ENDOGLIN/CD105 is expressed in KIT positive cells in the gut and in gastrointestinal stromal tumours

Journal of Cellular and Molecular Medicine

Petra Gromova³  Brian P. Rubin⁴  An Thys³  Pierre Cullus²  Christophe Erneux¹ 

[1]IRIBHM, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium

[2]Department of Biostatistics and Medical Computing, Université Libre de Bruxelles, Brussels, Belgium

[3]Laboratory of Neurophysiology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium

[4]Anatomic Pathology and Molecular Genetics, Cleveland Clinic, Lerner Research Institute and Taussig Cancer Center, Cleveland, OH, USA

关键词: ENDOGLIN;    KIT;    gastrointestinal stromal tumour;    interstitial cells of Cajal;   

DOI  :  10.1111/j.1582-4934.2011.01315.x

来源: Wiley

【 摘 要 】

Abstract

ENDOGLIN/CD105 (ENG) is a transmembrane glycoprotein and an auxiliary unit of the transforming growth factor-β (TGF-β); receptor, expressed predominantly in vascular endothelium. Noteworthy, Eng mRNA expression has been reported also in Kit⁺ interstitial cells of Cajal (ICC) in the mouse intestine. Gastrointestinal stromal tumours (GIST) are thought to derive from ICC. Here we have investigated Eng expression in the Kit^K641E mouse GIST model, in human GIST and in the Ba/F3 cell model. In wild type (WT) mouse antrum, Eng immunoreactivity (-ir) was detected in CD34⁺/CD31⁺ endothelium and in Kit⁺ ICC. In Kit^K641E mice, hyperplasia of Kit⁺ cells made Eng-ir even more evident. Quantitative PCR confirmed the increased expression of Eng transcript in Kit^K641E mice. On human GIST TMA, 26/49 cases stained positive for ENG. Strong ENG staining was associated with malignant and high-risk tumours. ENG negative cases were predominantly of the epithelioid type or harboured PDGFRA mutation. In vitro, Eng mRNA was up-regulated in Ba/F3 cell lines stably expressing various oncogenic Kit mutations (K641E, del559, del814). This effect appeared to be independent of Kit activation, as neither the stimulation of WT Kit by its ligand SCF, nor the inhibition of Kit autophosphorylation by imatinib mesylate in oncogenic mutants, altered Eng expression. Elevated Eng expression in Kit oncogenic mutants appeared rather to be indirectly mediated by DNA hypomethylation, because treatment with the demethylating agent 5-Aza/dC increased Eng mRNA expression in Kit^WT cells. ENG expression in ICC and in GIST deserves further consideration as ENG is emerging as a potential target for cancer therapy.

【 授权许可】

Unknown   
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd