血小板反应蛋白2通过改变NOD/SCID/γC基因敲除（NOG）小鼠的微环境来抑制人恶性黑色素瘤的转移。

Thrombospondin 2 inhibits metastasis of human malignant melanoma through microenvironment-modification in NOD/SCID/gammaCnull (NOG) mice.

作者信息

Chijiwa Tsuyoshi, Abe Yoshiyuki, Ikoma Norihiro, Yamazaki Hitoshi, Tsukamoto Hideo, Suemizu Hiroshi, Kawai Kenji, Wakui Masatoshi, Nishime Chiyoko, Matsumoto Hozumi, Matsuyama Masahiro, Mukai Masaya, Ueyama Yoshito, Nakamura Masato

机构信息

Department of Pathology, Tokai University School of Medicine, Shimokasuya, Isehara, Kanagawa 259-1193, Japan.

出版信息

Int J Oncol. 2009 Jan;34(1):5-13.

PMID:19082472

Abstract

Thrombospondin (TSP) 2 interacts with matrix metalloproteinases (MMPs) and matrix serine proteases such as plasminogen activator (PA). Malignant melanoma is an aggressive human neoplasm showing aggressive metastatic features. We examined the effects of TSP2 gene introduction in the human malignant melanoma cell line A375. We established three clones transfected with human TSP2 (A375/TSP2). The in vitro invasiveness was remarkably suppressed (42-61%) in the TSP2-transfectants, while growth properties were preserved. The A375/TSP2 showed significantly decreased liver metastatic potential (liver weight: 3.88+/-0.30 g in A375/TSP2, 7.07+/-0.67 g in vector-transfectant (A375/V), p<0.01, Mann-Whitney U test) in super immuno-deficient mice (NOD/SCID/gammacnull, NOG). The PA inhibitor-1 (PAI-1) and PAI-2 mRNAs were significantly overexpressed in A375/TSP2. The increased activities of PAI-1 and PAI-2 were confirmed by reverse zymography. The vascularity of metastatic lesions was significantly decreased in A375/TSP2 (vascular density: 0.62+/-0.15% in A375/TSP2, 4.96+/-0.61% in A375/V, p<0.01, Welch test). These results suggest that TSP2 suppresses hematogenous metastasis through microenvironment-modification including PAI up-regulation and anti-vascularization in human malignant melanoma.

摘要

血小板反应蛋白（TSP）2与基质金属蛋白酶（MMPs）以及基质丝氨酸蛋白酶如纤溶酶原激活剂（PA）相互作用。恶性黑色素瘤是一种具有侵袭性转移特征的侵袭性人类肿瘤。我们检测了TSP2基因导入人恶性黑色素瘤细胞系A375后的作用。我们建立了三个转染人TSP2的克隆（A375/TSP2）。在TSP2转染细胞中，体外侵袭性显著受到抑制（42%-61%），而生长特性得以保留。在超级免疫缺陷小鼠（NOD/SCID/γc基因敲除小鼠，NOG）中，A375/TSP2的肝转移潜能显著降低（肝重量：A375/TSP2为3.88±0.30 g，载体转染细胞（A375/V）为7.07±0.67 g，p<0.01，Mann-Whitney U检验）。PA抑制剂-1（PAI-1）和PAI-2的mRNA在A375/TSP2中显著过表达。通过反向酶谱法证实了PAI-1和PAI-2活性的增加。A375/TSP2转移灶的血管生成显著减少（血管密度：A375/TSP2为0.62±0.15%，A375/V为4.96±0.61%，p<0.01，Welch检验）。这些结果表明，TSP2通过包括上调PAI和抗血管生成在内的微环境修饰来抑制人恶性黑色素瘤的血行转移。