Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis.
Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis.
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发表时间：
1995-10
期刊：
影响因子：
11.2
通讯作者：
J. Rak;Y. Mitsuhashi;L. Bayko;J. Filmus;S. Shirasawa;T. Sasazuki;R. Kerbel
中科院分区：
文献类型：
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作者：
J. Rak;Y. Mitsuhashi;L. Bayko;J. Filmus;S. Shirasawa;T. Sasazuki;R. Kerbel
直径超过1-2 mm的实体瘤的体内生长需要诱导和维持血管生成反应。这可以通过从肿瘤细胞释放各种血管生成生长因子而发生。一种这样的因子是血管内皮生长因子/血管通透性因子（VEGF/VPF），其是血管内皮细胞的分泌的和特异性的有丝分裂原。我们发现，在人类癌症中检测到的最常见的遗传变化之一，即，突变ras癌基因的表达与转化上皮细胞中VEGF/VPF的显著上调有关。因此，在分别表达突变K-ras或H-ras癌基因的人和啮齿动物肿瘤细胞系中检测到VEGF/VPF mRNA和分泌的功能蛋白水平的升高。人结肠癌细胞中突变K-ras等位基因的遗传破坏与VEGF/VPF活性的降低相关。此外，通过用L-739，749（一种蛋白法尼基转移酶抑制剂）处理H-ras转化的大鼠肠上皮细胞中突变RAS蛋白功能的药理学破坏引起VEGF/VPF的显著抑制。结果表明，显性作用的ras癌基因可能不仅通过对肿瘤细胞增殖的直接影响，而且通过间接影响，即，通过促进肿瘤血管生成。因此，可以想象，靶向突变ras癌基因的siRNA可以部分地通过抑制肿瘤诱导的血管生成来抑制体内实体瘤生长。
The growth of solid tumors in vivo beyond 1-2 mm in diameter requires induction and maintenance of an angiogenic response. This can occur through the release of various angiogenic growth factors from tumor cells. One such factor is vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), a secreted and specific mitogen for vascular endothelial cells. We show that one of the most commonly encountered genetic changes detected in human cancer, i.e., expression of mutant ras oncogenes, is associated with marked up-regulation of VEGF/VPF in transformed epithelial cells. Thus, elevation of the levels of both VEGF/VPF mRNA and secreted functional protein were detected in human and rodent tumor cell lines expressing mutant K-ras or H-ras oncogenes, respectively. Genetic disruption of the mutant K-ras allele in human colon carcinoma cells was associated with a reduction in VEGF/VPF activity. Furthermore, pharmacological disruption of mutant RAS protein function in H-ras transformed rat intestinal epithelial cells by treatment with L-739,749 (a protein farnesyltransferase inhibitor) caused a significant suppression of VEGF/VPF. The results suggest that dominantly acting ras oncogenes may contribute to the growth of solid tumors in vivo not only by a direct effect on tumor cell proliferation but also indirectly, i.e., by facilitating tumor angiogenesis. Hence, pharmacologically targeting mutant ras oncogenes could conceivably suppress solid tumor growth in vivo, in part, by inhibiting tumor-induced angiogenesis.