title: Transcriptional activation of integrin beta6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma.
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.
authors.affiliation: Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. rbates@caregroup.harvard.edu
authors.forename: Richard C
authors.initials: RC
authors.lastname: Bates
authors.forename: David I
authors.initials: DI
authors.lastname: Bellovin
authors.forename: Courtney
authors.initials: C
authors.lastname: Brown
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Maynard
authors.forename: Bingyan
authors.initials: B
authors.lastname: Wu
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Kawakatsu
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
authors.forename: Peter
authors.initials: P
authors.lastname: Oettgen
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Mercurio
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology*; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039482:Integrin alpha5 / Q000096:biosynthesis*; D039641:Integrin beta Chains / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000473:pathology; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011379:Prognosis; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D039482:Integrin alpha5; D039641:Integrin beta Chains; D016212:Transforming Growth Factor beta; C072170:integrin beta6