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.

Keywords: adipokines; adipose tissue; cancer metabolism; cancer relapse; cytokines; extra cellular vesicles; extracellular matrix; metastasis; obesity; tumor progression.

Figure 1

Schematic diagram depicting the keys steps of the metastatic cascade from initial presentation as an in situ tumor mass at the primary site to macroscopically detected metastatic lesions at secondary sites.

Figure 2

Summary of cross talk between adipose tissue and cancer cells that promote metastasis. Hyperinsulinemia in obesity induces insulin growth factor (IGF)-1 signaling, which promotes epithelial to mesenchymal transition (EMT) and cancer stem cells (CSCs) though ZEB and SNAIL transcription factors leading to an increase in pluripotency transcription factors (OCT4, SOX2 and NANOG) and the developmental signaling pathways (Wnt and NOTCH). Interleukin 1β (IL-1β) promotes promote tumor cell homing to the bone marrow and angiogenesis through vascular endothelial growth factor (VEGF) signaling. Interleukin 6 (IL-6) and leptin induces epithelial to mesenchymal transition (EMT) and CSCsthough JAK/STAT3 signaling. Tumor necrosis factor α (TNFα) induces trans endothelial migration and CSCs though nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. Fatty acid binding proteins (FABP) modulates fatty acid metabolism from neighboring adipocytes to provide fuel for tumor cells to metastasis. Matrix metalloproteinase 11 (MMP-11) dedifferentiates mature adipocytes into cancer associated adipocytes (CAAs) leading to extra cellular matrix (ECM) remodeling and fibrosis. Asparagine promotes EMT in primary tumors and increases tumor cell proliferation at distinct metastatic sites.