BERKELEY, CA (UroToday.com) - Renal cell carcinomas (RCC) are some of the most vascularised of tumors. Hence, they constitute a paradigm for the treatment with anti-angiogenesis drugs especially targeting the vascular endothelial growth factor (VEGF) or its receptors. Despite an increase in the time to progression, these treatments do not cure the patients, and, for a majority of them, they do not improve their overall survival. Two major questions must be taken into consideration;
- Is it possible to identify patients who will benefit of these treatments;
- Are there more relevant therapeutic targets than the VEGF/VEGFR axis at the diagnosis or after progression under anti VEGF/VEGFR treatments.
The presence of redundant angiogenic factors to VEGF was an evident hypothesis to explain such results. A major publication by Sparmann and Bar-Sagi described co-expression of the inflammatory mediator interleukin-8 with VEGF in tumors. Moreover, interleukin 8 is expressed concomitantly to VEGF in many tumors especially highly vascularized tumors. Interleukin 8, also named CXCL8, is the founding member of a family of pro-angiogenic/pro-inflammatory cytokines named ELR+CXCL comprising CXCL1, 2, 3, 5, 6, 7 and 8. The presence of these cytokines, in addition to VEGF, was tested in tumor samples of a cohort of patients with RCC and was correlated to patient outcome. Despite the fact that VEGF was increased in the tumor samples compared to normal tissues, it was not indicative of overall survival. Each CXCL cytokine was tested in the same way. CXCL8 showed a trend toward significance of overall survival but did not reach statistical significance; CXCL1 over-expression is indicative of survival (p=0.017) but was not an independent marker of survival compare to the metastatic status or the Fuhrman grade (a classical clinical status of RCC); finally, CXCL7 was determined as an independent marker of overall survival compared to the above-mentioned clinical parameters (p=0.0015). These clinical observations were supported by xenografts of different models of human RCC cells in nude mice. Tumors developed slowly in mice but, surprisingly, tumor grow is accelerated by one of the most common anti-angiogenesis treatments used in the clinic, bevacizumab, a humanized monoclonal antibody targeting VEGF. In comparison, in the same experimental model, commercially available anti-human CXCL7 antibodies totally blocks tumor growth. The presence of CXCL7 receptors, CXCR1 and CXCR2 on tumor, inflammatory and endothelial cells strongly suggested that this cytokine promotes at the same time tumor cell proliferation, inflammatory processes, and angiogenesis. To further address the role of ELR+CXCL cytokines in RCC development, we have determined the effects of a CXCR1/2 inhibitor on the growth of experimental human tumors in mice. This inhibitor also drastically blocked tumor growth in mice by inhibiting tumor and endothelial cell proliferation.
Hence, we concluded that the CXCL7/CXCR1,2 axis represents a new potent target for the treatment of RCC. The relevance of this new strategy compared to the usual targeting of VEGF/VEGFR axis is currently under consideration.
- Sparmann, A., and Bar-Sagi, D. (2004) Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis, Cancer Cell 6, 447-458.
- Brat, D. J., Bellail, A. C., and Van Meir, E. G. (2005) The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis, Neuro Oncol 7, 122-133.
- Vandercappellen, J., Van Damme, J., and Struyf, S. (2008) The role of CXC chemokines and their receptors in cancer, Cancer Lett 267, 226-244.
- Grepin, R., Guyot, M., Giuliano, S., Boncompagni, M., Ambrosetti, D., Chamorey, E., Scoazec, J. Y., Negrier, S., Simonnet, H., and Pages, G. (2014) The CXCL7/CXCR1/2 axis is a key driver in the growth of clear cell renal cell carcinoma, Cancer Res 74, 873-883.
- Grepin, R., Guyot, M., Jacquin, M., Durivault, J., Chamorey, E., Sudaka, A., Serdjebi, C., Lacarelle, B., Scoazec, J. Y., Negrier, S., Simonnet, H., and Pages, G. (2012) Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines, Oncogene 31, 1683-1694.
Sandy Giuliano,a Mélanie Guyot,a Renaud Grepin,b and Gilles Pagesa as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
aUniversity of Nice Sophia Antipolis, UMR CNRS 7284/U INSERM 1081
bCentre Scientifique de Monaco, Monaco