Endothelin receptor blockade inhibits molecular effectors of Kaposi's sarcoma cell invasion and tumor growth <i>in vivo</i>

作     者：Rosanò, L Spinella, F Di Castro, V Nicotra, MR Albini, A Natali, PG Bagnato, A 

作者机构：Regina Elena Inst Canc Res Lab Mol Pathol & Ultrastruct I-00158 Rome Italy Regina Elena Inst Canc Res Dept Immunol I-00158 Rome Italy CNR Mol Biol & Pathol Inst Rome Italy Natl Inst Canc Res Ctr Adv Biotechnol Genoa Italy 

出 版 物：《AMERICAN JOURNAL OF PATHOLOGY》 (Am. J. Pathol.)

年 卷 期：2003年第163卷第2期

页      面：753-762页

核心收录：

学科分类：1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

基　　金：CNR-Italian Ministry of Education, University and Research Ministero della Salute Ministero dell’Istruzione, dell’Università e della Ricerca, MIUR Associazione Italiana per la Ricerca sul Cancro, AIRC Fondazione Italiana per la Ricerca sul Cancro, FIRC 

摘      要：Endothelin-1 (ET-1) and its receptors are overexpressed in human Kaposi s sarcoma lesions. Here we show that in human KS IMM cell line ET-1 increased secretion and activation of matrix-metalloproteinase-2 (MMP-2), -3, -7, -9 and -13, as well as of membrane-type 1-MMP (MT1-MMP). ET-1 and ET-3 also enhanced the expression of tissue inhibitor of MMP-2, essential for MT1-MMP-mediated MMP-2 activation. Combined addition of both ETB receptor (ETBR) and ETAR antagonists completely blocked the ET-1-induced MMP activity. By immunohistochemistry, we observed that ET-1 increased MMP-2 and MT1-MMP expression and their localization at the cell surface. Treatment with both antagonists resulted also in the suppression of ET-1-induced phosphorylation of focal adhesion proteins, FAK and paxillin, which are essentials for cell motility. ET-1 induced a dose-dependent enhancement in KS IMM cell migration and MMP-dependent invasiveness that were inhibited by ET-1 receptor antagonists. The small molecule, A-182086, an orally bioavailable ETA/BR antagonist, completely inhibited cell proliferation and tumor growth in KS IMM xenografts. These findings demonstrate that ET-1-driven autocrine loop is crucial for enhanced invasiveness of KS IMM cells and promote tumor growth in vivo. Such activities can be blocked by the ETA/BR antagonists, which may be effective anti-angiogenic and anti-tumor molecules for the treatment of Kaposi s sarcoma.