Obesity Contributes to Ovarian Cancer Metastatic Success through Increased Lipogenesis, Enhanced Vascularity, and Decreased Infiltration of M1 Macrophages

Abstract

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy, with high mortality attributable to widespread intra-peritoneal (i.p.) metastases. Recent meta-analyses report an association between obesity, ovarian cancer incidence, and ovarian cancer survival, but the effect of obesity on metastasis has not been evaluated. The objective of this study was to use an integrative approach combining in vitro, ex vivo, and in vivo studies to test the hypothesis that obesity contributes to ovarian cancer metastatic success. Initial in vitro studies using three-dimensional meso-mimetic cultures showed enhanced cell-cell adhesion to the lipid-loaded mesothelium. Furthermore, in an ex vivo colonization assay, ovarian cancer cells exhibited increased adhesion to mesothelial explants excised from mice modeling diet-induced obesity (DIO), in which they were fed a "Western" diet. Examination of mesothelial ultrastructure revealed a substantial increase in the density of microvilli in DIO mice. Moreover, enhanced i.p. tumor burden was observed in overweight or obese animals in three distinct in vivo models. Further histological analyses suggested that alterations in lipid regulatory factors, enhanced vascularity, and decreased M1/M2 macrophage ratios may account for the enhanced tumorigenicity. Together, these findings show that obesity potently impacts ovarian cancer metastatic success, which likely contributes to the negative correlation between obesity and ovarian cancer survival.

Loss of the novel mitochondrial protein FAM210B promotes metastasis via PDK4-dependent metabolic reprogramming

“…14 Therefore, we applied the suppression of mortality by SMART to screen genes involved in tumor progression. We showed that low expression of the new gene FAM210B attenuated the TSA effects in cancer cells and promoted malignant metastasis through metabolic reprogramming.…”

Effect of Pantethine on Ovarian Tumor Progression and Choline Metabolism

“…Finally, it was recently shown that obesity contributes to ovarian cancer metastases formation (38). Adipose tissue is a key component of the ovarian cancer metastatic microenvironment (39, 40).…”

“…Adipose tissue is a key component of the ovarian cancer metastatic microenvironment (39, 40). Increased body fat enhances tumor cell–mesothelial cell adhesion and promotes intraperitoneal metastatic dissemination (38). As a known hypolipidemic agent, pantethine may influence metastases formation through its hypolipidemic effects.…”

Emerging Concepts Linking Obesity with the Hallmarks of Cancer

“…Peritumoural fat from obese patients with colorectal cancer has increased expression of genes involved in inflammation, including those encoding cyclo-oxygenase-2 (COX2) and peroxisome proliferator-activated receptor gamma (PPARg) compared with nonobese patients [72]. Increased peritoneal ovarian tumour metastatic growth was observed in obese versus control mice, in three different models of DIO, and this was correlated with enhanced vascularity and a decreased M1:M2 macrophage ratio [73]. These data suggest an altered tumour microenvironment influenced by crosstalk between peritumoural fat and tumour cells [68].…”