The angiogenic phenotype has been characterized in a mouse model involving the human papillomavirus type-16 (HPV-16) oncogenes that develops cervical cancers via lesional stages analogous to those in humans. These studies revealed intense angiogenesis in high-grade cervical intraepithelial neoplasias (CIN-3) and carcinomas. Matrix metalloprotease-9 (MMP-9), a pro-angiogenic protease implicated in mobilization of VEGF, appeared in the stroma concomitant with the angiogenic switch, expressed by infiltrating macrophages, as occur in humans. Preclinical trials sought to target MMP-9 and angiogenesis with a prototypical MMP inhibitor and with a bisphosphonate, zoledronic acid (ZA), revealing both to be anti-angiogenic, producing comparable effects to a MMP-9 gene knockout in impairing angiogenic switching, progression of pre-malignant lesions, and tumor growth. ZA treatment increased neoplastic epithelial and endothelial cell apoptosis without affecting hyperproliferation, indicating ZA was not anti-mitotic. The analyses revealed cellular and molecular targets of ZA’s actions: ZA suppressed MMP-9 expression by infiltrating macrophages, and inhibited metalloprotease activity, reducing association of VEGF with its receptor on angiogenic endothelial cells. Given its track record in clinical use with limited toxicity, ZA holds promise as an unconventional and safe MMP-9 inhibitor for antiangiogenic therapy of cervical cancer, and potentially for additional tumors and other diseases where MMP-9 expression by infiltrating macrophages is evident.
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