Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines.
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.