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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 actions in pancreatic cancers: a working model. FGFR3 action in cancer cells from epithelial origin limits tumor growth. During tumor progression, FGFR3 disruption or loss of expression promotes cell growth. If epithelial to mesenchymal transition occurs, then FGFR3 will function as an oncogene favoring tumor progression.
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Figure 6: FGFR3 actions in pancreatic cancers: a working model. FGFR3 action in cancer cells from epithelial origin limits tumor growth. During tumor progression, FGFR3 disruption or loss of expression promotes cell growth. If epithelial to mesenchymal transition occurs, then FGFR3 will function as an oncogene favoring tumor progression.

Mentions: The present data raise the possibility that FGFR3 has biphasic effects during multistage carcinogenesis in carcinomas, acting first as a tumor suppressor through oncogene-induced senescence via STATs activation and apoptosis enhancement. In this context, FGFR3 loss would help tumor progression. Alternatively, after additional mutations have occurred in the developing tumor, decoupling FGFR3 from its canonical inhibitory pathway (STATs), FGFR3 signal might be redirected to other intracellular factors, promoting tumor progression (Figure 6). In the same way, epithelial to mesenchymal phenotype transition would reveal FGFR3 as an oncogene by coupling the receptor to MAP kinases pathways. This model supports a new aspect of FGFR3 function, explaining why in epithelial cancers FGFR3 activating mutations were associated with good prognosis tumors whereas in soft tissue cancers, FGFR3 promoted tumor progression. More importantly, this work might open a new debate on the use of FGFR3 inhibitors in anticancer therapy.


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 actions in pancreatic cancers: a working model. FGFR3 action in cancer cells from epithelial origin limits tumor growth. During tumor progression, FGFR3 disruption or loss of expression promotes cell growth. If epithelial to mesenchymal transition occurs, then FGFR3 will function as an oncogene favoring tumor progression.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: FGFR3 actions in pancreatic cancers: a working model. FGFR3 action in cancer cells from epithelial origin limits tumor growth. During tumor progression, FGFR3 disruption or loss of expression promotes cell growth. If epithelial to mesenchymal transition occurs, then FGFR3 will function as an oncogene favoring tumor progression.
Mentions: The present data raise the possibility that FGFR3 has biphasic effects during multistage carcinogenesis in carcinomas, acting first as a tumor suppressor through oncogene-induced senescence via STATs activation and apoptosis enhancement. In this context, FGFR3 loss would help tumor progression. Alternatively, after additional mutations have occurred in the developing tumor, decoupling FGFR3 from its canonical inhibitory pathway (STATs), FGFR3 signal might be redirected to other intracellular factors, promoting tumor progression (Figure 6). In the same way, epithelial to mesenchymal phenotype transition would reveal FGFR3 as an oncogene by coupling the receptor to MAP kinases pathways. This model supports a new aspect of FGFR3 function, explaining why in epithelial cancers FGFR3 activating mutations were associated with good prognosis tumors whereas in soft tissue cancers, FGFR3 promoted tumor progression. More importantly, this work might open a new debate on the use of FGFR3 inhibitors in anticancer therapy.

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