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Mol Cancer Ther. 2018 Feb;17(2):532-543. doi: 10.1158/1535-7163.MCT-17-0643. Epub 2017 Nov 16.

A Role for CXCR4 in Peritoneal and Hematogenous Ovarian Cancer Dissemination.

Author information

1
Program Against Cancer Therapeutic Resistance (ProCURE), Institut Català d'Oncologia, Hospital Duran i Reynals, Barcelona, Spain.
2
Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain.
3
Liquid Biopsy Analysis Unit, Oncomet, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
4
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
5
Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPaz, Madrid, Spain.
6
MD Anderson International Foundation, Madrid, Spain.
7
Laboratori d'Oncologia Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain.
8
Servei d'Anatomia Patològica, Hospital Universitari de Bellvitge, Barcelona, Spain.
9
Xenopat, Carrer de la Feixa Llarga S/N, L'Hospitalet de Llobregat, Barcelona, Spain.
10
Departament de Patologia i Terapèutica Experimental, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
11
Program Against Cancer Therapeutic Resistance (ProCURE), Institut Català d'Oncologia, Hospital Duran i Reynals, Barcelona, Spain. fvinyals@iconcologia.net.
12
Departament de Ciències Fisiològiques, Universitat de Barcelona, Barcelona, Spain.

Abstract

Epithelial ovarian cancer is characterized by a low recovery rate because the disease is typically diagnosed at an advanced stage, by which time most patients (80%) already exhibit disseminated neoplasia. The cytokine receptor CXCR4 has been implicated in the development of metastasis in various tumor types. Using a patient-derived tissue macroarray and mRNA expression analysis, we observed high CXCR4 levels in high-grade serous epithelial ovarian carcinomas, the most metastatic tumor, compared with those in endometrioid carcinomas. CXCR4 inhibition by treatment with the CXCR4 antagonist AMD3100 or by expression of shRNA anti-CXCR4 similarly inhibited angiogenesis in several models of ovarian carcinomas orthotopically grown in nude mice, but the effect on tumor growth was correlated with the levels of CXCR4 expression. Moreover, CXCR4 inhibition completely blocked dissemination and metastasis. This effect was associated with reduced levels of active Src, active ERKs, the inhibition of EMT transition, and block of hematogenous ovarian cancer dissemination decreasing circulating human tumoral cells (CTC). In tumors, CXCR4-expressing cells also had more mesenchymal characteristics. In conclusion, our results indicate that CXCR4 expression confers a proinvasive phenotype to ovarian carcinoma cells. Thus, anti-CXCR4 therapy is a possible agent for a complementary treatment of advanced disseminated epithelial high-grade serous ovarian cancer patients. Mol Cancer Ther; 17(2); 532-43. ©2017 AACR.

PMID:
29146630
DOI:
10.1158/1535-7163.MCT-17-0643
[Indexed for MEDLINE]
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