The adhesion molecule NCAM promotes ovarian cancer progression via FGFR signalling.
Bottom Line: NCAM is absent from normal ovarian epithelium but becomes highly expressed in a subset of human EOC, in which NCAM expression is associated with high tumour grade, suggesting a causal role in cancer aggressiveness.This pro-malignant function of NCAM is mediated by its interaction with fibroblast growth factor receptor (FGFR).Our results point to NCAM-mediated stimulation of FGFR as a novel mechanism underlying EOC malignancy and indicate that this interplay may represent a valuable therapeutic target.
Affiliation: IFOM - The FIRC Institute of Molecular Oncology, Milano, Italy.Show MeSH
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Mentions: To further characterize the role of the NCAM/FGFR complex in EOC dissemination to distant organs, SKOV3 cells were injected intraperitoneally into immunodeficient mice, a widespread model for EOC peritoneal metastasis (Arlt et al, 2006; Donahue et al, 2011; Shaw et al, 2004; Slack-Davis et al, 2009). For this purpose, we used SKOV3 cells co-expressing GFP and either an empty vector, full-length NCAM or NCAM-ΔFN2. The expression of NCAM, either full-length or ΔFN2, did not affect tumour volume, as assessed by measuring the neoplastic mass that formed in the omentum, which is the primary site colonized by SKOV3 cells upon intraperitoneal (i.p.) injection (Sawada et al, 2008; data not shown). After 5 weeks, peritoneal dissemination was assessed as the formation of GFP-positive tumour masses attached to the bowel, liver and diaphragm, all typical sites of EOC metastasis in patients. As shown in Fig 6A and B, NCAM expression resulted in increased number of bowel metastases as compared to mock-transfected cells (see Fig S10 of Supporting Information for additional images). NCAM also enhanced the dissemination of SKOV3 cells to the liver and the diaphragm, although the increase in liver metastasis did not reach statistical significance (Fig 6C). Notably, no enhancement of metastatic dissemination to organs of the peritoneal cavity was observed using cells expressing NCAM-ΔFN2 (Fig 6A–C). Rather, these cells gave rise to a number of bowel metastases that was even lower than that of mock-transfected cells (Fig 6B), a phenomenon that was not further investigated. Taken together, these findings implicate that the association of NCAM with FGFR is a prerequisite for EOC spreading in vivo.
Affiliation: IFOM - The FIRC Institute of Molecular Oncology, Milano, Italy.