Thrombospondin-1 promotes alpha3beta1 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 anchorage-independent and do not attach on most extracellular matrix proteins, OH-1, and several other SCLC cell lines attached on substrates coated with thrombospondin-1 (TSP1). SCLC cells grew long-term as adherent cells on a TSP1-coated substrate. Adhesion of SCLC cells on TSP1 was inhibited by heparin, function-blocking antibodies recognizing alpha3 or beta1 integrin subunits, and by soluble alpha3beta1 integrin ligands. SCLC cells extended neurite-like processes on a TSP1 substrate, which was also mediated by alpha3beta1 integrin. Process formation on a TSP1 substrate was specifically stimulated by epidermal growth factor and somatostatin. Adhesion on TSP1 weakly inhibited SCLC cell proliferation, but this inhibition was strongly enhanced in the presence of epidermal growth factor. TSP1 and an alpha3beta1 integrin-binding peptide from TSP1 also inhibited proliferation when added in solution. High-affinity binding of 125I-labeled TSP1 to OH-1 cells was heparin-dependent and may be mediated by sulfated glycolipids, which are 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 alpha3beta1 integrin and sulfated glycolipids cooperate to mediate adhesion of SCLC cells on TSP1. Interaction with TSP1 through this integrin inhibits growth and induces neurotypic differentiation, which suggests that this response to TSP1 may be exploited to inhibit the progression of SCLC.
Guo
N
N
Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland 20892-1500, USA.
Templeton
N S
NS
Al-Barazi
H
H
Cashel
J A
JA
Sipes
J M
JM
Krutzsch
H C
HC
Roberts
D D
DD
D018288:Carcinoma, Small Cell; D002448:Cell Adhesion / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D039201:Integrin alpha3beta1; D016023:Integrins / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008175:Lung Neoplasms; D016501:Neurites / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D013004:Somatostatin / Q000494:pharmacology; D019700:Thrombospondin 1 / Q000493:pharmacokinetics / Q000494:pharmacology / Q000502:physiology*; D014407:Tumor Cells, Cultured
D039201:Integrin alpha3beta1; D016023:Integrins; D019700:Thrombospondin 1; D013004:Somatostatin; D004815:Epidermal Growth Factor