Chronic exposure of colorectal cancer cells to bevacizumab promotes compensatory pathways that mediate tumour cell migration.
Chronic exposure of colorectal cancer cells to bevacizumab promotes compensatory pathways that mediate tumour cell migration.
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DOI：
10.1038/bjc.2011.81
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发表时间：
2011-04-12
影响因子：
8.8
通讯作者：
Ellis, L. M.
中科院分区：
文献类型：
--
作者：
Fan, F.;Samuel, S.;Gaur, P.;Lu, J.;Dallas, N. A.;Xia, L.;Bose, D.;Ramachandran, V.;Ellis, L. M.
贝伐单抗（Bev）是一种抗血管内皮生长因子（VEGF）的单克隆抗体，与化疗联合用于治疗转移性结直肠癌（CRC）。Bev对血管生成的影响已经有了很好的描述，但Bev对肿瘤细胞的直接影响尚不清楚。进行本研究以确定CRC细胞在体外慢性Bev暴露后的分子和表型变化。将人CRC细胞系在体外长期暴露（3个月）于Bev以开发适应Bev的（Bev-A）细胞系。采用逆转录-聚合酶链反应和蛋白质印迹法检测血管内皮生长因子家族成员。使用标准体外测定法测定迁移和侵袭。进行肿瘤细胞的静脉内注射以评估小鼠中的转移潜力。发现贝伐珠单抗适应的细胞比对照细胞更具迁移性和侵袭性（P<0.001）。贝伐珠单抗适应细胞显示出较高水平的VEGF-A、-B、-C、胎盘生长因子（PlGF）、VEGF受体-1（VEGFR-1）和VEGFR-1磷酸化。此外，用SU 5416，一种VEGFR蛋白酪氨酸激酶抑制剂，处理导致显著降低细胞在体外的迁移（P<0.001）。贝伐珠单抗适应细胞的体内转移性更强（P<0.05）。CRC细胞长期暴露于Bev（1）增加VEGF-A、-B、-C、PlGF、VEGFR-1和VEGFR-1磷酸化的表达，（2）增加肿瘤细胞迁移和侵袭，和（3）体内转移潜力。我们的研究显示了自分泌VEGF信号在CRC细胞中的功能意义。
Bevacizumab (Bev), a monoclonal antibody to vascular endothelial growth factor (VEGF), is used in combination with chemotherapy for the treatment of metastatic colorectal cancer (CRC). The effects of Bev on angiogenesis have been well described, but the direct effect of Bev on tumour cells is unknown. This study was carried out to determine the molecular and phenotypic changes in CRC cells after chronic Bev exposure in vitro. Human CRC cell lines were chronically exposed (3 months) to Bev in vitro to develop Bev-adapted (Bev-A) cell lines. Vascular endothelial growth factor family members were determined by reverse transcription–polymerase chain reaction and western blotting. Migration and invasion was determined using standard in vitro assays. Intravenous injection of tumour cells was carried out to evaluate metastatic potential in mice. Bevacizumab-adapted cells were found to be more migratory and invasive than control cells (P<0.001). Bevacizumab-adapted cells showed higher levels of VEGF-A, -B, -C, placental growth factor (PlGF), VEGF receptor-1 (VEGFR-1) and phosphorylation of VEGFR-1. Furthermore, treatment with SU5416, a VEGFR protein tyrosine kinase inhibitor, led to significantly decreased cell migration in vitro (P<0.001). Bevacizumab-adapted cells were more metastatic in vivo (P<0.05). Chronic exposure of CRC cells to Bev (1) increased expression of VEGF-A, -B, -C, PlGF, VEGFR-1 and VEGFR-1 phosphorylation, (2) increased tumour cell migration and invasion, and (3) metastatic potential in vivo. Our study shows the functional significance of autocrine VEGF signalling in CRC cells.
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影响因子：
11.2
作者：
Folkins C;Shaked Y;Man S;Tang T;Lee CR;Zhu Z;Hoffman RM;Kerbel RS
通讯作者：
Kerbel RS
影响因子：
6.2
作者：
Wey, JS;Fan, F;Ellis, LM
通讯作者：
Ellis, LM
DOI：
10.1073/pnas.0708148104
发表时间：
2007-10-23
影响因子：
11.1
作者：
Ebos, John M. L.;Lee, Christina R.;Kerbel, Robert S.
通讯作者：
Kerbel, Robert S.
影响因子：
45.3
作者：
Giantonio, Bruce J.;Catalano, Paul J.;Benson, Al B., III
通讯作者：
Benson, Al B., III
影响因子：
50.3
作者：
Casanovas, O;Hicklin, DJ;Hanahan, D
通讯作者：
Hanahan, D