Impact of oncogenes in tumor angiogenesis:: Mutant K-ras up-regulation of vascular endothelial growth factor vascular permeability factor is necessary, but not sufficient for tumorigenicity of human colorectal carcinoma cells
Impact of oncogenes in tumor angiogenesis:: Mutant K-ras up-regulation of vascular endothelial growth factor vascular permeability factor is necessary, but not sufficient for tumorigenicity of human colorectal carcinoma cells
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DOI：
10.1073/pnas.95.7.3609
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发表时间：
1998-03-31
影响因子：
11.1
通讯作者：
Kerbel, RS
中科院分区：
文献类型：
--
作者：
Okada, F;Rak, JW;Kerbel, RS
两株大肠癌细胞K-ras单突变等位基因的靶向破坏（DLD-1和HCT-116）导致裸鼠体内致瘤能力丧失，并保留在单层培养中无限生长的能力，因为这些细胞系中突变K-ras癌基因的表达与血管内皮生长因子/血管通透性因子的显著上调有关将VEGF（121）反义表达载体转染入DLD-1和HCT-116细胞导致VEGF/VPF产生抑制3- 4倍。VEGF/VPF缺陷亚系，与亲本群体或载体对照不同，在细胞注射后长达6个月的时间内，它们在裸鼠中形成肿瘤的能力被深度抑制。相反，这些亚系的体外生长不受影响，因此证明了VEGF/VPF作为HCT-116和DLD-1细胞的血管生成因子的至关重要性，VEGF（121）基因转染两株非致瘤突变株K-VEGF（121）的研究ras敲除亚系导致一部分转染子体内致瘤能力的微弱但可检测的恢复，体外生长特性没有一致的变化，研究结果表明，突变ras癌基因依赖的VEGF/VPF表达是必要的，但不足以在体内进行性肿瘤生长，并强调癌基因，如突变K-ras，肿瘤血管生成的过程中的相对贡献。
Targeted disruption of the single mutant K-ras allele in two human colorectal carcinoma cell lines (DLD-1 and HCT-116) leads to loss of tumorigenic competence in nude mice with retention of ability to grow indefinitely in monolayer culture, Because expression of the mutant K-ras oncogene in these cell lines is associated with marked up regulation of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), we sought to determine whether this potent angiogenesis inducer plays a role in K-ras-dependent tumorigenic competence, Transfection of a VEGF(121) antisense expression vector into DLD-1 and HCT-116 cells resulted in suppression of VEGF/VPF production by a factor of 3- to 4-fold, The VEGF/VPF-deficient sublines, unlike the parental population or vector controls, were profoundly suppressed in their ability to form tumors in nude mice for as long as 6 months after cell injection, In contrast, in vitro growth of these sublines was unaffected, thus demonstrating the critical importance of VEGF/VPF as an angiogenic factor for HCT-116 and DLD-1 cells, Transfection of a full-length VEGF(121) cDNA into two nontumorigenic mutant K-ras knockout sublines resulted in a weak but detectable restoration of tumorigenic ability in vivo in a subset of the transfectants, with no consistent change in growth properties in vitro, The findings indicate that mutant ras-oncogene-dependent VEGF/VPF expression is necessary, but not sufficient for progressive tumor growth in vivo and highlight the relative contribution of oncogenes, such as mutant K-ras, to the process of tumor angiogenesis.