Obesity and Cancer Metastasis: Molecular and Translational Perspectives

Abstract

Obesity is a modern health problem that has reached pandemic proportions. It is an established risk factor for carcinogenesis, however, evidence for the contribution of adipose tissue to the metastatic behavior of tumors is also mounting. Over 90% of cancer mortality is attributed to metastasis and metastatic tumor cells must communicate with their microenvironment for survival. Many of the characteristics observed in obese adipose tissue strongly mirror the tumor microenvironment. Thus in the case of prostate, pancreatic and breast cancer and esophageal adenocarcinoma, which are all located in close anatomical proximity to an adipose tissue depot, the adjacent fat provides an ideal microenvironment to enhance tumor growth, progression and metastasis. Adipocytes provide adipokines, fatty acids and other soluble factors to tumor cells whilst immune cells infiltrate the tumor microenvironment. In addition, there are emerging studies on the role of the extracellular vesicles secreted from adipose tissue, and the extracellular matrix itself, as drivers of obesity-induced metastasis. In the present review, we discuss the major mechanisms responsible for the obesity–metastatic link. Furthermore, understanding these complex mechanisms will provide novel therapies to halt the tumor–adipose tissue crosstalk with the ultimate aim of inhibiting tumor progression and metastatic growth.

Adipose Tissue-Derived Extracellular Vesicles and the Tumor Microenvironment: Revisiting the Hallmarks of Cancer

“…Given that the increased levels of these pro-inflammatory cytokines are directly correlated with the volume of both visceral and subcutaneous adipose tissue depots in obese patients, this may explain how these adipose tissue depots fuel the tumor microenvironment. Adipose tissue reinforces tumor progression in obesity [8,11,39]; for example, once in the tumor microenvironment, adipocytes are delipidated, possibly fueling breast cancer cells and overexpressing matrix metalloproteinase (MMP) 11, supporting the invasion of breast cancer cells [40]. However, there is still a lack of information on the establishment of such cooperation.…”

“…One of the mechanisms by which exosomes from ADMSCs induce cancer cell proliferation is through the modulation of Wnt/β-catenin signaling. Metastatic osteosarcoma is enriched in MSC-adipocytes and in vitro studies suggest that exosomes from ADMSCs increase proliferation and growth of osteosarcoma cells via the procollagen galactosyltransferase 2 (COLGALT2) pathway [39].…”

“…Recent studies have demonstrated a link between adipocyte EVs and tumor progression in melanoma, lung, and breast cancer [39]. Lazar et al observed that although adipocyte-derived exosomes increased melanoma cell migration and invasion, they did not affect proliferation in vitro.…”

“…Adipocytes maintain crosstalk with cancer cells, fueling the tumor microenvironment with free fatty acids, leptin, ketone bodies, and other macromolecules that alter the metabolism in neoplastic cells. These free fatty acids enter tumor cells via lipid transporters such as fatty acid-binding protein (FABP4) and fatty acid transport protein (FATP1) [39]. Such alterations in lipid availability favor β-oxidation and leptin activation of PI3K/MAPK and JAK/STAT pathways, promoting cell proliferation and survival [9].…”

“…Furthermore, the Warburg effect can also be induced by glycolytic enzymes transported from bone marrow adipocytes to cancer cells. Following uptake by the cells, the cells undergo oxidative stress and secrete reactive oxygen species (ROS) into the tumor microenvironment, promoting the "reverse Warburg effect" to trigger aerobic glycolysis and production of high energy metabolites [39]. Clement et al demonstrated that AD-EVs provide fatty acids to the melanoma microenvironment that are stored in lipid droplets, and are used to maintain fatty acid oxidation (FAO) in mitochondria.…”