Contribution of the PI3K/MMPs/Ln-5γ2 and EphA2/FAK/Paxillin signaling pathways to tumor growth and vasculogenic mimicry of gallbladder carcinomas.
Int J Oncol
; 42(6): 2103-15, 2013 Jun.
Article
em En
| MEDLINE
| ID: mdl-23588386
ABSTRACT
Vasculogenic mimicry (VM) is a new tumor blood supply in some highly aggressive malignant tumors. We previously reported VM in human gallbladder carcinomas, 3-D matrices in vitro and nude mouse xenografts in vivo of highly aggressive GBC-SD cells and its clinical significance. In this study, we further studied the underlying mechanisms of VM in gallbladder carcinomas via the 3-D matrix in vitro, the nude mouse xenografts in vivo of GBC-SD or SGC-996 cells, immunohistochemistry (H&E staining and CD31-PAS double staining), electron microscopy, expression of MMP-2, MT1-MMP, PI3K, Ln-5γ2, EphA2, FAK and Paxillin-P proteins/mRNAs determined by SABC, ELISA, immunofluorescence, western blotting and qRT-PCR, respectively. It was shown that all of untreated highly aggressive GBC-SD cells and xenografts formed vasculogenic-like structures within 2 weeks of seeding and injecting, and facilitated the growth of tumor cells or xenografts; whereas poorly aggressive SGC-996 cells or GBC-SD cells treated by TIMP-2 were unable to form the vasculogenic-like structures with the same conditions; and tumor xenograft growth was inhibited. Expression of MMP-2, MT1-MMP proteins/mRNAs from sections and supernates of 3-D matrix in vitro, expression of PI3K, MMP-2, MT1-MMP, Ln-5γ2, EphA2, FAK and Paxillin-P proteins/mRNAs from sections of xenografts in vivo in untreated GBC-SD group was upregulated significantly (all P<0.001); however, expression of these VM signal-related proteins/mRNAs in the SGC-996 group and GBC-SD treated by the TIMP-2 group was significantly downregulated (all P<0.001). Thus, we identified for the first time that highly aggressive GBC-SD cells formed VM in vitro and in vivo through the upregulation of PI3K/MMPs/Ln-5γ2 and/or EphA2/FAK/Paxillin signaling. PI3K/MMPs/Ln-5γ2 and EphA2/FAK/Paxillin as key signaling pathways in a coordinated manner contributed to tumor growth and VM of gallbladder carcinomas and provided novel targets that could be potentially exploited for therapeutic intervention of human gallbladder carcinomas.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Metaloendopeptidases
/
Fosfatidilinositol 3-Quinases
/
Receptor EphA2
/
Quinase 1 de Adesão Focal
/
Paxilina
/
Neoplasias da Vesícula Biliar
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Neovascularização Patológica
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Int J Oncol
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2013
Tipo de documento:
Article