Limits...
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.

Show MeSH

Related in: MedlinePlus

FGFR3 conveys a negative signal in the pancreatic beta cell line BTC. A) BTC cells were cultured in the absence (CT) or in the presence of the neutralizing anti-FGFR3. Alternatively, cells were transiently transfected with a vector overexpressing FGFR3-IIIc or a control vector (CT). B) Tumors were produced from parental BTC cells (n = 12) or clones of BTC cells overexpressing stably FGFR3-IIIc (n = 17). Tumor masses were determined 6 weeks after cells were injected. ***: p < 0.001, **: p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3750311&req=5

Figure 3: FGFR3 conveys a negative signal in the pancreatic beta cell line BTC. A) BTC cells were cultured in the absence (CT) or in the presence of the neutralizing anti-FGFR3. Alternatively, cells were transiently transfected with a vector overexpressing FGFR3-IIIc or a control vector (CT). B) Tumors were produced from parental BTC cells (n = 12) or clones of BTC cells overexpressing stably FGFR3-IIIc (n = 17). Tumor masses were determined 6 weeks after cells were injected. ***: p < 0.001, **: p < 0.01.

Mentions: To further explore the impact of FGFR3 in epithelial cells, the proliferation of the mouse pancreatic epithelial beta cell line BTC [15] was assessed in the presence of a neutralizing anti-FGFR3 antibody or with FGFR3-IIIc splice overexpression in vitro. The inhibition of FGFR3 activity increased BTC cell proliferation, while transient forced expression of FGFR3-IIIc significantly diminished BTC cell expansion (Figure 3A). When BTC cells overexpressing FGFR3-IIIc were xenografted in immune deficient mice, tumor progression was strongly inhibited as compared to control cells (Figure 3B and Additional file 5: Figure S5). This suggests that as in pancreatic adenocarcinoma cell lines with epithelial phenotype, FGFR3 limits beta cell growth.


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 conveys a negative signal in the pancreatic beta cell line BTC. A) BTC cells were cultured in the absence (CT) or in the presence of the neutralizing anti-FGFR3. Alternatively, cells were transiently transfected with a vector overexpressing FGFR3-IIIc or a control vector (CT). B) Tumors were produced from parental BTC cells (n = 12) or clones of BTC cells overexpressing stably FGFR3-IIIc (n = 17). Tumor masses were determined 6 weeks after cells were injected. ***: p < 0.001, **: p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: FGFR3 conveys a negative signal in the pancreatic beta cell line BTC. A) BTC cells were cultured in the absence (CT) or in the presence of the neutralizing anti-FGFR3. Alternatively, cells were transiently transfected with a vector overexpressing FGFR3-IIIc or a control vector (CT). B) Tumors were produced from parental BTC cells (n = 12) or clones of BTC cells overexpressing stably FGFR3-IIIc (n = 17). Tumor masses were determined 6 weeks after cells were injected. ***: p < 0.001, **: p < 0.01.
Mentions: To further explore the impact of FGFR3 in epithelial cells, the proliferation of the mouse pancreatic epithelial beta cell line BTC [15] was assessed in the presence of a neutralizing anti-FGFR3 antibody or with FGFR3-IIIc splice overexpression in vitro. The inhibition of FGFR3 activity increased BTC cell proliferation, while transient forced expression of FGFR3-IIIc significantly diminished BTC cell expansion (Figure 3A). When BTC cells overexpressing FGFR3-IIIc were xenografted in immune deficient mice, tumor progression was strongly inhibited as compared to control cells (Figure 3B and Additional file 5: Figure S5). This suggests that as in pancreatic adenocarcinoma cell lines with epithelial phenotype, FGFR3 limits beta cell growth.

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