Hamano Yuki, Kalluri Raghu
Center for Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Biochem Biophys Res Commun. 2005 Jul 29;333(2):292-8. doi: 10.1016/j.bbrc.2005.05.130.
Angiogenesis, the formation of new blood vessels, is required for physiological development of vertebrates and repair of damaged tissue, but in the pathological setting contributes to progression of cancer. During tumor growth, angiogenesis is supported by up-regulation of angiogenic stimulators (pro-angiogenic) and down-regulation of angiogenic inhibitors (anti-angiogenic). The switch to the angiogenic phenotype (angiogenic switch) allows the tumors to grow and facilitate metastasis. The bioactive NC1 domain of type IV collagen alpha3 chain, called tumstatin, imparts anti-tumor activity by inducing apoptosis of proliferating endothelial cells. Tumstatin binds to alphaVbeta3 integrin via a mechanism independent of the RGD-sequence recognition and inhibits cap-dependent protein synthesis in the proliferating endothelial cells. The physiological level of tumstatin is controlled by matrix metalloproteinase-9, which most effectively cleaves it from the basement membrane and its physiological concentration in the circulation keeps pathological angiogenesis and tumor growth in check. These findings suggest that tumstatin functions as an endogenous inhibitor of pathological angiogenesis and functions as a novel suppressor of proliferating endothelial cells and growth of tumors.
血管生成，即新血管的形成，是脊椎动物生理发育和受损组织修复所必需的，但在病理情况下会促进癌症进展。在肿瘤生长过程中，血管生成受到血管生成刺激因子（促血管生成）上调和血管生成抑制因子（抗血管生成）下调的支持。向血管生成表型的转变（血管生成开关）使肿瘤得以生长并促进转移。IV型胶原α3链的生物活性NC1结构域，即tumstatin，通过诱导增殖内皮细胞凋亡赋予抗肿瘤活性。Tumstatin通过一种独立于RGD序列识别的机制与αVβ3整合素结合，并抑制增殖内皮细胞中帽依赖性蛋白合成。Tumstatin的生理水平由基质金属蛋白酶-9控制，该酶最有效地从基底膜上切割它，其在循环中的生理浓度可抑制病理性血管生成和肿瘤生长。这些发现表明，tumstatin作为病理性血管生成的内源性抑制剂，发挥着新型增殖内皮细胞抑制剂和肿瘤生长抑制剂的作用。
