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The adhesion molecule NCAM promotes ovarian cancer progression via FGFR signalling.

Zecchini S, Bombardelli L, Decio A, Bianchi M, Mazzarol G, Sanguineti F, Aletti G, Maddaluno L, Berezin V, Bock E, Casadio C, Viale G, Colombo N, Giavazzi R, Cavallaro U - EMBO Mol Med (2011)

Bottom Line: Epithelial ovarian carcinoma (EOC) is an aggressive neoplasm, which mainly disseminates to organs of the peritoneal cavity, an event mediated by molecular mechanisms that remain elusive.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).

View Article: PubMed Central - PubMed

Affiliation: IFOM - The FIRC Institute of Molecular Oncology, Milano, Italy.

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NCAM promotes peritoneal dissemination of EOC through its FGFR-binding domainGFP-expressing SKOV3 cells transfected with empty vector (mock), full-length NCAM or NCAM-ΔFN2 were injected into the peritoneum of nude mice. Tumour dissemination was then assessed as described in Materials and Methods Section. **p < 0.005 and *p < 0.05.Brightfield (left panels) and fluorescence images (right panels) of the same fields showing bowel metastases. Arrows indicate GFP-positive tumour masses. Scale bar, 1 mm.Quantification of bowel metastases, represented as number of GFP-positive tumour masses per microscopic field. Data are expressed as means ± SD (n = 10 for each group).Metastatic dissemination of GFP-positive cells to the liver and to the diaphragm was determined by counting the total number of GFP-positive lesions per organ as described in Materials and Methods Section. Values are expressed as the mean percentage (±SD; n = 10 for each group) of GFP-positive cells over the total number of cells analysed.
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fig06: NCAM promotes peritoneal dissemination of EOC through its FGFR-binding domainGFP-expressing SKOV3 cells transfected with empty vector (mock), full-length NCAM or NCAM-ΔFN2 were injected into the peritoneum of nude mice. Tumour dissemination was then assessed as described in Materials and Methods Section. **p < 0.005 and *p < 0.05.Brightfield (left panels) and fluorescence images (right panels) of the same fields showing bowel metastases. Arrows indicate GFP-positive tumour masses. Scale bar, 1 mm.Quantification of bowel metastases, represented as number of GFP-positive tumour masses per microscopic field. Data are expressed as means ± SD (n = 10 for each group).Metastatic dissemination of GFP-positive cells to the liver and to the diaphragm was determined by counting the total number of GFP-positive lesions per organ as described in Materials and Methods Section. Values are expressed as the mean percentage (±SD; n = 10 for each group) of GFP-positive cells over the total number of cells analysed.

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.


The adhesion molecule NCAM promotes ovarian cancer progression via FGFR signalling.

Zecchini S, Bombardelli L, Decio A, Bianchi M, Mazzarol G, Sanguineti F, Aletti G, Maddaluno L, Berezin V, Bock E, Casadio C, Viale G, Colombo N, Giavazzi R, Cavallaro U - EMBO Mol Med (2011)

NCAM promotes peritoneal dissemination of EOC through its FGFR-binding domainGFP-expressing SKOV3 cells transfected with empty vector (mock), full-length NCAM or NCAM-ΔFN2 were injected into the peritoneum of nude mice. Tumour dissemination was then assessed as described in Materials and Methods Section. **p < 0.005 and *p < 0.05.Brightfield (left panels) and fluorescence images (right panels) of the same fields showing bowel metastases. Arrows indicate GFP-positive tumour masses. Scale bar, 1 mm.Quantification of bowel metastases, represented as number of GFP-positive tumour masses per microscopic field. Data are expressed as means ± SD (n = 10 for each group).Metastatic dissemination of GFP-positive cells to the liver and to the diaphragm was determined by counting the total number of GFP-positive lesions per organ as described in Materials and Methods Section. Values are expressed as the mean percentage (±SD; n = 10 for each group) of GFP-positive cells over the total number of cells analysed.
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fig06: NCAM promotes peritoneal dissemination of EOC through its FGFR-binding domainGFP-expressing SKOV3 cells transfected with empty vector (mock), full-length NCAM or NCAM-ΔFN2 were injected into the peritoneum of nude mice. Tumour dissemination was then assessed as described in Materials and Methods Section. **p < 0.005 and *p < 0.05.Brightfield (left panels) and fluorescence images (right panels) of the same fields showing bowel metastases. Arrows indicate GFP-positive tumour masses. Scale bar, 1 mm.Quantification of bowel metastases, represented as number of GFP-positive tumour masses per microscopic field. Data are expressed as means ± SD (n = 10 for each group).Metastatic dissemination of GFP-positive cells to the liver and to the diaphragm was determined by counting the total number of GFP-positive lesions per organ as described in Materials and Methods Section. Values are expressed as the mean percentage (±SD; n = 10 for each group) of GFP-positive cells over the total number of cells analysed.
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.

Bottom Line: Epithelial ovarian carcinoma (EOC) is an aggressive neoplasm, which mainly disseminates to organs of the peritoneal cavity, an event mediated by molecular mechanisms that remain elusive.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).

View Article: PubMed Central - PubMed

Affiliation: IFOM - The FIRC Institute of Molecular Oncology, Milano, Italy.

Show MeSH
Related in: MedlinePlus