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(American Journal of Pathology. 2001;159:1949-1956.)
© 2001 American Society for Investigative Pathology

Regular Articles

Thrombospondin-1 Gene Expression Affects Survival and Tumor Spectrum of p53-Deficient Mice

Jack Lawler^*, Wei-Min Miao^*, Mark Duquette^*, Noël Bouck, Roderick T. Bronson and Richard O. Hynes

From the Department of Pathology,^*
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; the Department of Pathology,
Tufts University Schools of Medicine and Veterinary Medicine, Boston, Massachusetts; the Department of Biology,
Howard Hughes Medical Institute and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; and the Department of Microbiology-Immunology and Robert H. Lurie Comprehensive Cancer Center,
Northwestern University Medical School, Chicago, Illinois

In vitro and in vivo data indicate that thrombospondin-1 (TSP1) inhibits tumor progression in several ways including direct effects on cellular growth and apoptosis in the stromal compartment. To evaluate the importance of TSP1 for the progression of naturally arising tumors in vivo, we have crossed TSP1-deficient mice with p53-deficient mice. In p53-null mice, the absence 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 allele, 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 types, a statistically significant (P 0.05) decrease in the incidence of osteosarcomas is observed in the absence of TSP1. To determine more directly if host TSP1 inhibits tumor growth, B16F10 melanoma and F9 testicular teratocarcinoma cells have been implanted in C57BL/6J and 129Sv TSP1-null mice, respectively. The B16F10 tumors grow approximately twice as fast in the TSP1-null background and exhibit an increase in vascular density, a decrease in the rate of tumor cell apoptosis, and an increase in the rate of tumor cell proliferation. Increased tumor growth is also observed in the absence of TSP1 on the 129Sv genetic background. These data indicate that endogenous host TSP1 functions as a modifier or landscaper gene to suppress tumor growth.

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