An amino-bisphosphonate targets MMP-9–expressing macrophages and angiogenesis to impair cervical carcinogenesis
Enrico Giraudo, Masahiro Inoue, Douglas Hanahan
Enrico Giraudo, Masahiro Inoue, Douglas Hanahan
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Article Oncology

An amino-bisphosphonate targets MMP-9–expressing macrophages and angiogenesis to impair cervical carcinogenesis

Abstract

A mouse model involving the human papillomavirus type-16 oncogenes develops cervical cancers by lesional stages analogous to those in humans. In this study the angiogenic phenotype was characterized, revealing intense angiogenesis in high-grade cervical intraepithelial neoplasias (CIN-3) and carcinomas. MMP-9, a proangiogenic protease implicated in mobilization of VEGF, appeared in the stroma concomitant with the angiogenic switch, expressed by infiltrating macrophages, similar to what has been observed 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 antiangiogenic, producing effects comparable to a Mmp9 gene KO in impairing angiogenic switching, progression of premalignant lesions, and tumor growth. ZA therapy increased neoplastic epithelial and endothelial cell apoptosis without affecting hyperproliferation, indicating that ZA was not antimitotic. The analyses implicated 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” MMP-9 inhibitor for antiangiogenic therapy of cervical cancer and potentially for additional cancers and other diseases where MMP-9 expression by infiltrating macrophages is evident.

Authors

Enrico Giraudo, Masahiro Inoue, Douglas Hanahan

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Figure 7

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ZA inhibits the formation of VEGF/VEGF-R2 complexes on the neoplastic va...
ZA inhibits the formation of VEGF/VEGF-R2 complexes on the neoplastic vasculature, phenocopying a MMP-9 gene KO. (A) Decrease in tumor incidence in 7-month-old HPV/E2-MMP-9–/– (66% reduction; n = 25) compared with HPV/E2-MMP-2–/– (n = 15) and control mice (n = 40). (B) Reduction of tumor volume in 7-month-old HPV/E2-MMP-9–/– (76% reduction; n = 25) compared with HPV/E2-MMP-2–/– and control mice. Tumor volume and histological scores were determined as described in Methods. (C–G) VEGF/VEGF-R2 complex was detected by immunohistochemistry using GVM39 Ab (green), while the ECs were visualized with the anti–Meca-32 Ab (red). Significant reduction in the VEGF/VEGF-R2 complex was observed on vessels in HPV/E2-MMP-9–/– (77% reduction compared with controls; n = 15) and ZA-treated (73% reduction compared with controls; n = 8) mice compared with HPV/E2-MMP-2–/– (n = 10) and controls (n = 20) (C). Representative analyses of tumors are shown in D–G. Arrows indicate the VEGF/VEGF-R2 complex associated to the vessels. Scale bar: 25 μm. Values are mean ± SEM. #P < 0.001. P values were calculated using the Wilcoxon test.