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J. Cell Biol., Volume 142, Number 4, August 24, 1998 1145-1156

Growth Factor-dependent Activation of alpha vbeta 3 Integrin in Normal Epithelial Cells: Implications for Tumor Invasion

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

* DIBIT, Department of Biological and Technological Research, San Raffaele Scientific Institute, 20132 Milano, Italy; Dagger  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 vbeta 3 integrin was diffused all over the membrane, disconnected from the cytoskeleton, and unable to mediate adhesion. Conversely, in HTU-34 cells, alpha vbeta 3 was clustered at focal contacts (FCs) and mediated firm attachment and spreading. alpha vbeta 3 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 vbeta 3 activated state. Antibody-mediated inhibition of HGF/SF function in HTU-34 cells disrupted alpha vbeta 3 enrichment at FCs and impaired adhesion. Accordingly, activation of alpha vbeta 3 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


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