipids promote MAPK activation and mediate the adhesion, migration and invasion. Chronic hypernutrition such as high level of dietary saturated fatty acids (SFA) and trans-fatty acids stimulates intracellular pathways leading to oxidative stress through multiple biochemical mechanisms include hypoxia, therefore, a low grade oxidative condition is unbroken. Hypoxia promotes growth stimulatory functions or enhanced pro-tumorigenic and angiogenesis and metastasis. In conclusion, this review is mainly focused on effects of several cytokines derived from accumulated adipocytes on carcinogenesis, particularly obesity-associated tumor microenvironment and their underlying molecular mechanisms.