Transcriptional activation of integrin beta6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma.
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.
Bates
Richard C
RC
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
Bellovin
David I
DI
Brown
Courtney
C
Maynard
Elizabeth
E
Wu
Bingyan
B
Kawakatsu
Hisaaki
H
Sheppard
Dean
D
Oettgen
Peter
P
Mercurio
Arthur M
AM
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
D014408:Biomarkers, Tumor; D039482:Integrin alpha5; D039641:Integrin beta Chains; D016212:Transforming Growth Factor beta; C072170:integrin beta6