Chemotherapy Resistance in Diffuse-Type Gastric Adenocarcinoma Is Mediated by RhoA Activation in Cancer Stem-Like Cells.

摘要: Purpose: The Lauren diffuse type of gastric adenocarcinoma (DGA), as opposed to the intestinal (IGA), often harbor mutations in RHOA but little is known about role RhoA DGA. Experimental Design: We examined activity and pathway inhibition DGA cell lines two mouse xenograft models. was also assessed patient tumor samples. Results: higher compared IGA lines, further increased when grown spheroids enrich for cancer stem-like cells (CSC) or sorted using CSC marker CD44. shRNA inhibitor Rhosin decreased expression stem transcription factor, Sox2, spheroid formation by 78-81%. had 3-5 fold greater migration invasion than monolayer cells, this Rho-dependent. Diffuse GA were resistant a cytotoxicity assay 5-fluorouracil cisplatin chemotherapy, resistance could be reversed with inhibition. In models, inhibited growth 40-50%, 32-60%, combination 77-83%. 288 tumors, correlated worse OS patients (p=0.017) not (p=0.612). Conclusions: signaling promotes phenotypes cells. Increased can reverse chemotherapy xenografts. Thus promising new target patients.