Journal Article

Thrombospondin 1—a regulator of adenoma growth and carcinoma progression in the APC<sup>Min/+</sup> mouse model

Linda S. Gutierrez, Mark Suckow, Jack Lawler, Victoria A. Ploplis and Francis J. Castellino

in Carcinogenesis

Volume 24, issue 2, pages 199-207
Published in print February 2003 | ISSN: 0143-3334
Published online February 2003 | e-ISSN: 1460-2180 | DOI:
Thrombospondin 1—a regulator of adenoma growth and carcinoma progression in the APCMin/+ mouse model

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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.

Keywords: APC, adenomatous polyposis coli; H&E, hematoxylin–eosin; Min, multiple intestinal neoplasia; TSP-1, thrombospondin 1; vWF, von Willebrand Factor; WT, wild-type.

Journal Article.  6176 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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