Thrombospondin-1 selectively inhibits early-stage carcinogenesis and angiogenesis but not tumor lymphangiogenesis and lymphatic metastasis in transgenic mice
Thrombospondin-1 selectively inhibits early-stage carcinogenesis and angiogenesis but not tumor lymphangiogenesis and lymphatic metastasis in transgenic mice
复制标题
DOI：
10.1038/sj.onc.1205956
复制
发表时间：
2002-11-14
期刊：
影响因子：
8
通讯作者：
Detmar, M
中科院分区：
文献类型：
--
作者：
Hawighorst, T;Oura, H;Detmar, M
内源性血管生成抑制剂血小板反应蛋白-1（TSP-1）在多步致癌的早期阶段以及控制血源性与淋巴转移中所发挥的作用尚不清楚。为了研究这些问题，我们比较了正常小鼠和转基因小鼠中肿瘤的发展，在标准的两步化学皮肤致癌方案后，在表皮中靶向过表达TSP-1。TSP-1的过表达导致癌前上皮的延迟和减少的发展。增生，但不抑制恶性转化为鳞状细胞癌。TSP-1过表达也抑制肿瘤血管生成和远处器官转移，但不能抑制肿瘤相关的淋巴管生成或淋巴肿瘤扩散到区域淋巴结。伴随着这些结果，我们发现，内皮TSP-1受体CD 36大多是缺乏皮肤淋巴管。我们的研究结果表明TSP-1在预防肿瘤发生的癌前阶段中的潜在用途，并可能对进一步开发抗血管生成癌症疗法产生影响。
The roles played by the endogenous angiogenesis inhibitor thrombospondin-1 (TSP-1) in the early stages of multi-step carcinogenesis and in the control of hematogenous versus lymphatic metastasis are unknown. To investigate these issues we compared tumor development in normal mice and in transgenic mice with targeted overexpression of TSP-1 in the epidermis following a standard two-step chemical skin carcinogenesis regimen. Overexpression of TSP-1 resulted in delayed and reduced development of premalignant epithelial. hyperplasias, but did not inhibit the malignant conversion to squamous cell carcinomas. TSP-1 overexpression also suppressed tumor angiogenesis and distant organ metastasis, but failed to inhibit tumor-associated lymphangiogenesis or lymphatic tumor spread to regional lymph nodes. Concomitant with these results, we found that the endothelial TSP-1 receptor CD36 was mostly absent from cutaneous lymphatic vessels. Our findings indicate the potential use of TSP-1 for the prevention of premalignant stages of tumorigenesis and are likely to have implications for the further development of anti-angiogenic cancer therapies.