Thrombospondins I and II messenger RNA expression in lung carcinoma: Relationship with p53 alterations, angiogenic growth factors, and vascular density

Thrombospondin (TSP) is a M-r 450,000 multifunctional matrix glycoprotein t hat interferes with tumor growth, angiogenesis, and metastasis, It has rece ntly been shown that TSP expression is enhanced by the product of the p53 g ene and that a down-regulation of TSP may be observed when alterations of t he p53 protein occur. Moreover, a number of studies have demonstrated a reg ulatory activity of p53 on human vascular endothelial growth factor (VEGF), although additional investigations mill be necessary to understand their r elationship. In non-small cell lung carcinoma (NSCLC), neoangiogenesis, p53 alterations, and VEGF expression seem to have meaningful implications in t he development and progression of this type of cancer. The aim of this stud y is to identify and quantitate TSP I and TSP II mRNA in NSCLCs with respec t to p53 alterations, angiogenic growth factor expression, and microvascula r density. A series of 24 cases of NSCLC were analyzed. Eleven of 24 of the cases were positive for TSP II mRNA, whereas 8 of 24 showed TSP I mRNA exp ression. A significant inverse association was found between TSP I mRNA and fibroblast growth factor (FGF) protein expression (P = 0.00001), Tumors wi th low FGF protein expression (less than or equal to 40% of positive cells) presented a number of TSP I cDNA molecules, significantly higher than tumo rs expressing high levels of FGF protein. No association was found between TSP mRNA expression and other angiogenic growth factors (i.e., VEGF) or tum oral neovascularization. On the contrary, tumors with high levels of FGF sh owed a higher number of microvessels (P = 0.05), By PCR-single-strand confo rmational polymorphism analysis, we observed aberrations of the p53 gene in 19 of the 24 tumor samples. No association was found between p53 alteratio ns and TSP mRNA expression, Instead, an interestingly significant associati on was found between the presence of p53 mutations and high VEGF protein ex pression (P = 0.01) and neovascularization (P = 0.03), Highly vascularized tumors showed higher VEGF protein expression (r = 0.45; P = 0.02), These da ta support the concept that in NSCLC, p53 exerts an important role in the c ontrol of neoangiogenesis. This influence is probably mediated by VEGF, The inverse association we found between TSP I and basic FGF suggests a differ ent role of TSP I and TSP II in the angiogenic "switch," supporting the hyp othesis that especially TSP I may have a significant function in tumor angi ogenesis.