Bates RC, Bellovin DI, Brown C, Maynard E, Wu B, Kawakatsu H et al.. Transcriptional activation of integrin 6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J Clin Invest 115: 339-347

Harvard University, Cambridge, Massachusetts, United States
Journal of Clinical Investigation (Impact Factor: 13.22). 03/2005; 115(2):339-47. DOI: 10.1172/JCI23183
Source: PubMed


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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Available from: Richard Craig Bates
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    • "Importantly, Ets-1 could transcriptionally regulate the expression of integrin beta6, which has been reported by Bates et al. [22]. Thus, a signal loop involving Ets-1 and αvβ6 probably exists to play a key role in tumor cellular growth and migration. "
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    ABSTRACT: Background Both transcriptional factor Ets-1 and integrin αvβ6 play an important role in the development and progression of cancer. The aim of our study was to investigate the expression of Integrin αvβ6 and Ets-1, two proteins’ correlation and their clinical significance in colorectal cancerous tissues. Results The specimens were arranged into microarray using the immunohistochemistry method to investigate the expression of integrin αvβ6 and transcriptional factor Ets-1 in these tissues. Among the 158 tissue specimens, 36.07% were positive for αvβ6 expression, and 57.59% were positive for Ets-1 expression. There were obvious statistical differences existed regarding differentiation, N stage, M stage and TNM stage between αvβ6 and Ets-1 positively and negatively expressing tumors. The correlation analysis confirmed the expression of αvβ6 and Ets-1 were positively correlated in colorectal cancer. The Kaplan-Meier survival analysis showed that patients who were both αvβ6 and Ets-1 positive relapsed earlier than those who were both αvβ6 and Ets-1 negative; and the former group had much shorter survival time than the latter. And Cox model indicated that αvβ6 and Ets-1 were the independent prognostic factors (RR = 2.175, P = 0.012 and RR = 3.903, P < 0.001). Conclusions The expression of αvβ6 and Ets-1 were positively correlated, and their expression degrees were associated with the differentiation, N stage, M stage and TNM stage of the tumors. Hence, the combination of αvβ6 and Ets-1 can be used as a prognostic marker in colorectal cancer, especially for the early stage.
    Full-text · Article · Sep 2014 · Cell and Bioscience
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    • "Integrin ανβ6 is a transmembrane receptor composed of non-covalently linked αν and β6 subunits, where the β6 subunit partners exclusively with αν and is expressed only in epithelial tissues [7]. ανβ6 is often concentrated in poorly differentiated tumours proximal to invading cancer margins [8]–[11]. It has also been identified as an important factor in the “epithelial to mesenchymal transition” (EMT) that is characterised by loss of cell adhesion, repression of E-cadherin and increased cell motility during carcinoma progression [12]. "
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    ABSTRACT: Integrin ανβ6 is highly expressed in a range of human cancers and frequently correlates with patient survival. This study examines correlations between ανβ6 expression and patient clinico-pathological features in Stage B and Stage C rectal cancer, including overall survival. Expression of ανβ6 was measured in 362 Stage B or C rectal cancer tissue samples at the tumour central region, invasive tumour front and adjacent non-neoplastic mucosa using immunohistochemistry. Distribution of ανβ6 was found to be significantly higher at the invasive front compared to central regions of the tumour (p<0.001) or adjacent non-neoplastic mucosa (p<0.001) suggesting ανβ6 plays a role in tumour cell invasion. However, integrin ανβ6 expression was not associated with clinico-pathological features or overall survival indicating it is not an independent prognostic marker differentiating Stage B or C rectal cancer. Previous ανβ6 studies have suggested the expression of ανβ6 is involved in the earlier stages (i.e. Stages A/B) of tumour progression rather than the later stages (i.e. Stages C/D). However, our study has revealed that in rectal cancer ανβ6 expression does not increase between Stages B and C, but may occur earlier, namely before or during Stage B cancer.
    Full-text · Article · May 2014 · PLoS ONE
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    • "The integrin αvβ6 occurs in many epithelial tumors and has been considered to play a prominent role in tumor invasion and metastasis [14]. Recently, it was reported as an independent unfavorable prognostic indicator in aggressive colonic and gastric carcinomas of humans [12,13], which was confirmed in our study according to the Cox regression model. Similar to the study of Bates [12], our results also showed that the αvβ6 expression were significantly associated with clinical stage and the depth of invasion of tumors. "
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    ABSTRACT: Background Both eukaryotic translation initiation factor 4E (eIF4E) and integrin αvβ6 play an important role in the development and progression of cancer. The aim of this study was to investigate the expression of eIF4E and Integrin αvβ6, their clinical significance as well as the two proteins’ correlation in colonic carcinoma tissues. Results The expression levels of eIF4E and integrin αvβ6 were analyzed in colon cancerous and paraneoplastic tissues of 138 cases via tissue microarray (TMA)- immunohistochemistry. And their clinical significance as well as the two proteins’ correlation was also investigated. The expression of eIF4E was significantly associated with clinical TNM stage (P = 0.009), while T stage (P = 0.011) and TNM stage (P = 0.012) were significantly associated with integrin αvβ6 expression. Moderately weak correlation exists between the two proteins (r =0.299, P <0.001). The survival analysis by Kaplan-Meier and Cox regression model showed that protein expression of high eIF4E and positive integrin αvβ6, as independent prognostic factors (RR = 2.417, P = 0.001 and RR = 2.393, P = 0.001), tended to have a significantly poorer 5-year survival rate (P = 0.013 and 0.025, respectively, the log-rank test). Conclusion eIF4E and Integrin αvβ6 were indicators of tumor’s progression and poor prognosis of patients with colon cancer. And the potential signaling loop involving them may provide a helpful therapeutic target in prevention and treatment of colon cancer.
    Full-text · Article · Apr 2014 · Cell and Bioscience
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