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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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Antibody-mediated inhibition of NCAM/FGFR interplay reduces EOC peritoneal disseminationGFP-expressing SKOV3 cells transfected with full-length NCAM were injected into the peritoneum of nude mice. Mice were then treated with 123C3 or anti-HA antibodies, as described in Materials and Methods Section. **p < 0.005 and *p < 0.05.A. 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.B. Quantification of bowel metastases, represented as the average number of GFP-positive tumour masses per microscopic field. Data are expressed as means ± SD (n = 6 for each group).C,D. Metastatic dissemination of GFP-positive cells to the liver (C) and to the diaphragm (D) was determined by FACS analysis as described in Materials and Methods Section. Values are expressed as the mean percentage (±SD, n = 6 for each group) of GFP-positive cells over the total number of cells analysed.
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fig07: Antibody-mediated inhibition of NCAM/FGFR interplay reduces EOC peritoneal disseminationGFP-expressing SKOV3 cells transfected with full-length NCAM were injected into the peritoneum of nude mice. Mice were then treated with 123C3 or anti-HA antibodies, as described in Materials and Methods Section. **p < 0.005 and *p < 0.05.A. 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.B. Quantification of bowel metastases, represented as the average number of GFP-positive tumour masses per microscopic field. Data are expressed as means ± SD (n = 6 for each group).C,D. Metastatic dissemination of GFP-positive cells to the liver (C) and to the diaphragm (D) was determined by FACS analysis as described in Materials and Methods Section. Values are expressed as the mean percentage (±SD, n = 6 for each group) of GFP-positive cells over the total number of cells analysed.

Mentions: We therefore asked if this interaction could be specifically targeted to interfere with tumour dissemination. To address this question, mice xenotransplanted with SKOV3-NCAM cells were subjected to i.p. treatment with the mAb 123C3 that, as described above, interferes with NCAM-mediated activation of FGFR. The dissemination of SKOV3-NCAM cells to bowel and diaphragm was dramatically reduced in 123C3-treated mice, and a significant decrease was also observed in liver metastasis. In contrast, a control mAb showed no effect in SKOV3 cell dissemination (Fig 7). The mAb 123C3 does not cross-react with mouse NCAM (not shown), thus its inhibitory function on EOC metastasis is due to the neutralization of NCAM in cancer cells rather than in the microenvironment. These findings indicate that antibody-mediated targeting of the NCAM/FGFR interplay suppresses the metastatic potential of EOC cells, an observation that has relevant therapeutic implications.


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)

Antibody-mediated inhibition of NCAM/FGFR interplay reduces EOC peritoneal disseminationGFP-expressing SKOV3 cells transfected with full-length NCAM were injected into the peritoneum of nude mice. Mice were then treated with 123C3 or anti-HA antibodies, as described in Materials and Methods Section. **p < 0.005 and *p < 0.05.A. 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.B. Quantification of bowel metastases, represented as the average number of GFP-positive tumour masses per microscopic field. Data are expressed as means ± SD (n = 6 for each group).C,D. Metastatic dissemination of GFP-positive cells to the liver (C) and to the diaphragm (D) was determined by FACS analysis as described in Materials and Methods Section. Values are expressed as the mean percentage (±SD, n = 6 for each group) of GFP-positive cells over the total number of cells analysed.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3377089&req=5

fig07: Antibody-mediated inhibition of NCAM/FGFR interplay reduces EOC peritoneal disseminationGFP-expressing SKOV3 cells transfected with full-length NCAM were injected into the peritoneum of nude mice. Mice were then treated with 123C3 or anti-HA antibodies, as described in Materials and Methods Section. **p < 0.005 and *p < 0.05.A. 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.B. Quantification of bowel metastases, represented as the average number of GFP-positive tumour masses per microscopic field. Data are expressed as means ± SD (n = 6 for each group).C,D. Metastatic dissemination of GFP-positive cells to the liver (C) and to the diaphragm (D) was determined by FACS analysis as described in Materials and Methods Section. Values are expressed as the mean percentage (±SD, n = 6 for each group) of GFP-positive cells over the total number of cells analysed.
Mentions: We therefore asked if this interaction could be specifically targeted to interfere with tumour dissemination. To address this question, mice xenotransplanted with SKOV3-NCAM cells were subjected to i.p. treatment with the mAb 123C3 that, as described above, interferes with NCAM-mediated activation of FGFR. The dissemination of SKOV3-NCAM cells to bowel and diaphragm was dramatically reduced in 123C3-treated mice, and a significant decrease was also observed in liver metastasis. In contrast, a control mAb showed no effect in SKOV3 cell dissemination (Fig 7). The mAb 123C3 does not cross-react with mouse NCAM (not shown), thus its inhibitory function on EOC metastasis is due to the neutralization of NCAM in cancer cells rather than in the microenvironment. These findings indicate that antibody-mediated targeting of the NCAM/FGFR interplay suppresses the metastatic potential of EOC cells, an observation that has relevant therapeutic implications.

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