Antitumor effect of parathyroid hormone-related protein neutralizing antibody in human renal cell carcinoma in vitro and in vivo

• Published in: Carcinogenesis (New York) Vol. 27; no. 1; pp. 73 - 83
• Main Authors: Talon, Isabelle, Lindner, Véronique, Sourbier, Carole, Schordan, Eric, Rothhut, Sylvie, Barthelmebs, Mariette, Lang, Hervé, Helwig, Jean-Jacques, Massfelder, Thierry
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.01.2006; Oxford Publishing Limited (England)
• Subjects: 3-; 5-dimethylthiazol-2-yl)-2; 5-diphenyltetrazolium bromide; Animals; Antibodies, Monoclonal - therapeutic use; Apoptosis; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Carcinoma, Renal Cell - immunology; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - therapy; Cell Proliferation; conventional renal cell carcinoma; Gene Expression Regulation, Neoplastic - drug effects; HIF; Humans; hypoxia-induced factor; In Vitro Techniques; Kidney Neoplasms - immunology; Kidney Neoplasms - metabolism; Kidney Neoplasms - therapy; Kidneys; Male; Medical sciences; Mice; Mice, Nude; MTT; Neovascularization, Pathologic; Nephrology. Urinary tract diseases; parathyroid hormone-1 receptor; parathyroid hormone-related protein; Parathyroid Hormone-Related Protein - genetics; Parathyroid Hormone-Related Protein - immunology; PTH1R; PTHrP; pVHL; RCC; Tumors; Tumors of the urinary system; VHL; VHL gene products; von Hippel–Lindau; Kidney disease; Antineoplastic agent; Human; In vivo; Urinary system disease; Carcinoma; Grawitz tumor; Parathyroid hormone related peptide; Malignant tumor; In vitro; Neutralization
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgi203

Functional inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene occurs in 40–80% of human conventional renal cell carcinomas (RCCs). We showed recently that VHL-deficient RCCs 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 evaluated in vitro and in vivo in a panel of human RCC lines expressing or not pVHL. PTHrP is upregulated compared with 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.