Fibulins 3 and 5 antagonize tumor angiogenesis in vivo
Fibulins 3 and 5 antagonize tumor angiogenesis in vivo
复制标题
DOI：
10.1158/0008-5472.can-04-4096
复制
发表时间：
2006-03-01
期刊：
影响因子：
11.2
通讯作者：
Schiemann, WP
中科院分区：
文献类型：
--
作者：
Albig, AR;Neil, JR;Schiemann, WP
如果没有血管生成，致命的肿瘤生长和进展就不会发生，血管生成促进癌细胞增殖、存活和扩散。 Fibulins (FBLN) 5 和 3 是广泛表达的细胞外基质蛋白，以特定的方式调节细胞增殖。 FBLN-5 表达减少与人类癌症的形成和进展有关，而其组成型表达在体外会拮抗内皮细胞血管生成。因此，FBLN-5可以通过阻止肿瘤血管生成来抑制肿瘤发生。 FBLN-3与FBLN-5同源，在内皮细胞中表达，但其在肿瘤发生和血管生成中的作用尚不清楚。我们发现 FBLN-3 表达在一些人类肿瘤中发生改变，并且其在内皮细胞中的组成型表达抑制了它们的增殖、侵袭和血管生成，以及通过 p38 丝裂原激活蛋白激酶激活来测量它们对血管内皮生长因子的反应。在内皮细胞中，两种 FBLN (a) 减少碱性成纤维细胞生长因子 (bFGF) 刺激的血管生成； (b) 抑制基质金属蛋白酶的表达和活性； (c) 刺激组织金属蛋白酶抑制剂的表达。更重要的是，两种 FBLN 都能阻止血管生成和血管浸润到植入遗传正常小鼠的补充 bFGF 的基质胶塞中，并降低皮下植入的 MCA102 纤维肉瘤细胞产生的肿瘤的生长和血管密度。进入同系小鼠。我们的研究结果将 FBLN-3 和 FBLN-5 确立为新型血管抑制剂，能够减少肿瘤血管生成，从而减少体内肿瘤生长，并表明这些血管抑制活性有一天可能被用来对抗癌症患者的肿瘤血管生成和转移。
Lethal tumor growth and progression cannot occur without angiogenesis, which facilitates cancer cell proliferation, survival, and dissemination. Fibulins (FBLN) 5 and 3 are widely expressed extracellular matrix proteins that regulate cell proliferation in a context-specific manner. Reduced FBLN-5 expression has been associated with cancer formation and progression in humans, whereas its constitutive expression antagonizes endothelial cell angiogenic sprouting in vitro. Thus, FBLN-5 may suppress tumorigeriesis by preventing tumor angiogenesis. FBLN-3 is homologous to FBLN-5 and expressed in endothelial cells, yet its role in tumorigenesis and angiogenesis is unknown. We find FBLN-3 expression to be altered in some human tumors and that its constitutive expression in endothelial cells inhibited their proliferation, invasion, and angiogenic sprouting, as well as their response to vascular endothelial growth factor as measured by p38 mitogen-activated protein kinase activation. In endothelial cells, both FBLNs (a) reduced angiogenic sprouting stimulated by basic fibroblast growth factor (bFGF); (b) inhibited matrix metalloproteinase expression and activity; and (c) stimulated tissue inhibitor of metalloproteinase expression. More importantly, both FBLNs prevented angiogenesis and vessel infiltration into bFGF-supplemented Matrigel plugs implanted in genetically normal mice, as well as decreased the growth and blood vessel density in tumors produced by MCA102 fibrosarcoma cells implanted s.c. into syngeneic mice. Our findings establish FBLN-3 and FBLN-5 as novel angiostatic agents capable of reducing tumor angiogenesis and, consequently, tumor growth in vivo and suggest that these angiostatic activities may one day be exploited to combat tumor angiogenesis and metastasis in cancer patients.