University of Nice Sophia Antipolis, UMR CNRS 6543, Nice, France.
Oncogene. 2012 Mar 29;31(13):1683-94. doi: 10.1038/onc.2011.360. Epub 2011 Sep 12.
The anti-VEGF targeted antibody bevacizumab (BVZ) has been approved for treating renal cell carcinomas (RCCs). Although BVZ increases the progression-free survival of patients with metastatic RCC, the effect on overall survival is poor. To gain insight into the limited efficacy of BVZ on overall survival, we analyzed patient samples of RCC for angiogenic factors that may participate in escape from anti-VEGF therapy. Our study shows that the level of vascular endothelial growth factor (VEGF) in tumors was increased compared with normal tissue. The level of interleukin-8/CXCL8, a pro-angiogenic member of the CXCL family of cytokines, was also increased in tumors. These observations gave us a good reason to analyze the combined effects of BVZ and anti-CXCL8 antibodies on tumor growth. Surprisingly, we report that BVZ accelerates the growth of RCC in nude mice with in vivo selection of tumor cells with an increased growth capacity. Downregulation of receptor tyrosine phosphatase-κ, a phosphatase implicated in EGF receptor regulation, may partly explain this phenomenon. Modification of the vascular network and development of lymphatic vessels through VEGF-C production and compensatory production of pro-angiogenic CXCL cytokines were also observed. The apparent normalization of the vascular network prompted us to associate BVZ with the chemotherapeutic agent paclitaxel. While efficient in vitro, paclitaxel did not reverse the anti-VEGF effects in vivo. Anti-CXCL8-targeting antibodies were promising as they decreased intra-tumor VEGF production; decreased the pro-angiogenic CXCL/anti-angiogenic CXCL ratio and did not induce lymphangiogenesis. These observations hold clinical implication as they highlight putative markers implicated in escape from BVZ treatment. They also recommend proceeding with caution in the use of anti-VEGF therapy alone for treatment of RCC.
抗血管内皮生长因子靶向抗体贝伐珠单抗（BVZ）已被批准用于治疗肾细胞癌（RCC）。尽管 BVZ 增加了转移性 RCC 患者的无进展生存期，但对总生存期的影响不佳。为了深入了解 BVZ 对总生存期的疗效有限，我们分析了 RCC 患者样本中的血管生成因子，这些因子可能参与了逃避抗 VEGF 治疗。我们的研究表明，肿瘤中血管内皮生长因子（VEGF）的水平与正常组织相比有所增加。细胞因子 CXCL 家族中的促血管生成成员白细胞介素-8/CXCL8 的水平也在肿瘤中增加。这些观察结果使我们有充分的理由分析 BVZ 和抗 CXCL8 抗体对肿瘤生长的联合作用。令人惊讶的是，我们报告称，BVZ 加速了裸鼠中 RCC 的生长，在体内选择具有增加生长能力的肿瘤细胞时会发生这种情况。受体酪氨酸磷酸酶-κ（一种参与 EGF 受体调节的磷酸酶）的下调可能部分解释了这一现象。通过 VEGF-C 的产生和促血管生成 CXCL 细胞因子的代偿性产生，对血管网络的修饰和淋巴管的发育也进行了观察。血管网络的明显正常化促使我们将 BVZ 与化疗药物紫杉醇联合使用。紫杉醇在体外有效，但在体内并未逆转抗 VEGF 作用。靶向抗 CXCL8 的抗体很有前途，因为它们降低了肿瘤内 VEGF 的产生；降低了促血管生成 CXCL/抗血管生成 CXCL 比值，并且没有诱导淋巴管生成。这些观察结果具有临床意义，因为它们突出了与逃避 BVZ 治疗相关的假定标志物。它们还建议在单独使用抗 VEGF 治疗治疗 RCC 时要谨慎行事。
