Macrophage Blockade Using CSF1R Inhibitors Reverses the Vascular Leakage
Underlying Malignant Ascites in Late-Stage Epithelial Ovarian Cancer
#MMPMID26471360
Moughon DL
; He H
; Schokrpur S
; Jiang ZK
; Yaqoob M
; David J
; Lin C
; Iruela-Arispe ML
; Dorigo O
; Wu L
Cancer Res
2015[Nov]; 75
(22
): 4742-52
PMID26471360
show ga
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.
|Animals
[MESH]
|Anisoles/*pharmacology
[MESH]
|Ascites/etiology/*prevention & control
[MESH]
|Capillary Permeability/*drug effects
[MESH]
|Carcinoma, Ovarian Epithelial
[MESH]
|Cell Line, Tumor
[MESH]
|Disease Models, Animal
[MESH]
|Female
[MESH]
|Flow Cytometry
[MESH]
|Humans
[MESH]
|Immunohistochemistry
[MESH]
|Macrophages/*drug effects
[MESH]
|Mice
[MESH]
|Neoplasms, Glandular and Epithelial/*complications
[MESH]
free
free
free
