Role of MCP-1 in Promoting Adiposity-Driven Ovarian Cancer
Rattan R, Buekers TE, Raja V, Hijaz M, Hanna RK, Hamid S, Giri S, and Munkarah AR. Role of MCP-1 in Promoting Adiposity-Driven Ovarian Cancer. Gynecol Oncol 2019; 154:95.
Objective: Ovarian cancer cells use fat from adipocytes to fuel their growth. We have shown that ovarian cancer cells exposed to adipocyte-conditioned media have an increased expression of monocyte chemoattractant protein-1 (MCP-1). MCP-1 aids in inflammatory response and increases adhesion and invasion of ovarian cancer cells. We showed that a high-fat diet induced aggressive ovarian cancer tumors in mice and produced increased amounts of MCP-1 and decreased expression of phosphorylated AMPK (amino monophosphate-activated kinase). In the current study we tested our hypothesis that MCP-1 promotes migration/invasion of ovarian cancer cells by promoting inflammatory immune response via inhibition of AMPK. Method: ID8 ovarian cancer cells were treated with MCP-1, and effects on proliferation, migration, and invasion were assessed by MTT assay, scratch assay, and a migration/invasion assay, respectively. Western blots were performed to identify effects of MCP-1 on phosphorylated AMPK (pAMPK). Preclinical efficacy of a MCP-1 neutralizing monoclonal antibody (mAb, 100 μg/bd kg wt thrice a week) was investigated in an immunocompetent syngeneic mouse ID8 ovarian cancer model on high-fat or regular diet. Tumor growth was monitored by in situ luciferase guided imaging and immunohistochemical markers, and immune response was assessed by flow cytometry. Results: In vitro MCP-1 did not affect the ovarian cancer cell proliferation but increased the rate of cell migration (P < 0.01) and invasion (P < 0.05). MCP-1 reduced AMPK activity. Activation of AMPK by metformin reversed the increase seen in MCP-1 mediated migration and invasion (P < 0.05). In vivo MCP-1 mAb treatment slowed the progression of ovarian cancer tumor growth and decreased the metastatic spread in mice as seen by decreased tumor burden (P < 0.01) and Ki-67 (P < 0.01). Neutralizing MCP-1 decreased the infiltration of tumor-associated macrophages and myeloid-derived suppressor cells (P < 0.05), while it increased infiltration of T cells (P < 0.05), with the effect being more pronounced in obese mice than in regular mice. Conclusion: MCP-1 plays a crucial role in promoting ovarian cancer growth possibly by inhibition of AMPK, especially under conditions of increased adiposity.