Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors.
Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors.
复制标题
DOI：
--
复制
发表时间：
2003-06
期刊：
影响因子：
11.2
通讯作者：
O. Stoeltzing;S. Ahmad;Wenbiao Liu;M. McCarty;J. Wey;A. Parikh;F. Fan;N. Reinmuth;Michiya Kawaguchi;C. Bucana;L. Ellis
中科院分区：
文献类型：
--
作者：
O. Stoeltzing;S. Ahmad;Wenbiao Liu;M. McCarty;J. Wey;A. Parikh;F. Fan;N. Reinmuth;Michiya Kawaguchi;C. Bucana;L. Ellis
血管生成素（Angiopoietin，Ang）-1和-2是胚胎和出生后新生血管形成的重要调节因子。Ang-1激活内皮细胞特异性酪氨酸激酶受体Tie-2，这反过来又导致增强的内皮细胞存活和稳定。Ang-1对肿瘤血管生成的影响仍有争议;尽管我们先前已经证明，Ang-1在结肠癌细胞中的过表达导致s.c.尽管Ang-1可能促进肿瘤生长，但其他人已经表明Ang-1可能是促血管生成的。很少有研究涉及Angs在转移性生长器官中生长的肿瘤中的作用。我们推测过表达Ang-1可能通过抑制血管生成来抑制生长在肝脏中的结肠癌的生长。我们还想研究Ang-1影响体内血管生成的机制。用Ang-1构建体或空载体（pcDNA）稳定转染人结肠癌细胞（HT 29），并直接注射到裸鼠的肝脏中。37天后，收获肝脏并称重，并测量肿瘤大小。在另外的实验中，为了验证Ang-1的旁分泌作用，将对照细胞和Ang-1转染的细胞的各种混合物注射到肝脏中，并评估肿瘤生长。采用明胶海绵血管生成实验研究了重组Ang-1对血管生成的直接影响。使用来自转染细胞的条件培养基的皮内Miles测定研究Ang-1对血管通透性的影响。Ang-1组肝重（P <0.05）、肿瘤体积（P <0.05）、血管计数（P < 0.01）和肿瘤细胞增殖（P < 0.01）均显著低于对照组（pcDNA）。Ang-1组的肿瘤血管比pcDNA组的血管有更高程度的周细胞覆盖（P < 0.02）。在细胞混合物实验中，即使只有1：10的Ang-1转染细胞/对照细胞的混合物也导致肝肿瘤体积的显著减小（P < 0.04）。在血管生成实验中，加入Ang-1后，明胶海绵中的血管计数显著减少（P < 0.01）。Ang-1转染细胞的条件培养液对血管通透性的抑制作用显著高于对照细胞（P < 0.05）。我们的研究结果表明，血管紧张素-1是一个重要的调节血管生成和血管通透性，这种影响可能是次要的增加内皮支持和血管稳定。因此，Ang-1有可能作为转移性结直肠癌患者的抗渗透剂。
Angiopoietin (Ang)-1 and -2 are critical regulators of embryonic and postnatal neovascularization. Ang-1 activates the endothelial cell-specific tyrosine kinase receptor Tie-2, which in turn leads to enhanced endothelial cell survival and stabilization. The effects of Ang-1 on tumor angiogenesis remain controversial; although we have previously demonstrated that Ang-1 overexpression in colon cancer cells leads to a decrease in s.c. tumor growth, others have shown that Ang-1 may be proangiogenic. Few studies have addressed the role of the Angs in tumors growing in the organ of metastatic growth. We hypothesized that overexpression of Ang-1 may inhibit the growth of colon cancers growing in the liver by inhibition of angiogenesis. We also wanted to investigate the mechanisms by which Ang-1 affects angiogenesis in vivo. Human colon cancer cells (HT29) were stably transfected with an Ang-1 construct or an empty vector (pcDNA) and injected directly into the livers of nude mice. After 37 days, livers were harvested and weighed, and tumor sizes were measured. In an additional experiment, to validate the paracrine effect of Ang-1, various mixtures of control cells and Ang-1-transfected cells were injected into livers, and tumor growth was assessed. Direct effects of recombinant Ang-1 on angiogenesis were studied with an in vivo Gelfoam angiogenesis assay. The impact of Ang-1 on vascular permeability was investigated using an intradermal Miles assay with conditioned media from transfected cells. Liver weights (P < 0.05), tumor volumes (P < 0.05), vessel counts (P < 0.01), and tumor cell proliferation (P < 0.01) in the Ang-1 group were significantly lower than those in the control (pcDNA) group. Tumor vessels in the Ang-1 group developed a significantly higher degree of pericyte coverage (P < 0.02) than vessels in pcDNA tumors. In the cell mixture experiment, even as few as a 1:10 mixture of Ang-1-transfected cells/control cells resulted in a significant reduction of hepatic tumor volumes (P < 0.04). In the angiogenesis assay, vessel counts in Gelfoam implants were significantly decreased by the addition of Ang-1 (P < 0.01). Finally, conditioned medium from Ang-1-transfected cells decreased vascular permeability more than that from control cells (P < 0.05). Our results suggest that Ang-1 is an important regulator of angiogenesis and vascular permeability and that this effect may be secondary to increasing periendothelial support and vessel stabilization. Thus, Ang-1 could potentially serve as an antineoplastic or anti-permeability agent for patients with metastatic colorectal cancer.