Jack Lawler

Thrombospondin is one of a class of adhesive glycoproteins that mediate cell-to-cell and cell-to-matrix interactions. We have used two monoclonal antibodies to isolate cDNA clones of thrombospondin from a human endothelial cell cDNA library and have determined the complete nucleotide sequence of the coding region. Three regions of known amino acid sequence of human platelet thrombospondin confirm that the clones are authentic. Three types of repeating amino acid sequence are present in thrombospondin. The first is 57 amino acids long and shows homology with circumsporozoite protein from Plasmodium falciparum. The second is 50-60 amino acids long and shows homology with epidermal growth factor precursor. The third occurs as a continuous eightfold repeat of a 38-residue sequence; structural homology with parvalbumin and calmodulin indicates that these repeats constitute the multiple calcium-binding sites of thrombospondin. The amino acid sequence arg-gly-asp-ala is included in the last type 3 repeat. This sequence is probably the site for the association of thrombospondin with cells. In addition, localized homologies with procollagen, fibronectin, and von Willebrand factor are present in one region of the thrombospondin molecule.

Thrombospondin-1 (TSP-1) is a matricellular glycoprotein that influences cellular phenotype and the structure of the extracellular matrix. These effects are important components of the tissue remodeling that is associated with angiogenesis and neoplasia. The genetic mutations in oncogenes and tumor suppressor genes that occur within tumor cells are frequently associated with decreased expression of TSP-1. However, the TSP-1 that is produced by stromal fibroblasts, endothelial cells and immune cells suppresses tumor progression. TSP-1 inhibits angiogenesis through direct effects on endothelial cell migration and survival and through indirect effects on growth factor mobilization. TSP-1 that is present in the tumor microenvironment also acts to suppress tumor cell growth through activation of transforming growth factor beta in those tumor cells that are responsive to TGF beta. In this review, the molecular basis for the role of TSP-1 in the inhibition of tumor growth and angiogenesis is summarized.