Arbiser J L, Moses M A, Fernandez C A, Ghiso N, Cao Y, Klauber N, Frank D, Brownlee M, Flynn E, Parangi S, Byers H R, Folkman J
Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 1997 Feb 4;94(3):861-6. doi: 10.1073/pnas.94.3.861.
The switch from a quiescent tumor to an invasive tumor is accompanied by the acquisition of angiogenic properties. This phenotypic change likely requires a change in the balance of angiogenic stimulators and angiogenic inhibitors. The nature of the angiogenic switch is not known. Here, we show that introduction of activated H-ras into immortalized endothelial cells is capable of activating the angiogenic switch. Angiogenic switching is accompanied by up-regulation of vascular endothelial growth factor and matrix metalloproteinase (MMP) bioactivity and downregulation of tissue inhibitor of MMP. Furthermore, we show that inhibition of phosphatidylinositol-3-kinase leads to partial inhibition of tumor angiogenesis, thus demonstrating that activated H-ras activates tumor angiogenesis through two distinct pathways. Finally, we show evidence for two forms of tumor dormancy.
从静止肿瘤向侵袭性肿瘤的转变伴随着血管生成特性的获得。这种表型变化可能需要血管生成刺激因子和血管生成抑制因子平衡的改变。血管生成开关的本质尚不清楚。在此，我们表明将活化的H-ras导入永生化内皮细胞能够激活血管生成开关。血管生成转换伴随着血管内皮生长因子和基质金属蛋白酶（MMP）生物活性的上调以及MMP组织抑制剂的下调。此外，我们表明抑制磷脂酰肌醇-3-激酶会导致肿瘤血管生成的部分抑制，从而证明活化的H-ras通过两条不同途径激活肿瘤血管生成。最后，我们展示了两种肿瘤休眠形式的证据。
