Abstract
Obesity, and in particular visceral obesity, has been associated with an increased risk of developing cancers as well as higher rates of mortality following diagnosis. The impact of obesity on adipose-derived stromal cells (ASC), which contribute to the formation of tumor stroma, is unknown. Here we hypothesized that visceral source and diet-induced obesity (DIO) changes the ASC phenotype, contributing to the tumor promoting effects of obesity. We found that ASC isolated from subcutaneous (SC-ASC) and visceral (V-ASC) white adipose tissue(WAT) of lean(Le) and obese(Ob) mice exhibited similar mesenchymal cell surface markers expression, and had comparable effects on ovarian cancer cell proliferation and migration. Obese and visceral derived ASC proliferated slower and exhibited impaired differentiation into adipocytes and osteocytes in vitro as compared to ASC derived from subcutaneous WAT of lean mice. Intraperitoneal co-injection of ovarian cancer cells with obese or visceral derived ASC, but not lean SC-ASC, increased growth of intraperitoneal ID8 tumors as compared to controls. Obese and V-ASC increased stromal infiltration of inflammatory cells, including CD3+ T cells and F4/80+ macrophages. Obese and visceral derived ASC, but not lean SC-ASC, increased expression of chemotactic factors IL-6, MIP-2, and MCP-1 when cultured with tumor cells. Overall, these results demonstrate that obese and V-ASC have a unique phenotype, with more limited proliferation and differentiation capacity but enhanced expression of chemotactic factors in response to malignant cells which support infiltration of inflammatory cells and support tumor growth and dissemination.
Highlights
Obesity increases the risk and/or mortality of many cancers, including endometrial, colon, pancreatic, and ovarian cancers [1,2,3,4,5]
We found that tumors derived from mice receiving obese or visceral derived adipose-derived stromal cells (ASC) grew more rapidly than controls, while lean subcutaneous doi:10.1371/journal.pone.0136361.g006
It is worth noting that the majority of studies investigating ASC have utilized ASC derived from subcutaneous adipose tissue, most commonly from lean donors
Summary
Obesity increases the risk and/or mortality of many cancers, including endometrial, colon, pancreatic, and ovarian cancers [1,2,3,4,5]. Excess visceral white adipose tissue (WAT) has been shown to be particularity toxic, increasing risk and mortality independent of body mass index (BMI) in many cancers, including ovarian cancer [5]. Omental metastasis is a critical issue in ovarian cancer, which has the highest recurrence rate and lowest survival among gynecologic cancers. The mechanism behind this is not well known. To understand the role of ASC from different anatomically locations: subcutaneous and visceral adipose tissue, in ovarian cancer, we investigated the effect of dietinduced obesity (DIO) on these different ASCs and their role in tumor growth in the abdominal area by using a syngeneic intra-abdominal murine model of ovarian cancer. In vitro and in vivo assays were used to analyze ASC isolated from subcutaneous (SC-ASC) and visceral (V-ASC) WAT of lean (Le) and obese (Ob) mice to characterize the effects of obesity and adipose depot and ASC phenotype
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