GROWTH FACTOR-DEPENDENT ACTIVATION OF ALPHA-V-BETA-3 INTEGRIN IN NORMAL EPITHELIAL-CELLS - IMPLICATIONS FOR TUMOR INVASION

Integrin activation is a multifaceted phenomenon leading to increased affinity and avidity for matrix ligands. To investigate whether cytoki nes produced during stromal infiltration of carcinoma cells activate n onfunctional epithelial integrins, a cellular system of human thyroid clones derived from normal glands (HTU-5) and papillary carcinomas (HT U-34) was employed. In HTU-5 cells, alpha v beta 3 integrin was diffus ed all over the membrane, disconnected from the cytoskeleton, and unab le to mediate adhesion. Conversely, in HTU-34 cells, alpha v beta 3 wa s clustered at focal contacts (FCs) and mediated firm attachment and s preading alpha v beta 3 recruitment at FCs and ligand-binding activity , essentially alpha v beta 3 recruitment at FCs and ligand-binding act ivity, essentially identical to those of HTU-34, occurred in HTU-5 cel ls upon treatment with hepatocyte growth factor/scatter factor (HGF/SF ). The HTU-34 clone secreted HGF/SF and its receptor was constitutivel y tyrosine phosphorylated suggesting an autocrine loop responsible for alpha v beta 3 activated state. Antibody-mediated inhibition of HGF/S F function in HTU-34 cells disrupted alpha v beta 3 enrichment at FCs and impaired adhesion. Accordingly, activation of alpha v beta 3 in no rmal cells was produced by HTU-34 conditioned medium on the basis of i ts content of HGF/SF. These results provide the first example of a gro wth factor-driven integrin activation mechanism in normal epithelial c ells and uncover the importance of cytokine-based autocrine loops for the physiological control of integrin activation.