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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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Related in: MedlinePlus

FGFR3 engaged diverse intracellular pathways. Proteins extracts of tumors from Capan-2 and Mia PaCa-2, were analyzed by western-blot. See text for more details. CKIs: Cyclin-dependant kinase inhibitors. Membranes were reprobed for GAPDH to test equivalent loading. Results shown are representative of one out of at least 3 independent experiments.
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Figure 4: FGFR3 engaged diverse intracellular pathways. Proteins extracts of tumors from Capan-2 and Mia PaCa-2, were analyzed by western-blot. See text for more details. CKIs: Cyclin-dependant kinase inhibitors. Membranes were reprobed for GAPDH to test equivalent loading. Results shown are representative of one out of at least 3 independent experiments.

Mentions: In the presence of the ligand, the dimerization of the receptor triggers FGFR transphosphorylations, to create docking sites for downstream signaling factors activating pathways such as RAS and the downstream MAP Kinases, the PI3Kinase/Akt pathway or the Signal transducer and activator of Transcription (STAT) pathway. The protein extracts of tumors overexpressing FGFR3 with the strongest and opposite phenotypes (Capan-2 and Mia PaCa-2 cells) were analyzed by western-blotting. Active JNKs, detectable only in Capan-2 cells, were unchanged (not shown). In FGFR3-Capan-2 cells, other activated MAP Kinases were unchanged (Figure 4), but in Mia PaCa-2 cells both ERKs and P38 were over-activated (Figure 4). Conversely, phosphorylation of STATs was found strongly increased by FGFR3 overexpression in Capan-2 cells but was not detected in Mia PaCa-2 cells. This effect in Capan-2 cells disappeared when transduced with FGFR3-IIIc-KD. Although AKT was present in all the tumor extracts, no changes were observed in activated AKT (not shown). The proteins p21 and p27, downstream effectors of FGFR3 in chondrocytes [2] were mildly increased in FGFR3-Capan-2 tumors (Figure 3), but not in the Mia PaCa-2 (not detectable). Since apoptosis was found up-regulated in FGFR3-Capan-2 cells, we looked at apoptosis markers. BAX signal was stronger in FGFR3 conditions, while BCL2 remained unchanged (Figure 4). Thus the balance of anti-apoptotic/pro-apoptotic proteins was moved towards apoptosis. This was further confirmed by increased levels of both cleaved caspase 9 and caspase 3 (Figure 4). In Mia PaCa-2 s, there was no obvious change in the anti-apoptotic/pro-apoptotic balance and cleaved caspases were not detectable (Figure 4). Senescence often depends on p53 activation or stabilization. The Capan-2 cells were the only cell line in our hands bearing wild type copies of TP53. Total p53 and Phospho-p53 were not changed in FGFR3 overexpressing cells (not shown).


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 engaged diverse intracellular pathways. Proteins extracts of tumors from Capan-2 and Mia PaCa-2, were analyzed by western-blot. See text for more details. CKIs: Cyclin-dependant kinase inhibitors. Membranes were reprobed for GAPDH to test equivalent loading. Results shown are representative of one out of at least 3 independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: FGFR3 engaged diverse intracellular pathways. Proteins extracts of tumors from Capan-2 and Mia PaCa-2, were analyzed by western-blot. See text for more details. CKIs: Cyclin-dependant kinase inhibitors. Membranes were reprobed for GAPDH to test equivalent loading. Results shown are representative of one out of at least 3 independent experiments.
Mentions: In the presence of the ligand, the dimerization of the receptor triggers FGFR transphosphorylations, to create docking sites for downstream signaling factors activating pathways such as RAS and the downstream MAP Kinases, the PI3Kinase/Akt pathway or the Signal transducer and activator of Transcription (STAT) pathway. The protein extracts of tumors overexpressing FGFR3 with the strongest and opposite phenotypes (Capan-2 and Mia PaCa-2 cells) were analyzed by western-blotting. Active JNKs, detectable only in Capan-2 cells, were unchanged (not shown). In FGFR3-Capan-2 cells, other activated MAP Kinases were unchanged (Figure 4), but in Mia PaCa-2 cells both ERKs and P38 were over-activated (Figure 4). Conversely, phosphorylation of STATs was found strongly increased by FGFR3 overexpression in Capan-2 cells but was not detected in Mia PaCa-2 cells. This effect in Capan-2 cells disappeared when transduced with FGFR3-IIIc-KD. Although AKT was present in all the tumor extracts, no changes were observed in activated AKT (not shown). The proteins p21 and p27, downstream effectors of FGFR3 in chondrocytes [2] were mildly increased in FGFR3-Capan-2 tumors (Figure 3), but not in the Mia PaCa-2 (not detectable). Since apoptosis was found up-regulated in FGFR3-Capan-2 cells, we looked at apoptosis markers. BAX signal was stronger in FGFR3 conditions, while BCL2 remained unchanged (Figure 4). Thus the balance of anti-apoptotic/pro-apoptotic proteins was moved towards apoptosis. This was further confirmed by increased levels of both cleaved caspase 9 and caspase 3 (Figure 4). In Mia PaCa-2 s, there was no obvious change in the anti-apoptotic/pro-apoptotic balance and cleaved caspases were not detectable (Figure 4). Senescence often depends on p53 activation or stabilization. The Capan-2 cells were the only cell line in our hands bearing wild type copies of TP53. Total p53 and Phospho-p53 were not changed in FGFR3 overexpressing cells (not shown).

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