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

Oncogene volume 31, pages 1683–1694 (2012)Cite this article

Abstract

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.

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Acknowledgements

We thank Dr Marc Colombel (patients’ informed consent), Dr Jean Claude Chambard (lentivirus expressing the luciferase gene), Dr Elodie Delaplanche (biopsy management), Dr Florence Mège-Lechevallier (anatomo-pathology determination), Ms Cendrine Dubaud (animal studies) and Dr M Christiane Brahimi-Horn (careful reading of the manuscript). Financial support: Contract VEGFIL from the National Institute of Cancer (INCA), the French Association for Cancer Research (ARC, contract no. 4932) and Roche France.

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Author notes

  1. R Grepin and M Guyot: These authors contributed equally to this work.

Authors and Affiliations

  1. University of Nice Sophia Antipolis, UMR CNRS 6543, Nice, France

    R Grepin, M Guyot, M Jacquin, J Durivault & G Pages

  2. Department of Statistic (EC), Centre Antoine Lacassagne, Nice, France

    E Chamorey & A Sudaka

  3. Department of Anatomo-pathology (AS), Centre Antoine Lacassagne, Nice, France

    E Chamorey & A Sudaka

  4. Université de Marseille UFR Pharmacie, Laboratoire de Pharmacocinétique, Marseille, France

    C Serdjebi & B Lacarelle

  5. INSERM UMR S865, IFR62, Faculty Laennec, Lyon, France

    J-Y Scoazec

  6. Centre Léon Bérard, Lyon, France

    S Negrier

  7. UMR 5201, Faculté de Médecine Grange Blanche, Lille, France

    H Simonnet

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  1. R Grepin
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Correspondence to G Pages.

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Grepin, R., Guyot, M., Jacquin, M. et al. Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines. Oncogene 31, 1683–1694 (2012). https://doi.org/10.1038/onc.2011.360

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  • DOI: https://doi.org/10.1038/onc.2011.360

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