Carcinogenesis, Vol. 24, No. 2, 199-207,
February 2003
© 2003 Oxford University Press
CANCER BIOLOGY |
Thrombospondin 1—a regulator of adenoma growth and carcinoma progression in the APCMin/+ mouse model
1 Walther Cancer Research Center, W. M. Keck Center for Transgene Research, Department of Chemistry and Biochemistry, Freimann Life Sciences Center University of Notre Dame, Notre Dame, IN 46556, and
2 Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
Thrombospondin 1 (TSP-1) is a multifunctional extracellular matrix protein that is an endogenous regulator of tumor angiogenesis. The effects of TSP-1 on adenoma formation and development into cancerous lesions has been evaluated in the Min/+ (multiple intestinal neoplasia) mouse model. These mice develop multiple adenomas in the small intestine due to a mutation in the homologous APC (adenomatous polyposis coli) gene. As in its human counterpart, these adenomas may progress to carcinomas. Intestines of APCMin/+ mice were dissected and histologic evaluation of adenomas was then conducted. Significant increases in vascularization and proliferation were observed in adenomatous, as compared with normal, mucosa. TSP-1 immunostaining revealed significant decreases in the number and intensity of positive cells in adenomas, as compared with normal mucosa. TSP-1 scores were inversely correlated with vascularity and proliferation rate. Cross breeding of mice homozygous for a deletion of the TSP-1 gene (TSP-1-/-) with mice heterozygous for the APC gene mutation (APCMin/+), resulted in animals that showed a significant increase in adenoma number and diameter. Also, histopathological examination of these adenomas showed accelerated dysplasic changes, carcinoma in situ and early invasion, compared with their APCMin/+ littermates. Moreover, a significant decrease of TUNEL-positive cells was observed in intestinal adenomas of TSP-1-/-/APCMin/+ mice. This study reports the first in vivo impact of TSP-1 during early stages of tumor initiation and development in an intestinal carcinogenesis model and demonstrates that TSP-1 affects both angiogenesis and tumor cell apoptosis.
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