Novel Axl-driven signaling pathway and molecular signature characterize high-grade ovarian cancer patients with poor clinical outcome

Oncotarget. 2015 Oct 13;6(31):30859-75. doi: 10.18632/oncotarget.5087.

Abstract

High-grade epithelial ovarian cancer (HGEOC) is a clinically diverse and molecularly heterogeneous disease comprising subtypes with distinct biological features and outcomes. The receptor tyrosine kinases, expressed by EOC cells, and their ligands, present in the microenvironment, activate signaling pathways, which promote EOC cells dissemination. Herein, we established a molecular link between the presence of Gas6 ligand in the ascites of HGEOCs, the expression and activation of its receptor Axl in ovarian cancer cell lines and biopsies, and the progression of these tumors. We demonstrated that Gas6/Axl signalling converges on the integrin β3 pathway in the presence of the adaptor protein p130Cas, thus inducing tumor cell adhesion to the extracellular matrix and invasion. Accordingly, Axl and p130Cas were significantly co-expressed in HGEOC samples. Clinically, we identified an Axl-associated signature of 62 genes able to portray the HGEOCs with the shortest overall survival. These data biologically characterize a group of HGEOCs and could help guide a more effective therapeutic approach to be taken for these patients.

Keywords: Axl; Gas6; extracellular matrix; ovarian cancer; p130Cas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ascites / metabolism
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Biopsy
  • Carcinoma, Ovarian Epithelial
  • Cell Adhesion
  • Cell Line, Tumor
  • Crk-Associated Substrate Protein / genetics
  • Crk-Associated Substrate Protein / metabolism
  • Extracellular Matrix / metabolism
  • Female
  • Gene Expression Profiling* / methods
  • Gene Regulatory Networks
  • Humans
  • Integrin beta3 / genetics
  • Integrin beta3 / metabolism
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Neoplasm Grading
  • Neoplasms, Glandular and Epithelial / enzymology
  • Neoplasms, Glandular and Epithelial / genetics*
  • Neoplasms, Glandular and Epithelial / mortality
  • Neoplasms, Glandular and Epithelial / pathology
  • Neoplasms, Glandular and Epithelial / therapy
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / mortality
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / therapy
  • Predictive Value of Tests
  • Protein Interaction Maps
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • RNA Interference
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction / genetics*
  • Survival Analysis
  • Time Factors
  • Transfection
  • Treatment Outcome

Substances

  • BCAR1 protein, human
  • Biomarkers, Tumor
  • Crk-Associated Substrate Protein
  • ITGB3 protein, human
  • Integrin beta3
  • Intercellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • growth arrest-specific protein 6
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase