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Assessment of Ovarian Cancer Spheroid Attachment and Invasion of Mesothelial Cells in Real Time
Published on: May 20, 2014
The RON and MET oncogenes are co-expressed in human ovarian carcinomas and cooperate in activating invasiveness
Piera Maggiora1, Annalisa Lorenzato, Stefano Fracchioli
1Laboratory of Cancer Genetics of the Institute for Cancer Research and Treatment, University of Torino School of Medicine, SP 142, Km 3.95, 10060 Candiolo (Torino), Italy.
Abstract:
RON is a member of the receptor tyrosine kinase gene family that includes the MET oncogene, whose germline mutations have been causally related to human tumorigenesis. In vitro, RON and MET receptors cross-talk, synergize in intracellular signaling, and cooperate in inducing morphogenic responses. Here we show that the RON and MET oncogenes were expressed in 55% and 56% of human ovarian carcinomas, respectively, and were significantly coexpressed in 42% (P < 0.001). In ovarian carcinoma samples and cell lines we did not find mutations in RON and MET gene kinase domain, nor coexpression of RON and MET receptor ligands (MSP and HGF, respectively). We show that motility and invasiveness of ovarian cancer cells coexpressing MET and RON receptors were elicited by HGF and, to a lesser extent, by MSP. More interestingly, invasion of both reconstituted basement membrane and collagen gel was greatly enhanced by the simultaneous addition of the two ligands. These data suggest that coexpression of the MET and RON receptors confer a selective advantage to ovarian cancer cells and might promote ovarian cancer progression.
Insights
Ovarian cancer cells expressing both RON and MET receptors show increased motility and invasiveness. Simultaneous ligand stimulation significantly enhances invasion, suggesting co-receptor expression promotes ovarian cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The receptor tyrosine kinase (RTK) family includes MET, linked to human tumorigenesis.
- RON and MET receptors are known to interact and synergize in signaling pathways.
Purpose of the Study:
- To investigate the expression and functional significance of RON and MET co-expression in human ovarian carcinomas.
- To determine the role of RON and MET signaling in ovarian cancer cell motility and invasiveness.
Main Methods:
- Analysis of RON and MET expression in human ovarian carcinoma samples and cell lines.
- Assessment of ovarian cancer cell motility and invasiveness in response to ligands MSP and HGF.
- Evaluation of invasion through basement membrane and collagen gel models.
Main Results:
- RON and MET were coexpressed in 42% of human ovarian carcinomas.
- No mutations were found in the kinase domains of RON and MET.
- Ovarian cancer cells coexpressing MET and RON showed increased motility and invasiveness elicited by HGF and MSP.
- Simultaneous addition of HGF and MSP significantly enhanced invasion.
Conclusions:
- Coexpression of MET and RON receptors provides a selective advantage to ovarian cancer cells.
- The MET-RON signaling axis may play a critical role in promoting ovarian cancer progression and metastasis.
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