Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 115, Issue 2, Pages 339-347Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200523183
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Funding
- NCI NIH HHS [R01 CA080789, CA 80789, CA107548, R01 CA107548] Funding Source: Medline
- NIDDK NIH HHS [DK34854, P30 DK034854] Funding Source: Medline
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We used a spheroid model of colon carcinoma to analyze integrin dynamics as a function of the epithelial-mesenchymal transition (EMT), a process that provides a paradigm for understanding how carcinoma cells acquire a more aggressive phenotype. This EMT involves transcriptional activation of the beta6 integrin subunit and a consequent induction of alphavbeta6 expression. This integrin enhances the tumorigenic properties of colon carcinoma, including activation of autocrine TGF-beta. and migration on interstitial fibronectin. Importantly, this study validates the clinical relevance of the EMT. Kaplan-Meier analysis of beta6 expression in 488 colorectal carcinomas revealed a striking reduction in median survival time of patients with high beta6 expression. Elevated receptor expression did not simply reflect increasing tumor stage, since log-rank analysis showed a more significant impact on the survival of patients with early-stage, as opposed to late-stage, disease. Cox regression analysis confirmed that this integrin is an independent variable for these tumors. These findings define the alphavbeta6 integrin as an important risk factor for early-stage disease and a novel therapeutic candidate for colorectal cancer.
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