Department of Neurosurgery, Grosshadern Hospital, Ludwig-Maximilian University, Munich, Germany.
J Neurooncol. 2011 Aug;104(1):103-12. doi: 10.1007/s11060-010-0480-6. Epub 2011 Feb 11.
Though clinical trials demonstrated effectiveness of the anti-VEGF antibody bevacizumab (Avastin) in adjuvant therapies for some solid tumours, there are rather few experimental data about cellular effects of bevacizumab on tumour cells and tumour associated endothelial cells. Recent reports demonstrate resistance mechanisms and secondary re-angiogenesis after a transient normalization of tumour vessels. Therefore we investigated the influence of bevacizumab on human glioma cells and human brain derived as well as tumour derived endothelial cells focussing on the role of VEGF-C and -D as potential alternative pro-angiogenic factors. Bevacizumab treatment showed no influence on proliferation after short term exposure (1-5 days) but slowed down endothelial cell proliferation by 25-30% after 14 days treatment. There was no significant induction of apoptosis after short or long term exposure. Tube formation capabilities were significantly impaired by bevacizumab with a continuing effect after 14 days of treatment even after omitting the antibody. VEGF-C and -D had no effect on endothelial cells in untreated or short term treatment groups. However, cells developed responsiveness to these factors in terms of increased proliferation and tube formation after 14 days bevacizumab treatment. Furthermore, bevacizumab induced expression of VEGF-C and -D in glioma cells. Treatment with bevacizumab may induce alterations in human brain and tumour endothelial cells leading to escape mechanisms from anti-VEGF therapy. VEGF-C and -D thus might act as alternative pro-angiogenic factors during anti-VEGF therapy.
尽管临床试验证明了抗血管内皮生长因子抗体贝伐单抗（阿瓦斯汀）在某些实体瘤辅助治疗中的有效性，但关于贝伐单抗对肿瘤细胞和肿瘤相关内皮细胞的细胞作用的实验数据相当少。最近的报告表明，在肿瘤血管短暂正常化后，存在耐药机制和继发性再血管生成。因此，我们研究了贝伐单抗对人神经胶质瘤细胞以及人源性和肿瘤源性内皮细胞的影响，重点关注 VEGF-C 和 VEGF-D 作为潜在的替代促血管生成因子的作用。贝伐单抗治疗在短期暴露（1-5 天）后对增殖没有影响，但在 14 天治疗后将内皮细胞增殖减慢 25-30%。短期或长期暴露后均无明显的细胞凋亡诱导。贝伐单抗显著抑制了管腔形成能力，即使在 14 天的治疗后停止使用该抗体，这种抑制作用仍持续存在。VEGF-C 和 VEGF-D 对未经处理或短期处理组的内皮细胞没有影响。然而，在 14 天的贝伐单抗治疗后，这些细胞对这些因子的增殖和管腔形成能力产生了反应。此外，贝伐单抗诱导了胶质瘤细胞中 VEGF-C 和 VEGF-D 的表达。贝伐单抗治疗可能导致人源和肿瘤内皮细胞发生改变，从而产生抗血管内皮生长因子治疗的逃逸机制。因此，VEGF-C 和 VEGF-D 可能在抗血管内皮生长因子治疗期间作为替代促血管生成因子发挥作用。
