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A role of angiogenesis in cancer metastasis - Cloning and characterization of genes associated with invasion-independent metastasis-

血管生成在癌症转移中的作用 - 与侵袭无关转移相关基因的克隆和表征 -

基本信息

批准号：
12670212
负责人：
SUGINO Takashi
金额：
$ 2.43万
依托单位：
Fukushima Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

It is generally believed that active invasion by cancer cells is essential to the metastatic process. In this report, we describe a murine mammary tumor (MCH66) model of metastasis that does hot require invasion into the vascular wall of the target organ, in this case, the lung. The process involves intravasation of tumor nests surrounded by sinusoidal blood vessels, followed by intravascular tumor growth in the lung, without penetration of the vascular wall during the process. Comparative studies using a non-metastatic MCH66 clone (MCH66C8) and another highly invasive metastatic cell line (MCH416) suggested that high angiogenic activity and sinusoidal remodeling of tumor blood vessels wereprerequisites for MCH66 metastasis. Differential CDNA analysis identified several genes that were over-expressed by MCH66, including genes for the angiogenesis factor pleiotrophin, and ECM-associated molecules that may modulate the microenvironment towards neovascularization. Our analyses suggest that tumor angiogenesis plays a role in the induction of invasion-independent metastasis.Of the invasion-independent metastasis-associated gene candidates cloned as above, Pleiotrophin (PTN), Secretory leukocyte protease inhibitor (SLPI), Fibulin-5, Insulin-like growth factor-binding protein-5 (IGFBP5), LPS-binding protein (LPSBP), Cellular retinol binding protein-1 (CRBP1) were transfected in MCH66C8 and MCH416. Transfectants of PTN (C8-PTN or 416-PTN) did not facilitate lung metastasis or develop sinusoidal vasculature. Induction of invasion-independent metastasis by other 5 genes were under investigation at presentThis model should prove useful in screening and development of new therapeutic agents for cancer metastasis.

一般认为，癌细胞的主动侵袭是转移过程所必需的。在这份报告中，我们描述了一个小鼠乳腺肿瘤（MCH 66）转移模型，热需要入侵到血管壁的靶器官，在这种情况下，肺。该过程涉及由窦状血管包围的肿瘤巢的内渗，随后是肺中的血管内肿瘤生长，在该过程中没有穿透血管壁。使用非转移性的MCH 66克隆（MCH 66 C8）和另一种高侵袭性转移细胞系（MCH 416）的比较研究表明，高血管生成活性和肿瘤血管的窦状隙重塑是MCH 66转移的先决条件。差异cDNA分析确定了由MCH 66过度表达的几个基因，包括血管生成因子多效生长因子的基因和可能调节微环境朝向新血管形成的ECM相关分子。在上述克隆的与侵袭无关的转移相关的候选基因中，多效生长因子（PTN）、分泌性白细胞蛋白酶抑制剂（SLPI）、纤维蛋白-5、胰岛素样生长因子结合蛋白-5（IGFBP 5）、脂多糖结合蛋白（LPSBP）、将细胞视黄醇结合蛋白-1（CRBP 1）转染到MCH 66 C8和MCH 416中。PTN（C8-PTN或416-PTN）的转染子不促进肺转移或发展窦状血管。目前，其他5个基因诱导肿瘤侵袭非依赖性转移的研究正在进行中，该模型有望用于筛选和开发新的肿瘤转移治疗药物。