Macrophage Blockade Using CSF1R Inhibitors Reverses the Vascular Leakage Underlying Malignant Ascites in Late-Stage Epithelial Ovarian Cancer

Abstract

Malignant ascites is a common complication in the late stages of epithelial ovarian cancer (EOC) that greatly diminishes the quality of life of patients. Malignant ascites is a known consequence of vascular dysfunction, but current approved treatments are not effective in preventing fluid accumulation. In this study, we investigated an alternative strategy of targeting macrophage functions to reverse the vascular pathology of malignant ascites using fluid from human patients and an immunocompetent murine model (ID8) of EOC that mirrors human disease by developing progressive vascular disorganization and leakiness culminating in massive ascites. We demonstrate that the macrophage content in ascites fluid from human patients and the ID8 model directly correlates with vascular permeability. To further substantiate macrophages’ role in the pathogenesis of malignant ascites, we blocked macrophage function in ID8 mice using a colony-stimulating factor 1 receptor kinase inhibitor (GW2580). Administration of GW2580 in the late stages of disease resulted in reduced infiltration of protumorigenic (M2) macrophages and dramatically decreased ascites volume. Moreover, the disorganized peritoneal vasculature became normalized and sera from GW2580-treated ascites protected against endothelial permeability. Therefore, our findings suggest that macrophage-targeted treatment may be a promising strategy toward a safe and effective means to control malignant ascites of EOC.

The Multifaceted Role of Perivascular Macrophages in Tumors

“…It also remains to be seen whether such PV TAMs (and TMEMs generally) exist in other types of primary tumor than just mammary cancers. This may prove to be the case as TAMs have also recently been reported to promote vascular permeability in a mouse ovarian tumor model (Moughon et al, 2015). …”

Upregulation of IGF1 by tumor-associated macrophages promotes the proliferation and migration of epithelial ovarian cancer cells

“…An inhibitor of IDO, which is associated with the formation of TAMs, can control the growth of OC in vivo (40). An MCSF inhibitor was found to reduce the infiltration of TAMs, and promote the survival of peritoneal blood vessels, thereby reducing the production of ascites in mice transplanted with OC cells (41).…”

Major clinical research advances in gynecologic cancer in 2015

“…However, CSF-1R inhibition by GW2580, a selective CSF-1R inhibitor, was shown to reverse the abnormal vascular features and reduce vascular dysfunction and in this ID8 model as well as human OVCAR3 xenograft model. Notably, the high 3:1 ratio of M2:M1 macrophage was reduced to approximately 1:1 by GW2580 treatment [81]. Considering the abundant secretion of CSF-1 in many ovarian cancers, this study suggests that malignant ascites derived from vascular dysfunction could be safely controlled by blocking the function of tumor-associated macrophage via selective blockade of CSF-1R.…”

“…Similarly, colony-stimulating factor 1 (CSF-1), a cytokine that regulates the differentiation, growth and function of macrophages, is also known to be elevated in the ascites of ovarian cancer patients, and which associated with poor prognosis [7879]. On the other hand, anti-VEGF antibody, bevacizumab, has been reported to cause fatal side effects, for example, intestinal perforation in up to 10% of patients in clinical trials [80], Moughon et al [81] demonstrated that macrophage-targeted treatment with CSF-1R inhibitors lessen the number of pro-tumor macrophages and allow the vessels in the abdomen to become normal again, easing ascites accumulation without any concern about fatal side effects. In an immunocompetent murine model (ID8) of ovarian cancer which mimic late stages of human ovarian cancer with ascites, the macrophage content in the ascites directly correlated with vascular permeability.…”