Endorepellin in vivo: Targeting the tumor vasculature and retarding cancer growth and metabolism
Endorepellin in vivo: Targeting the tumor vasculature and retarding cancer growth and metabolism
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DOI：
10.1093/jnci/djj441
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发表时间：
2006-11-15
期刊：
影响因子：
--
通讯作者：
Iozzo, Renato V.
中科院分区：
文献类型：
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作者：
Bix, Gregory;Castello, Remedios;Iozzo, Renato V.
背景控制癌症的抗血管生成方法需要更好地理解血管生成和发现调节这一关键生物过程的新化合物。在这里，我们研究了endorepelin的作用，血管生成抑制蛋白片段，是来自串珠素，硫酸乙酰肝素蛋白聚糖的C-末端，在体内控制肿瘤血管生成。研究方法：我们将人重组内排斥素全身给予荷原位鳞状细胞癌异种移植瘤或同系刘易斯肺癌肿瘤的小鼠。我们通过定量免疫组化和正电子发射断层扫描成像监测肿瘤生长、血管生成、代谢、缺氧和有丝分裂指数。此外，我们确定了本地化注射endorepelin使用近红外标记和免疫组织化学的冷冻肿瘤切片。最后，我们分离出肿瘤来源的内皮细胞，并测试内排斥素是否可以与这些细胞相互作用，并破坏体外毛细血管形态发生。所有统计学检验均为双侧检验。结果如下：如通过免疫组织化学分析所确定的，内皮排斥素特异性靶向肿瘤脉管系统，并在肿瘤血管周围区域中积累，在那里它作为离散沉积物持续数天。这导致了肿瘤血管生成的抑制（如通过减少的CD 31阳性细胞所测量的，平均对照= 1902个CD 31阳性像素，平均内排斥素治疗= 343.9，平均值之间的差异= 1558，95%置信区间[CI] = 1296至1820，P
Background. The antiangiogenic approach to controlling cancer requires a better understanding of angiogenesis and the discovery of new compounds that modulate this key biological process. Here we investigated the role of endorepellin, an angiostatic protein fragment that is derived from the C-terminus of perlecan, a heparan sulfate proteoglyean, in controlling tumor angiogenesis in vivo. Methods: We administered human recombinant endorepellin systemically to mice bearing orthotopic squamous carcinoma xenografts or syngeneic Lewis lung carcinoma tumors. We monitored tumor growth, angiogenesis, metabolism, hypoxia, and mitotic index by using quantitative immunohistochemistry and positron emission tomography scan imaging. In addition, we determined the localization of injected endorepellin using near-infrared labeling and immunohistochemistry of frozen tumor sections. Finally, we isolated tumor-derived endothelial cells and tested whether endorepellin could interact with these cells and disrupt in vitro capillary morphogenesis. All statistical tests were two-sided. Results: Endorepellin specifically targeted the tumor vasculature as determined by immunohistochemical analysis and accumulated in the tumor perivascular zones where it persisted for several days as discrete deposits. This led to inhibition of tumor angiogenesis (as measured by decreased CD31-positive cells, mean control = 1902 CD31-positive pixels, mean endorepellin treated = 343.9, difference between means = 1558, 95% confidence interval [CI] = 1296 to 1820, P