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

一般认为癌细胞的主动侵袭在肿瘤转移过程中是必不可少的。在这篇报道中，我们描述了一个小鼠乳腺肿瘤(MCH66)的转移模型，它确实需要侵袭到靶器官的血管壁，在这种情况下，肺。这个过程包括肿瘤巢内被正弦血管包围，随后肿瘤在肺内血管内生长，在这个过程中不穿透血管壁。用一个非转移性MCH66克隆(MCH66C8)和另一个高侵袭性转移细胞系(MCH416)进行的比较研究表明，高血管生成活性和肿瘤血管的血窦重构是MCH66转移的先决条件。差异CDNA分析确定了MCH66过度表达的几个基因，包括血管生成因子多营养素基因，以及可能调节微环境走向新生血管的ECM相关分子。在上述克隆的侵袭性非侵袭性转移相关候选基因中，Pleiotroin(PTN)、分泌性白细胞蛋白酶抑制物(SLPI)、Fiblin-5、胰岛素样生长因子结合蛋白-5(Igfbp5)、内毒素结合蛋白(LPSBP)、细胞视黄醇结合蛋白-1(CRBP1)分别在MCH66C8和MCH416中表达。PTN的转染体(C8-PTN或416-PTN)不促进肺转移或形成血窦血管。目前，其他5个基因对非侵袭性转移的诱导作用正在研究中，该模型有望在肿瘤转移治疗药物的筛选和开发中发挥作用。

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.