Thrombospondin 1--a regulator of adenoma growth and carcinoma progression in the APC(Min/+) mouse model.
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 APC(Min/+) 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 (APC(Min/+)), 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 APC(Min/+) littermates. Moreover, a significant decrease of TUNEL-positive cells was observed in intestinal adenomas of TSP-1(-/-)/APC(Min/+) 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.
Gutierrez
Linda S
LS
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, USA.
Suckow
Mark
M
Lawler
Jack
J
Ploplis
Victoria A
VA
Castellino
Francis J
FJ
D000236:Adenoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000502:physiology*; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000378:metabolism; D017491:Genes, APC; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D051379:Mice; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D019700:Thrombospondin 1 / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D018809:Proliferating Cell Nuclear Antigen; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors