Thrombospondin-1 gene expression affects survival and tumor spectrum of p53-deficient mice

In vitro and in vivo data indicate that thrombospondin-1 (TSP1) inhibits tu mor progression in several ways including direct effects on cellular growth and apoptosis in the stromal. compartment. To evaluate the importance of T SP1 for the progression of naturally arising tumors in vivo, we have crosse d TSP1-deficient mice with p53-deficient mice. In p53-null mice, the absenc e of TSP1 decreases survival from 160 +/- 52 days to 149 +/- 42 days. A log -rank test comparing survival curves for these two populations yields a two -sided P value of 0.0272. For mice that are heterozygous for the p53-null a llele, survival is 500 +/- 103 days In the presence of TSP1 expression, and 426 +/- 125 days in its absence (P = 0.0058). Whereas TSP1 expression did not cause a measurable change in the incidence of the majority of tumor typ es, a statistically significant (P less than or equal to 0.05) decrease in the incidence of osteosarcomas is observed in the absence of TSP1. To deter mine more directly if host TSP1 inhibits tumor growth, B16F10 melanoma and F9 testicular teratocarcinoma cells have been implanted in C57BL/6J and 129 Sv TSP1-null mice, respectively. The B16F10 tumors grow approximately twice as fast in the TSP1-null background and exhibit an increase in vascular de nsity, a decrease in the rate of tumor cell apoptosis, and an increase in t he rate of tumor cell proliferation. Increased tumor growth is also observe d in the absence of TSP1 on the 129Sv genetic background. These data indica te that endogenous host TSP1 functions as a modifier or landscaper gene to suppress tumor growth.