Chronic inhibition of tumor cell-derived VEGF enhances the malignant phenotype of colorectal cancer cells.
Chronic inhibition of tumor cell-derived VEGF enhances the malignant phenotype of colorectal cancer cells.
复制标题
DOI：
10.1186/1471-2407-13-229
复制
发表时间：
2013-05-07
期刊：
影响因子：
3.8
通讯作者：
Rokutan K
中科院分区：
文献类型：
--
作者：
Yamagishi N;Teshima-Kondo S;Masuda K;Nishida K;Kuwano Y;Dang DT;Dang LH;Nikawa T;Rokutan K
血管内皮生长因子-a（VEGF）靶向治疗已成为许多人类恶性肿瘤的重要治疗方法。VEGF抑制剂实际上对几种类型的癌症有效，然而，这种益处是短暂的，绝大多数最初对治疗有反应的患者将产生耐药性。获得性耐药的可能机制之一可能是VEGF抑制剂对表达VEGF受体（VEGFR）的肿瘤细胞的直接作用。因此，我们在这里研究了慢性VEGF抑制对人结直肠癌（CRC）细胞表型变化的直接影响。为了长期抑制癌细胞来源的VEGF，将人CRC细胞系（HCT 116和RKO）长期暴露（2个月）于抗VEGF单克隆抗体（mAb）或破坏VEGF基因（VEGF-KO）。VEGF家族成员的作用通过VEGF受体酪氨酸激酶抑制剂（VEGFR-TKI）治疗阻断。TUNEL法检测VEGF抑制条件下缺氧诱导的细胞凋亡。使用3-D球状体细胞培养系统评估球状体形成能力。通过抗VEGF mAb对分泌的/细胞外VEGF的慢性抑制冗余地增加VEGF家族成员（PlGF、VEGFR 1和VEGFR 2），诱导对缺氧诱导的细胞凋亡的抗性，并增加球状体形成能力。这种凋亡抗性被VEGFR-TKI部分消除，VEGFR-TKI阻断由VEGF家族成员组成的补偿途径，或者通过敲低Vegf mRNA，其抑制所有Vegf基因产物的细胞内功能。有趣的是，慢性和完全耗尽所有的VEGF基因产物的VEGF基因敲除进一步增强这些表型的补偿途径独立的方式。这些加速的表型被VEGF-KO细胞系中上调的低氧诱导因子-1 α的敲低显著抑制。我们的研究结果表明，肿瘤细胞源性VEGF的慢性抑制加速肿瘤细胞恶性表型。
Vascular endothelial growth factor-a (VEGF)-targeted therapies have become an important treatment for a number of human malignancies. The VEGF inhibitors are actually effective in several types of cancers, however, the benefits are transiently, and the vast majority of patients who initially respond to the therapies will develop resistance. One of possible mechanisms for the acquired resistance may be the direct effect(s) of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGFR). Thus, we investigated here the direct effect of chronic VEGF inhibition on phenotype changes in human colorectal cancer (CRC) cells. To chronically inhibit cancer cell-derived VEGF, human CRC cell lines (HCT116 and RKO) were chronically exposed (2 months) to an anti-VEGF monoclonal antibody (mAb) or were disrupted the Vegf gene (VEGF-KO). Effects of VEGF family members were blocked by treatment with a VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI). Hypoxia-induced apoptosis under VEGF inhibited conditions was measured by TUNEL assay. Spheroid formation ability was assessed using a 3-D spheroid cell culture system. Chronic inhibition of secreted/extracellular VEGF by an anti-VEGF mAb redundantly increased VEGF family member (PlGF, VEGFR1 and VEGFR2), induced a resistance to hypoxia-induced apoptosis, and increased spheroid formation ability. This apoptotic resistance was partially abrogated by a VEGFR-TKI, which blocked the compensate pathway consisted of VEGF family members, or by knockdown of Vegf mRNA, which inhibited intracellular function(s) of all Vegf gene products. Interestingly, chronic and complete depletion of all Vegf gene products by Vegf gene knockout further augmented these phenotypes in the compensate pathway-independent manner. These accelerated phenotypes were significantly suppressed by knockdown of hypoxia-inducible factor-1α that was up-regulated in the VEGF-KO cell lines. Our findings suggest that chronic inhibition of tumor cell-derived VEGF accelerates tumor cell malignant phenotypes.
登录
查看更多内容
影响因子：
5.3
作者：
Masuda K;Abdelmohsen K;Gorospe M
通讯作者：
Gorospe M
影响因子：
15.8
作者：
Lee TH;Seng S;Sekine M;Hinton C;Fu Y;Avraham HK;Avraham S
通讯作者：
Avraham S
影响因子：
11.2
作者：
Dang, DT;Chen, F;Dang, LH
通讯作者：
Dang, LH
缺氧诱导因子1α对于浸润性胰岛细胞肿瘤中的侵入性表型是必需的。
影响因子：
4.6
作者：
Takeda, Takaaki;Okuyama, Hiroaki;Nishizawa, Yasuko;Tomita, Shuhei;Inoue, Masahiro
通讯作者：
Inoue, Masahiro
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--