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J Cell Physiol ; 230(1): 43-51, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24760775

RESUMO

Tumor angiogenesis is accompanied by vasculogenesis, which is involved in the differentiation and mobilization of human bone marrow cells. In order to further characterize the role of vasculogenesis in the tumor growth process, the effects of FGF2 on the differentiation of human bone marrow AC133(+) cells (BM-AC133(+)) into vascular precursors were studied in vitro. FGF2, like VEGFA, induced progenitor cell differentiation into cell types with endothelial cell characteristics. SSR128129E, a newly discovered specific FGFR antagonist acting by allosteric interaction with FGFR, abrogated FGF2-induced endothelial cell differentiation, showing that FGFR signaling is essential during this process. To assess the involvement of the FGF/FRGR signaling in vivo, the pre-clinical model of Lewis lung carcinoma (LL2) in mice was used. Subcutaneous injection of LL2 cells into mice induced an increase of circulating EPCs from peripheral blood associated with tumor growth and an increase of intra-tumoral vascular index. Treatment with the FGFR antagonist SSR128129E strongly decreased LL2 tumor growth as well as the intra-tumoral vascular index (41% and 50% decrease vs. vehicle-treated mice respectively, P < 0.01). Interestingly, SSR128129E treatment significantly decreased the number of circulating EPCs from the peripheral blood (53% inhibition vs. vehicle-treated mice, P < 0.01). These results demonstrate for the first time that the blockade of the FGF/FGFR pathway by SSR128129E reduces EPC recruitment during angiogenesis-dependent tumor growth. In this context, circulating EPCs could be a reliable surrogate marker for tumor growth and angiogenic activity.


Assuntos
Carcinoma Pulmonar de Lewis/irrigação sanguínea , Células-Tronco Hematopoéticas/citologia , Indolizinas/farmacologia , Neovascularização Patológica/patologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , ortoaminobenzoatos/farmacologia , Antígeno AC133 , Animais , Antígenos CD/biossíntese , Células da Medula Óssea/metabolismo , Adesão Celular , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular , Células Endoteliais/citologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Glicoproteínas/biossíntese , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos , RNA Mensageiro/biossíntese , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais
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