Transcriptional activation of integrin beta6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma.

Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Journal of Clinical Investigation (Impact Factor: 13.77). 03/2005; 115(2):339-47. DOI: 10.1172/JCI23183
Source: PubMed

ABSTRACT 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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    ABSTRACT: Background: It is known that active Src kinase promotes survival of ovarian cancer cell lines and inhibition of c-Src has been shown to restore sensitivity of drug-resistant human ovarian cancer cells to cisplatin. In this study we exam-ined the effects of a 10 mer peptide on proliferation of human colon and ovarian cancer cells when used alone and in combination with cisplatin. Materials and Methods: A 10 mer peptide, RSKAKNPLYR, derived from a 15 mer ERK2 binding sequence present on the cytoplasmic domain of the β6 integrin subunit was tested for its effect on proliferation of HT29 colon cancer cells under serum-free conditions by means of the MTT assay. Cell proliferation studies to exam-ine the effects of cisplatin combined with peptide were conducted in serum-containing medium using the 10 mer peptide fused to a hydrophobic signal peptide sequence. Drug combination studies were performed on HT29 cells and a cis-platin-resistant cell line (ADDP) derived from an ovarian cancer cell line A2780. The effects of peptides on Src kinase activity were assessed in a cell-free in vitro kinase assay. Results: The 10 mer peptide was as effective as the 15 mer parent compound at inhibiting proliferation of HT29 cells. Exposure of HT29 and ADDP cells to a combination of cis-platin and the fusion peptide resulted in synergistic inhibition of cell growth. Both the 10 mer peptide alone and when fused to the signal peptide sequence inhibited Src kinase activity. Conclusion: Our findings raise the possibility of com-bination therapy comprising peptide and cisplatin for cisplatin-resistant ovarian cancers and other cancers that are high expressors of c-Src.

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