Adipocytes: active facilitators in epithelial ovarian cancer progression?

Abstract

There is growing evidence that adipocytes play important roles in the progression of multiple cancers. Moreover, in obesity, adipocytes alter their original functions and contribute to the metabolic and inflammatory changes of adipose tissue microenvironment, which can further enhance tumor development. At present, the roles of adipocytes in the pathogenesis of epithelial ovarian cancer (EOC) are far from being fully elucidated. Herein, we summarized the recent advances in understanding the roles of adipocytes in EOC progression. Adipocytes, close neighbors of EOC tissue, promote EOC growth, invasion, metastasis and angiogenesis through adipokine secretion, metabolic remodeling and immune microenvironment modulation. Moreover, adipocytes are important therapeutic targets and may work as useful anticancer drug delivery depot for EOC treatment. Furthermore, adipocytes also act as a therapeutic obstacle for their involvement in EOC treatment resistance. Hence, better characterization of the adipocytes in EOC microenvironment and the crosstalk between adipocytes and EOC cells may provide insights into EOC progression and suggest novel therapeutic opportunities.

Keywords: Adipocytes; Cancer progression; Epithelial ovarian cancer.

Fig. 1

The role of adipocytes in EOC metastasis. Adipocyte-secreted cytokines, such as IL-6, IL-8, IL-11 and IL-33, induced EMT and detachment of EOC cells by inhibiting E-cadherin expression. Adipocytes affect the travel of EOC cells in the peritoneal fluid through modulating several functions including (1) ascites formation by secreting VEGF, which increases vascular permeability; (2) EOC anoikis resistance by secreting IGF-1, IL-6 and IL-8, which activate the survival pathway and EMT of EOC; (3) EOC movement by secreting MCP-1, IL-6 and IL-8, which activate the mitogenic pathway of EOC. Adipocytes affect EOC implantation through modulating (1) EOC adhesion by secreting TNF-α and HGF, which promote CD44 expression; (2) EOC invasion by secreting Leptin, which promote MMP2 expression. Together, these roles of adipocytes facilitate adipocyte-induced EOC metastasis

Fig. 2

The role of adipocytes in immune microenvironment modulation. Adipocyte death leads to macrophage infiltration into adipose tissue, where they encircle the dying adipocytes to form crown-like structures (CLS). These macrophages are associated with the secretion of multiple inflammatory factors, which modulate the microenvironment to a state of chronic low-grade inflammation. Moreover, increased expression level of PD-L1 in mature adipocytes could interact with T cell surface PD-1 to impair CD8+ T cell activation and cause immunosuppression. Together, these roles of adipocytes facilitate evolution of the immune microenvironment and EOC progression