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© The Rockefeller University Press, 0021-9525/1998//1145 $5.00
The Journal of Cell Biology, Volume 142, Number 4, , 1998 1145-1156

Articles

Growth Factor–dependent Activation of {alpha}vβ3 Integrin in Normal Epithelial Cells: Implications for Tumor Invasion



Livio Trusolino*,{ddagger}, Guido Serini*,{ddagger}, Germana Cecchini*, Cristina Besati*, Francesco Saverio Ambesi-Impiombato§, Pier Carlo Marchisio*,{ddagger}, and Rosaria De Filippi§

* DIBIT, Department of Biological and Technological Research, San Raffaele Scientific Institute, 20132 Milano, Italy; {ddagger} Department of Biomedical Sciences and Human Oncology, University of Torino School of Medicine, 10126 Torino, Italy; and § Department of Pathology, Clinical and Experimental Medicine, University of Udine School of Medicine, 33100 Udine, Italy

Integrin activation is a multifaceted phenomenon leading to increased affinity and avidity for matrix ligands. To investigate whether cytokines produced during stromal infiltration of carcinoma cells activate nonfunctional epithelial integrins, a cellular system of human thyroid clones derived from normal glands (HTU-5) and papillary carcinomas (HTU-34) was employed. In HTU-5 cells, {alpha}vβ3 integrin was diffused all over the membrane, disconnected from the cytoskeleton, and unable to mediate adhesion. Conversely, in HTU-34 cells, {alpha}vβ3 was clustered at focal contacts (FCs) and mediated firm attachment and spreading. {alpha}vβ3 recruitment at FCs and ligand-binding activity, essentially identical to those of HTU-34, occurred in HTU-5 cells upon treatment with hepatocyte growth factor/scatter factor (HGF/SF). The HTU-34 clone secreted HGF/SF and its receptor was constitutively tyrosine phosphorylated suggesting an autocrine loop responsible for {alpha}vβ3 activated state. Antibody-mediated inhibition of HGF/SF function in HTU-34 cells disrupted {alpha}vβ3 enrichment at FCs and impaired adhesion. Accordingly, activation of {alpha}vβ3 in normal cells was produced by HTU-34 conditioned medium on the basis of its content of HGF/SF. These results provide the first example of a growth factor–driven integrin activation mechanism in normal epithelial cells and uncover the importance of cytokine-based autocrine loops for the physiological control of integrin activation.

Key Words: integrins • thyroid • hepatocyte growth factor/scatter factor • c-Met • tumor invasion

Abbreviations used in this paper: ECM, extracellular matrix; FC, focal contact; FN, fibronectin; GF, growth factor; HGF/SF, hepatocyte growth factor/scatter factor; MIF, mean intensity fluorescence; MMP-2, metalloproteinase-2; SFM, serum-free medium; VN, vitronectin.

The major support for this work was from Associazione Italiana per la Ricerca sul Cancro (AIRC, Milano, Italy) to PCM. Partial support came from Agenzia Spaziale Italiana (ASI, Roma, Italy) to PCM within a space biology program aimed at studying cell adhesion in ground experiments.

Drs. Marchisio and De Filippi share senior authorship.

Address all correspondence to Pier Carlo Marchisio, M.D., Ph.D., Molecular Histology Unit, 2A1, DIBIT, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milano, Italy. Tel.: (39) 02 26 43 48 34. Fax: (39) 02 26 43 48 55. E-mail: marchisio.piercarlo{at}hsr.it


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