Thrombospondin-1 promotes alpha 3 beta 1 integrin-mediated adhesion and neurite-like outgrowth and inhibits proliferation of small cell lung carcinoma cells

Although human small cell lung carcinoma (SCLC) cell lines are typically an chorage-independent and do not attach on most extracellular matrix proteins , OH-1, and several other SCLC cell lines attached on substrates coated wit h thrombospondin-1 (TSP1). SCLC cells grew longterm as adherent cells on a TSP1-coated substrate. Adhesion of SCLC cells on TSP1 was inhibited by hepa rin, function-blocking antibodies recognizing alpha 3 or beta 1 integrin su bunits, and by soluble alpha 3 beta 1 integrin ligands. SCLC cells extended neurite-like processes on a TSP1 substrate, which was also mediated by alp ha 3 beta 1 integrin, Process formation on a TSP1 substrate was specificall y stimulated by epidermal growth factor and somatostatin. Adhesion on TSP1 weakly inhibited SCLC fell proliferation, but this inhibition was strongly enhanced in the presence of epidermal growth factor. TSP1 and an alpha 3 be ta 1 integrin-binding peptide from TSP1 also inhibited proliferation when a dded in solution. High-affinity binding of I-125-labeled TSP1 to OH-1 cells was heparin-dependent and may be mediated by sulfated glycolipids, which a re the major sulfated glycoconjugates synthesized by these cells. Synthesis or secretion of TSP1 by SCLC cells could not be detected. On the basis of these results, the alpha 3 beta 1 integrin and sulfated glycolipids coopera te to mediate adhesion of SCLC cells on TSP1, Interaction with TSP1 through this integrin inhibits growth and induces neurotypic differentiation, whic h suggests that this response to TSP1 may be exploited to inhibit the progr ession of SCLC.