title: 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.
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California.
authors.forename: Diana L
authors.initials: DL
authors.lastname: Moughon
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California.
authors.forename: Shiruyeh
authors.initials: S
authors.lastname: Schokrpur
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California. Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Ziyue Karen
authors.initials: ZK
authors.lastname: Jiang
authors.affiliation: Department of Surgery and Cancer, Hammersmith hospital, Imperial College London, London, United Kingdom.
authors.forename: Madeeha
authors.initials: M
authors.lastname: Yaqoob
authors.affiliation: Department of Molecular and Medical Pharmacology, California Nanosystems Institute, Los Angeles, California.
authors.forename: John
authors.initials: J
authors.lastname: David
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California.
authors.forename: Crystal
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Molecular, Cell and Developmental Biology, Los Angeles, California. Molecular Biology Institute, University of California Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California.
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Iruela-Arispe
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Oliver
authors.initials: O
authors.lastname: Dorigo
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California. Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California. lwu@mednet.ucla.edu.
authors.forename: Lily
authors.initials: L
authors.lastname: Wu
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D001201:Ascites / Q000209:etiology / Q000517:prevention & control*; D002199:Capillary Permeability / Q000187:drug effects*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D009375:Neoplasms, Glandular and Epithelial / Q000150:complications*; D010051:Ovarian Neoplasms / Q000150:complications*; D011743:Pyrimidines / Q000494:pharmacology*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors
chemical_list: C506269:5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine; D000840:Anisoles; C000604004:Csf1r protein, mouse; D011743:Pyrimidines; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor