Posted July 24, 2014
Andrew Wilson, Ph.D., Vanderbilt University Medical Center, Nashville, Tennessee
Ovarian cancer is typically diagnosed in its advanced stage, characterized by peritoneal dissemination and accumulation of ascites, and few effective therapeutic options exist. Inflammation is a hallmark of cancer, and chronic inflammation is linked to ovarian cancer development and progression. Inflammation in ovarian cancer is mediated by the secretion of pro-inflammatory signals, called cytokines and chemokines, which are produced by peritoneal macrophages. This process is regulated by the nuclear factor-kappa B gene (NFΚB), which is often overexpressed in ovarian cancer tumors. Dr. Andrew Wilson of Vanderbilt University, with support from a Fiscal Year 2010 Ovarian Cancer Research Program Translational Pilot Award, sought to elucidate how NFΚB activation leads to ovarian tumor progression. Specifically, he was interested in determining if tumors progress due to NFΚB activation in the tumor cells themselves, in the surrounding peritoneal macrophages, or in both. To study this, Dr. Wilson developed a model in which he injected mouse ovarian cancer cells that "report" activity of NFΚB in the cell directly into the peritoneal cavity of mice. This models the development of ovarian cancer as well as ascites and peritoneal carcinomatosis. He assessed the ascites fluid of the mice and found that they had significantly higher levels of macrophages as compared with mice without injection of tumors. He then treated tumor-injected mice with an NFΚB inhibitor called thymoquine (TQ), which decreased NFΚB activity. Importantly, this treatment resulted in a shift in macrophage phenotype from the "pro-tumor" M2 subtype to an "anti-tumor" M1 subtype, suggesting that NFΚB activation in macrophages plays an important role in ovarian tumor progression. Furthermore, treatment with TQ in combination with the chemotherapeutic drug cisplatin led to cooperative effects in reducing tumor burden in these mice, providing further evidence supporting the targeting of NFΚB for ovarian cancer treatment. Moreover, the development of this mouse model represents an important resource for future testing of additional NFΚB inhibitors or other anti-inflammatory drugs for advanced ovarian cancer.