An Integrin Alpha(v)beta(3)-c-Src Oncogenic Unit Promotes Anchorage-independence and Tumor Progression

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2009 Sep 8

PMID 19734908

Citations 157

Authors

Jay S Desgrosellier

Leo A Barnes

David J Shields

Miller Huang

Steven K Lau

Nicolas Prevost

David Tarin

Sanford J Shattil

David A Cheresh

Affiliations

Soon will be listed here.

Abstract

Integrins regulate adhesion-dependent growth, survival and invasion of tumor cells. In particular, expression of integrin alpha(v)beta(3) is associated with progression of a variety of human tumors. Here we reveal a previously undescribed adhesion-independent role for integrin alpha(v)beta(3) in pancreatic cancer and other carcinomas. Specifically, alpha(v)beta(3) expressed in carcinoma cells enhanced anchorage-independent tumor growth in vitro and increased lymph node metastases in vivo. These effects required recruitment of c-Src to the beta(3) integrin cytoplasmic tail, leading to c-Src activation, Crk-associated substrate (CAS) phosphorylation and tumor cell survival that, unexpectedly, was independent of cell adhesion or focal adhesion kinase (FAK) activation. Pharmacological blockade of c-Src kinase activity or decreased expression of endogenous alpha(v)beta(3) integrin or c-Src not only inhibited anchorage-independent growth but also suppressed metastasis in vivo, yet these manipulations did not affect tumor cell migration or invasion. These data define an unexpected role for an integrin as a mediator of anchorage independence, suggesting that an alpha(v)beta(3)-c-Src signaling module may account for the aggressive behavior of integrin alpha(v)beta(3)-expressing tumors in humans.

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