Konishi T, Huang C L, Adachi M, Taki T, Inufusa H, Kodama K, Kohno N, Miyake M
Department of Thoracic Surgery, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Kamiyama-cho, Osaka 530-8480, Japan.
Int J Oncol. 2000 Mar;16(3):501-11. doi: 10.3892/ijo.16.3.501.
Tumor angiogenesis is an essential step for tumor cell growth, progression and metastasis. Vascular endothelial growth factor (VEGF) is mitogen specific for endothelial cells, and therefore is believed to play a key role in tumor angiogenesis. However, the mechanisms underlying the regulation of VEGF expression remain virtually unknown and the only major regulator of VEGF expression has been reported to be hypoxia. Recently, it was reported that a mutant p53 in#duced the expression of VEGF mRNA, and that wild-type p53 down-regulated endogenous VEGF mRNA levels. In contrast, it has also been reported that mutant ras oncogenes were associated with the marked up-regulation of VEGF in transformed epithelial cells. Based on these results, we performed a retrospective study of the p53 and K-ras genes status and VEGF gene expression in the tumor tissues from 181 patients with non-small cell lung cancer using SSCP, sequencing, RT-PCR and immunohistochemical techniques. Forty-six carcinomas (25.4%) were evaluated as having high VEGF expression, and 135 tumors (74.6%) had low VEGF expression. Of the 181 primary NSCLC studied, 63 carcinomas (34.8%) contained mutations of p53, whereas only 14 carcinomas (7.7%) had mutations of K-ras. There were no significant relationships between VEGF expression and p53 status or each mutant exon of p53. In contrast, a significant difference was found between VEGF expression and K-ras status. Of the 14 tumors with mutant K-ras genes, 7 cases (50.0%) had high VEGF expression whereas only 39 of the 167 tumors with wild-type K-ras (23.4%) had high VEGF expression (p=0.0278). The mean VEGF conservation rate for the 14 tumors with mutant K-ras genes was 0.77+/-0.58 and the rate of the 167 tumors with wild-type K-ras genes was 0.49+/-0.46 (p=0. 0350). Moreover, the overall survival rate of patients with high VEGF expression was lower than patients with low VEGF expression (45.7% vs 60.7%, p=0.0419). On the other hand, there was no significant difference in the overall survival rate between patients with a mutant p53 and those with a wild-type p53; there was also no difference in the overall survival between patients with a mutant K-ras and those with a wild-type K-ras. The Cox regression model analysis indicated that three variables, VEGF status, K-ras status and nodal status, were found to be significant indicators for prognosis (p=0.0236, p=0.0172 and p<0.0001, respectively). Our data suggest that a high expression of VEGF in lung cancer may be associated with a poor prognosis. This may be a clue to improving lung cancer diagnoses and therapies aimed at inhibiting tumor angiogenesis due to VEGF.
肿瘤血管生成是肿瘤细胞生长、进展和转移的关键步骤。血管内皮生长因子（VEGF）是内皮细胞特异性的促有丝分裂原，因此被认为在肿瘤血管生成中起关键作用。然而，VEGF表达调控的潜在机制仍几乎不为人知，据报道，VEGF表达的唯一主要调节因子是缺氧。最近，有报道称突变型p53可诱导VEGF mRNA的表达，而野生型p53可下调内源性VEGF mRNA水平。相反，也有报道称突变型ras癌基因与转化上皮细胞中VEGF的显著上调有关。基于这些结果，我们采用单链构象多态性（SSCP）、测序、逆转录-聚合酶链反应（RT-PCR）和免疫组化技术，对181例非小细胞肺癌患者肿瘤组织中的p53和K-ras基因状态及VEGF基因表达进行了回顾性研究。46例癌组织（25.4%）被评估为VEGF高表达，135例肿瘤（74.6%）为VEGF低表达。在181例原发性非小细胞肺癌中，63例癌组织（34.8%）含有p53突变，而只有14例癌组织（7.7%）有K-ras突变。VEGF表达与p53状态或p53的每个突变外显子之间无显著相关性。相反，VEGF表达与K-ras状态之间存在显著差异。在14例K-ras基因突的肿瘤中，7例（50.0%）为VEGF高表达，而在167例K-ras野生型肿瘤中，只有39例（23.4%）为VEGF高表达（p=0.0278）。14例K-ras基因突肿瘤的VEGF保守率平均为0.77±0.58，167例K-ras野生型肿瘤的保守率为0.49±0.46（p=0.0350）。此外，VEGF高表达患者的总生存率低于VEGF低表达患者（45.7%对60.7%，p=0.0419）。另一方面，p53突变患者与p53野生型患者的总生存率无显著差异；K-ras突变患者与K-ras野生型患者的总生存率也无差异。Cox回归模型分析表明，VEGF状态、K-ras状态和淋巴结状态这三个变量是预后的重要指标（p分别为0.0236、0.0172和p<0.0001）。我们的数据表明，肺癌中VEGF的高表达可能与预后不良有关。这可能为改善肺癌诊断和针对抑制VEGF介导的肿瘤血管生成的治疗提供线索。
