TRANSFECTION OF THROMBOSPONDIN-1 COMPLEMENTARY-DNA INTO A HUMAN BREAST-CARCINOMA CELL-LINE REDUCES PRIMARY TUMOR-GROWTH, METASTATIC POTENTIAL, AND ANGIOGENESIS

Previous studies demonstrated that metastatic MDA-MB-435 breast carcin oma cells synthesized and secreted less of the extracellular matrix pr otein thrombospondin 1 (TSP1) than nonmetastatic breast carcinoma cell lines, a trend also observed for melanoma and lung carcinoma cell lin es. To directly examine the effect of tumor cell TSP1 expression on tu mor growth and metastasis, MDA-MB-435 cells were transfected with full length THBS-1 cDNA linked to a constitutive cytomegalovirus promoter, or with the cytomegalovirus vector alone, Injection of transfected cl ones that overexpressed TSP1 into the mammary fat pad of nude mice res ulted in a dose-dependent inhibition of primary tumor size and an inhi bition of spontaneous pulmonary metastases, which occurred in 21-30% o f THBS-1 transfectants compared to 44-49% of controls (P = 0.007). An additional clone was identified that overexpressed a COOH-terminally t runcated TSP1. This clone produced larger primary tumors and an increa se in the occurrence of metastases relative to control transfectants, suggesting the participation of a previously understudied region of TS P1 in the regulation of tumor progression, The THBS-1 and control tran sfectants did not exhibit significant differences in growth, colonizat ion, or motility in vitro. However, a relative reduction in capillary densities in primary tumors formed by the wild-type THBS-1 transfectan ts was observed, suggestive of an angiostatic effect, The data indicat e that tumor cell production of TSP1 can exert a significant inhibitor y effect on tumor progression in the MDA-MB-435 breast carcinoma cell line, which may be attributable in part to a reduction in angiogenesis .