Inhibition of VEGF induces cellular senescence in colorectal cancer cells
Inhibition of VEGF induces cellular senescence in colorectal cancer cells
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DOI：
10.1002/ijc.26179
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发表时间：
2011-11-01
影响因子：
6.4
通讯作者：
Tai, Isabella T.
中科院分区：
文献类型：
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作者：
Hasan, Mohammad R.;Ho, Shirley H. Y.;Tai, Isabella T.
血管内皮生长因子（VEGF）抑制剂，如贝伐单抗，改善了转移性结直肠癌（CRC）的预后。最近的研究表明，VEGF可以延缓人内皮细胞的细胞衰老。由于已知VEGF受体在CRC中上调，我们假设VEGF抑制可能直接影响这种疾病的细胞衰老。在我们的研究中，我们观察到，与未处理或人IgG处理的对照细胞相比，贝伐单抗处理导致几种CRC细胞（如MIP 101、RKO、SW 620和SW 480细胞）的体外细胞衰老显著增加（p < 0.05）。从用VEGFR2激酶抑制剂Ki8751处理的细胞中也获得了类似的结果。在体内，在来自75%的用贝伐单抗处理的小鼠的MIP 101肿瘤异种移植物中检测到细胞衰老，而在来自用盐水或人IgG处理的小鼠的异种移植物中检测不到细胞衰老（p < 0.05）。有趣的是，我们还观察到，从接受贝伐单抗治疗的患者中获得的结肠癌组织中衰老细胞的比例比未经治疗的患者高4.4倍（p < 0.01）。为了了解VEGF抑制剂如何调节细胞衰老，我们注意到，在肿瘤细胞衰老生长停滞的两个重要调节剂中，贝伐珠单抗相关的细胞衰老增加与p16上调一致，但似乎独立于p53。siRNA沉默MIP 101细胞中的p16基因可抑制贝伐珠单抗诱导的细胞衰老，而沉默p53则无影响。这些发现表明VEGF抑制剂在CRC中具有新的抗肿瘤活性，涉及p16。
Vascular endothelial growth factor (VEGF) inhibitors, such as bevacizumab, have improved outcomes in metastatic colorectal cancer (CRC). Recent studies have suggested that VEGF can delay the onset of cellular senescence in human endothelial cells. As VEGF receptors are known to be upregulated in CRC, we hypothesized that VEGF inhibition may directly influence cellular senescence in this disease. In our study, we observed that treatment with bevacizumab caused a significant increase (p < 0.05) in cellular senescence in vitro in several CRC cells, such as MIP101, RKO, SW620 and SW480 cells, compared to untreated or human IgG-treated control cells. Similar results were also obtained from cells treated with a VEGFR2 kinase inhibitor Ki8751. In vivo, cellular senescence was detected in MIP101 tumor xenografts from 75% of mice treated with bevacizumab, while cellular senescence was undetectable in xenografts from mice treated with saline or human IgG (p < 0.05). Interestingly, we also observed that the proportion of senescent cells in colon cancer tissues obtained from patients treated with bevacizumab was 4.4-fold higher (p < 0.01) than those of untreated patients. To understand how VEGF inhibitors may regulate cellular senescence, we noted that among the two important regulators of senescent growth arrest of tumor cells, bevacizumab-associated increase in cellular senescence coincided with an upregulation of p16 but appeared to be independent of p53. siRNA silencing of p16 gene in MIP101 cells suppressed bevacizumab-induced cellular senescence, while silencing of p53 had no effect. These findings demonstrate a novel antitumor activity of VEGF inhibitors in CRC, involving p16.