Carcinogenesis Advance Access published online on August 4, 2005
Carcinogenesis, doi:10.1093/carcin/bgi203
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1 INSERM U727, Section of Renal Pharmacology and Physiopathology, Strasbourg, 67085 France, University Louis Pasteur, School of Medicine, Strasbourg, 67085 France; Hôpitaux Universitaires de Strasbourg, Department of Urology, Strasbourg, 67091 France
* To whom correspondence should be addressed. Functional inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene occurs in 40 to 80% of human conventional renal cell carcinomas (RCC). We showed recently that RCC cells deficient in VHL expressed large amounts of parathyroid hormone-related protein (PTHrP), and that PTHrP, acting through the PTH1 receptor (PTH1R), plays an essential role in tumor growth. We also showed that PTHrP expression is negatively regulated by the VHL gene products (pVHL). Our goal was to determine whether blocking the PTHrP/PTH1R system might be of therapeutic value against RCC, independent of VHL status and PTHrP expression levels. The antitumor activity of PTHrP neutralizing antibody and of PTH1R antagonist were avaluated in vitro and in vivo in a panel of human RCC cell lines expressing or not pVHL. PTHrP is up-regulated compared to normal tubular cells. In vitro, tumor cell growth and viability was decreased by up to 80% by the antibody in all cell lines. These effects resulted from apoptosis. Exogenously added PTHrP had no effect on cell growth and viability, but reversed the inhibitory effects of the antibody. The growth inhibition was reproduced by a specific PTH1R antagonist in all cell lines. In vivo, the treatment of nude mice bearing the Caki-1 RCC tumor with the PTHrP antibody inhibited tumor growth by 80%, by inducing apoptosis. Proliferation and neovascularization were not affected by the antiserum. Anti-PTHrP treatment induced no side effects as assessed by animal weight and blood chemistries. Current therapeutic strategies are only marginally effective against metastatic RCC, and adverse effects are common. This study provides a rationale for evaluating the blockade of PTHrP signaling as therapy for human RCC in a clinical setting.
Received March 30, 2005
Revised July 6, 2005
Accepted July 28, 2005
CANCER BIOLOGY
Anti-tumor effect of parathyroid hormone-related protein neutralizing antibody in human renal cell carcinoma in vitro and in vivo
2 INSERM U727, Section of Renal Pharmacology and Physiopathology, Strasbourg, 67085 France, University Louis Pasteur, School of Medicine, Strasbourg, 67085 France; Hôpitaux Universitaires de Strasbourg, Department of Pathology, Strasbourg, 67091 France
3 INSERM U727, Section of Renal Pharmacology and Physiopathology, Strasbourg, 67085 France, University Louis Pasteur, School of Medicine, Strasbourg, 67085 France
Thierry Massfelder, E-mail: thierry.massfelder{at}medecine.u-strasbg.fr
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