Thrombospondin 1 -: a regulator of adenoma growth and carcinoma progression in the APCMin/+ mouse model
Thrombospondin 1 -: a regulator of adenoma growth and carcinoma progression in the APCMin/+ mouse model
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DOI：
10.1093/carcin/24.2.199
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发表时间：
2003-02-01
期刊：
影响因子：
4.7
通讯作者：
Castellino, FJ
中科院分区：
文献类型：
--
作者：
Gutierrez, LS;Suckow, M;Castellino, FJ
血小板反应蛋白1（TSP-1）是一种多功能的细胞外基质蛋白，是肿瘤血管生成的内源性调节因子。在Min（/+）（多发性肠肿瘤）小鼠模型中评价了TSP-1对腺瘤形成和发展成癌性病变的作用。由于同源APC（腺瘤性结肠息肉病）基因突变，这些小鼠在小肠中发生多发性腺瘤。与人类腺瘤一样，这些腺瘤可能进展为癌。解剖APC（Min/+）小鼠的肠，然后进行腺瘤的组织学评价。与正常粘膜相比，在腺瘤中观察到血管化和增殖的显著增加。TSP-1免疫组化染色显示腺瘤中阳性细胞的数量和强度与正常粘膜相比显著减少。TSP-1评分与血管分布和增殖率呈负相关。TSP-1基因缺失纯合子小鼠（TSP-1（-/-））与APC基因突变杂合子小鼠（APC（Min/+））杂交，导致动物显示腺瘤数量和直径显著增加。此外，这些腺瘤的组织病理学检查显示，与APC（Min/+）同窝仔相比，加速了发育异常变化、原位癌和早期浸润。此外，在TSP-1（-/-）/APC（Min/+）小鼠的肠腺瘤中观察到TUNEL阳性细胞显著减少。本研究报告了TSP-1在肠道癌发生模型中肿瘤发生和发展的早期阶段的首次体内影响，并证明了TSPI影响血管生成和肿瘤细胞凋亡。
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 TSPI affects both angiogenesis and tumor cell apoptosis.