title: Thrombospondin 1--a regulator of adenoma growth and carcinoma progression in the APC(Min/+) mouse model.
abstract: 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.
authors.affiliation: 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.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Gutierrez
authors.forename: Mark
authors.initials: M
authors.lastname: Suckow
authors.forename: Jack
authors.initials: J
authors.lastname: Lawler
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Ploplis
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Castellino
mesh_terms: 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
chemical_list: 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