Adrenomedullin Blockade Suppresses Growth of Human Hormone Independent Prostate Tumor Xenograft in Mice

“Purpose: To study the role of Adrenomedullin (AM) system (AM and its receptors ‘AMR; CLR, RAMP2 and RAMP3’) in cancer of prostate (CaP) androgen-independent growth. Experimental design: Androgen-dependent and independent CaP models were used to investigate the role and mechanisms of AM in CaP hormone-independent growth and tumor-associated angiogenesis and lymphangiogenesis. Results: AM and AMR were immunohistochemically localized in the carcinomatous epithelial compartment of CaP specimens of high-grade (Gleason score >7) suggesting a role of the AM system in the CaP growth. We used the androgen-independent Du145 cells for which we demonstrate that AM stimulated cell proliferation in vitro through the cAMP/CRAF/MEK/ERK pathway. The proliferation of Du145 and PC3 cells is decreased by anti-AM antibody (αAM) supporting that AM may function as a potent autocrine/paracrine growth factor for CaP androgen-independent cells. In vivo, αAM therapy inhibits Du145 androgen-independent xenografts growth and interestingly LNCaP androgen-dependent xenografts growth only in castrated animals suggesting strongly that AM might play an important role in tumor regrowth following androgen ablation. Histological examination of αAM-treated tumors showed evidence of disruption of tumor vascularity, with depletion of vascular as well as lymphatic endothelial cells and pericytes, and increased lymphatic endothelial cell apoptosis. Importantly, αAM potently blocks tumor-associated lymphangiogenesis, but does not affect established vasculature and lymphatic vessels in normal adult mice. Conclusion: We conclude that expression of AM upon androgen ablation in CaP plays an important role in hormone-independent tumor growth and in neovascularization by supplying/amplifying signals essential for pathological neoangiogenesis and lymphangiogenesis.”