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

Abstract

Purpose: To study the role of the adrenomedullin system [adrenomedullin and its receptors (AMR), CLR, RAMP2, and RAMP3] in prostate cancer androgen-independent growth.Experimental Design: Androgen-dependent and -independent prostate cancer models were used to investigate the role and mechanisms of adrenomedullin in prostate cancer hormone-independent growth and tumor-associated angiogenesis and lymphangiogenesis.Results: Adrenomedullin and AMR were immunohistochemically localized in the carcinomatous epithelial compartment of prostate cancer specimens of high grade (Gleason score >7), suggesting a role of the adrenomedullin system in prostate cancer growth. We used the androgen-independent Du145 cells, for which we demonstrate that adrenomedullin stimulated cell proliferation in vitro through the cAMP/CRAF/MEK/ERK pathway. The proliferation of Du145 and PC3 cells is decreased by anti-adrenomedullin antibody (aAM), supporting the fact that adrenomedullin may function as a potent autocrine/paracrine growth factor for prostate cancer androgen-independent cells. In vivo, aAM therapy inhibits the growth of Du145 androgenindependent xenografts and interestingly of LNCaP androgen-dependent xenografts only in castrated animals, suggesting strongly that adrenomedullin might play an important role in tumor regrowth following androgen ablation. Histologic examination of aAM-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, aAM potently blocks tumor-associated lymphangiogenesis, but does not affect established vasculature and lymphatic vessels in normal adult mice.Conclusions: We conclude that expression of adrenomedullin upon androgen ablation in prostate cancer plays an important role in hormone-independent tumor growth and in neovascularization by supplying/amplifying signals essential for pathologic neoangiogenesis and lymphangiogenesis.

Adrenomedullin in lymphangiogenesis: from development to disease

“…The benefit of VEGF inhibitors could be strengthened by co-administration with AM inhibitors [87]. This hypothesis has already been tested in mouse models of prostate cancer, where anti-AM antibodies were found to disrupt tumor vasculature, decrease lymphatic vessel density, increase LEC death, and suppress tumor growth [88]. Though this anti-AM antibody has not been fully characterized or utilized in other studies, this finding supports the hypothesis that AM inhibition may improve cancer-related outcomes.…”

Radiosensitization by the investigational NEDD8-activating enzyme inhibitor MLN4924 (pevonedistat) in hormone-resistant prostate cancer cells

“…To determine whether MLN4924 could enhance radiation efficacy, we performed radiosensitization experiments in two hormone-resistant prostate cancer cell lines, DU145 and PC3 [24, 25]. Firstly, we determined the sensitivity of the two prostate cancer cell lines to MLN4924 as a single agent.…”

Galectin-3 Is Implicated in Tumor Progression and Resistance to Anti-androgen Drug Through Regulation of Androgen Receptor Signaling in Prostate Cancer

“…When each xenograft tumor reached a volume of approximately 200 mm 3 , the mice of the castrated groups were castrated by orchiectomy. Further growth of the tumors was monitored in all groups (22)(23)(24).…”