A Lentiviral CXCR4 overexpression and knockdown model in colorectal cancer cell lines reveals plerixafor-dependent suppression of SDF-1α-induced migration and invasion.
Onkologie
; 34(10): 502-8, 2011.
Article
em En
| MEDLINE
| ID: mdl-21985848
ABSTRACT
BACKGROUND:
The development of distant metastasis is associated with poor outcome in patients with colorectal cancer (CRC). The stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) have pivotal roles in the chemotaxis of migrating tumor cells during metastasis. Thus, hampering the SDF-1/CXCR4 cross-talk is a promising strategy to suppress metastasis.METHODS:
We investigated the invasive behavior of the lentivirally CXCR4 overexpressing CRC cell lines SW480, SW620 and RKO in chemotaxis and invasion assays toward an SDF-1α gradient. Low endogenous CXCR4 expression levels were determined by quantitative realtime polymerase chain reaction (PCR) and fluorescence-activated cell sorting (FACS) analyses.RESULTS:
A lentiviral CXCR4 overexpression and knockdown model was established in these CRC cells. In transwell migration assays, CXCR4 overexpression favored chemotaxis and invasion of cells in all 3 lines depending on an SDF-1α gradient (p < 0.001 vs. untransduced cells). Functional CXCR4 knockdown using lentiviral short hairpin RNA (shRNA) vectors significantly decreased the migration behavior in CRC cell lines (p < 0.001), confirming a CXCR4-specific effect. Pharmacologic inhibition of the SDF-1α/CXCR4 interaction by the bicyclam Plerixafor(TM) at 100 µM significantly abrogated CXCR4-dependent migration and invasion through Matrigel(TM) (SW480, SW620, RKO; p < 0.05).CONCLUSION:
Our results indicate that a CXCR4-antagonistic therapy might prevent tumor cell dissemination and metastasis in CRC patients, consequently improving survival.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
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Regulação Neoplásica da Expressão Gênica
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Quimiotaxia
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Lentivirus
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Fármacos Anti-HIV
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Receptores CXCR4
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Quimiocina CXCL12
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Vetores Genéticos
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Compostos Heterocíclicos
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Invasividade Neoplásica
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Onkologie
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Alemanha