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FGFR3 has tumor suppressor properties in cells with epithelial phenotype.

Lafitte M, Moranvillier I, Garcia S, Peuchant E, Iovanna J, Rousseau B, Dubus P, Guyonnet-Dupérat V, Belleannée G, Ramos J, Bedel A, de Verneuil H, Moreau-Gaudry F, Dabernat S - Mol. Cancer (2013)

Bottom Line: The receptor exerted dual effects: it suppressed tumor growth in pancreatic epithelial-like cells and had oncogenic properties in pancreatic mesenchymal-like cells.Both FGFR3 splice variants had similar effects and used the same intracellular signaling.TKIs against FGFR3 might result in adverse effects if used in the wrong cell context.

View Article: PubMed Central - HTML - PubMed

Affiliation: INSERM U1035, Université Bordeaux Segalen, 146 rue Léo Saignat, Bordeaux 33076, France.

ABSTRACT

Background: Due to frequent mutations in certain cancers, FGFR3 gene is considered as an oncogene. However, in some normal tissues, FGFR3 can limit cell growth and promote cell differentiation. Thus, FGFR3 action appears paradoxical.

Results: FGFR3 expression was forced in pancreatic cell lines. The receptor exerted dual effects: it suppressed tumor growth in pancreatic epithelial-like cells and had oncogenic properties in pancreatic mesenchymal-like cells. Distinct exclusive pathways were activated, STATs in epithelial-like cells and MAP Kinases in mesenchymal-like cells. Both FGFR3 splice variants had similar effects and used the same intracellular signaling. In human pancreatic carcinoma tissues, levels of FGFR3 dropped in tumors.

Conclusion: In tumors from epithelial origin, FGFR3 signal can limit tumor growth, explaining why the 4p16.3 locus bearing FGFR3 is frequently lost and why activating mutations of FGFR3 in benign or low grade tumors of epithelial origin are associated with good prognosis. The new hypothesis that FGFR3 can harbor both tumor suppressive and oncogenic properties is crucial in the context of targeted therapies involving specific tyrosine kinase inhibitors (TKIs). TKIs against FGFR3 might result in adverse effects if used in the wrong cell context.

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FGFR3 expression in normal and pancreatic tumor tissues. A: (a, b) FGFR3 signal was found in islets of normal pancreas. (c) Co-localization of FGFR3 (green) and insulin (red). Nuclei were stained with DAPI (blue). (d-l) FGFR3 expression was assessed according to the signal obtained in normal pancreas (strong in islets, weak in the exocrine tissue). Twelve percent of pancreatic endocrine carcinomas (PEC, n = 25) displayed no FGFR3 signal (d), 56% showed weak (e) and only 32% had strong (normal, f) FGFR3 expression. For Intraductal papillary mucinous neoplasms (IPMN, n = 30), 63.3% had no signal (g), 30% had weak signal (normal, h) and 6.7% showed strong (i) FGFR3 expression. In Pancreatic ductal adenocarcinomas (PDAC, n = 88), 30.6% displayed no FGFR3 signal (j), 48.9% had weak (normal, k) and 20.5% showed strong (l) FGFR3 expression. Bars represent 50 μm. B: Table recapitulating the scoring of pancreatic tumors for FGFR3 signal. Strong signals were as intense as signals obtained in normal pancreatic islets (A: a, b). Weak signals were similar to what was observed in normal pancreatic exocrine tissue (ducts and acinar cells, A: a, b).
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Figure 5: FGFR3 expression in normal and pancreatic tumor tissues. A: (a, b) FGFR3 signal was found in islets of normal pancreas. (c) Co-localization of FGFR3 (green) and insulin (red). Nuclei were stained with DAPI (blue). (d-l) FGFR3 expression was assessed according to the signal obtained in normal pancreas (strong in islets, weak in the exocrine tissue). Twelve percent of pancreatic endocrine carcinomas (PEC, n = 25) displayed no FGFR3 signal (d), 56% showed weak (e) and only 32% had strong (normal, f) FGFR3 expression. For Intraductal papillary mucinous neoplasms (IPMN, n = 30), 63.3% had no signal (g), 30% had weak signal (normal, h) and 6.7% showed strong (i) FGFR3 expression. In Pancreatic ductal adenocarcinomas (PDAC, n = 88), 30.6% displayed no FGFR3 signal (j), 48.9% had weak (normal, k) and 20.5% showed strong (l) FGFR3 expression. Bars represent 50 μm. B: Table recapitulating the scoring of pancreatic tumors for FGFR3 signal. Strong signals were as intense as signals obtained in normal pancreatic islets (A: a, b). Weak signals were similar to what was observed in normal pancreatic exocrine tissue (ducts and acinar cells, A: a, b).

Mentions: Strong FGFR3 immune signal was found in normal pancreatic islets, while a weak signal was present in the exocrine tissue (Figure 5a,b). FGFR3 was co-localized with insulin-positive cells, but was also present in non beta cells in islets (Figure 5c). Both splice variants appeared to be equally abundant in the normal pancreas (Additional file 8: Table S1).


FGFR3 has tumor suppressor properties in cells with epithelial phenotype.

Lafitte M, Moranvillier I, Garcia S, Peuchant E, Iovanna J, Rousseau B, Dubus P, Guyonnet-Dupérat V, Belleannée G, Ramos J, Bedel A, de Verneuil H, Moreau-Gaudry F, Dabernat S - Mol. Cancer (2013)

FGFR3 expression in normal and pancreatic tumor tissues. A: (a, b) FGFR3 signal was found in islets of normal pancreas. (c) Co-localization of FGFR3 (green) and insulin (red). Nuclei were stained with DAPI (blue). (d-l) FGFR3 expression was assessed according to the signal obtained in normal pancreas (strong in islets, weak in the exocrine tissue). Twelve percent of pancreatic endocrine carcinomas (PEC, n = 25) displayed no FGFR3 signal (d), 56% showed weak (e) and only 32% had strong (normal, f) FGFR3 expression. For Intraductal papillary mucinous neoplasms (IPMN, n = 30), 63.3% had no signal (g), 30% had weak signal (normal, h) and 6.7% showed strong (i) FGFR3 expression. In Pancreatic ductal adenocarcinomas (PDAC, n = 88), 30.6% displayed no FGFR3 signal (j), 48.9% had weak (normal, k) and 20.5% showed strong (l) FGFR3 expression. Bars represent 50 μm. B: Table recapitulating the scoring of pancreatic tumors for FGFR3 signal. Strong signals were as intense as signals obtained in normal pancreatic islets (A: a, b). Weak signals were similar to what was observed in normal pancreatic exocrine tissue (ducts and acinar cells, A: a, b).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750311&req=5

Figure 5: FGFR3 expression in normal and pancreatic tumor tissues. A: (a, b) FGFR3 signal was found in islets of normal pancreas. (c) Co-localization of FGFR3 (green) and insulin (red). Nuclei were stained with DAPI (blue). (d-l) FGFR3 expression was assessed according to the signal obtained in normal pancreas (strong in islets, weak in the exocrine tissue). Twelve percent of pancreatic endocrine carcinomas (PEC, n = 25) displayed no FGFR3 signal (d), 56% showed weak (e) and only 32% had strong (normal, f) FGFR3 expression. For Intraductal papillary mucinous neoplasms (IPMN, n = 30), 63.3% had no signal (g), 30% had weak signal (normal, h) and 6.7% showed strong (i) FGFR3 expression. In Pancreatic ductal adenocarcinomas (PDAC, n = 88), 30.6% displayed no FGFR3 signal (j), 48.9% had weak (normal, k) and 20.5% showed strong (l) FGFR3 expression. Bars represent 50 μm. B: Table recapitulating the scoring of pancreatic tumors for FGFR3 signal. Strong signals were as intense as signals obtained in normal pancreatic islets (A: a, b). Weak signals were similar to what was observed in normal pancreatic exocrine tissue (ducts and acinar cells, A: a, b).
Mentions: Strong FGFR3 immune signal was found in normal pancreatic islets, while a weak signal was present in the exocrine tissue (Figure 5a,b). FGFR3 was co-localized with insulin-positive cells, but was also present in non beta cells in islets (Figure 5c). Both splice variants appeared to be equally abundant in the normal pancreas (Additional file 8: Table S1).

Bottom Line: The receptor exerted dual effects: it suppressed tumor growth in pancreatic epithelial-like cells and had oncogenic properties in pancreatic mesenchymal-like cells.Both FGFR3 splice variants had similar effects and used the same intracellular signaling.TKIs against FGFR3 might result in adverse effects if used in the wrong cell context.

View Article: PubMed Central - HTML - PubMed

Affiliation: INSERM U1035, Université Bordeaux Segalen, 146 rue Léo Saignat, Bordeaux 33076, France.

ABSTRACT

Background: Due to frequent mutations in certain cancers, FGFR3 gene is considered as an oncogene. However, in some normal tissues, FGFR3 can limit cell growth and promote cell differentiation. Thus, FGFR3 action appears paradoxical.

Results: FGFR3 expression was forced in pancreatic cell lines. The receptor exerted dual effects: it suppressed tumor growth in pancreatic epithelial-like cells and had oncogenic properties in pancreatic mesenchymal-like cells. Distinct exclusive pathways were activated, STATs in epithelial-like cells and MAP Kinases in mesenchymal-like cells. Both FGFR3 splice variants had similar effects and used the same intracellular signaling. In human pancreatic carcinoma tissues, levels of FGFR3 dropped in tumors.

Conclusion: In tumors from epithelial origin, FGFR3 signal can limit tumor growth, explaining why the 4p16.3 locus bearing FGFR3 is frequently lost and why activating mutations of FGFR3 in benign or low grade tumors of epithelial origin are associated with good prognosis. The new hypothesis that FGFR3 can harbor both tumor suppressive and oncogenic properties is crucial in the context of targeted therapies involving specific tyrosine kinase inhibitors (TKIs). TKIs against FGFR3 might result in adverse effects if used in the wrong cell context.

Show MeSH
Related in: MedlinePlus