Effects of bevacizumab in mouse model of endometrial cancer: Defining the molecular basis for resistance.
Oncol Rep
; 25(3): 855-62, 2011 Mar.
Article
em En
| MEDLINE
| ID: mdl-21240464
ABSTRACT
Endometrial cancer is the most frequent gynecologic cancer in women. Long-term outcomes for patients with advanced stage or recurrent disease are poor. Targeted molecular therapy against the vascular endothelial growth factor (VEGF) and its receptors constitute a new therapeutic option for these patients. The goal of our study was to assess the potential effectiveness of inhibition of VEGF/VEGFR signaling in a xenograft model of endometrial cancer using bevacizumab (Avastin, a humanized antibody against VEGFA). We also aimed to identify molecular markers of sensitivity or resistance to this agent. We show that bevacizumab retards tumor growth in athymic mice by inhibiting molecular components of signaling pathways that sustain cell survival and proliferation. We also demonstrate that resistance to bevacizumab may involve up-regulation of anti-apoptotic genes and certain proto-oncogenes. We propose that down-regulation of ARHGAP6 and MMP15 transcripts indicates that tumors are sensitive to bevacizumab whereas inhibition of PKCδ- or S6K-dependent signaling and up-regulation of TNFRS4 or MMP13 and MMP14 mark a developing resistance to bevacizumab therapy. Interestingly, the significant activation of c-Jun oncogene detected in bevacizumab-treated tumors suggests that, in endometrial cancers, the c-Jun-mediated pathway(s) contribute to bevacizumab resistance.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carcinoma
/
Neoplasias do Endométrio
/
Resistencia a Medicamentos Antineoplásicos
/
Anticorpos Monoclonais
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Oncol Rep
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos