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
Published September 1, 2004
Citation Information: J Clin Invest. 2004;114(5):623-633. https://doi.org/10.1172/JCI22087.
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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 4

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ZA inhibits angiogenesis and reduces tumor incidence and growth. (A) Per...
ZA inhibits angiogenesis and reduces tumor incidence and growth. (A) Perfusion of HPV/E2 control mice and ZA-treated mice (6 weeks of treatment; PT) with fluorescin-lectin revealed dramatic changes in the 3-dimensional organization of the vasculature proximal to CIN-3 lesions of treated mice at 5 months of age. (B) Vessels’ density, as assessed by Meca-32 immunostaining, was significantly reduced in ZA-treated mice as compared with controls (56% reduction). Results are mean ± SEM of five fields per mouse from a total of eight mice. (C) CIN-2/3 lesion-bearing mice (T0, beginning of treatment; 3.5 months old) treated with ZA or vehicle for 6 weeks (PT) showed a 55% reduction in the tumor incidence at the end of the treatment (T1; 5 months old) (n = 16 control, n = 10 ZA-treated). (D) Tumor volume of ZA-treated mice was reduced by 61% compared with untreated controls (PT; n = 16 control, n = 10 ZA-treated). (E) Mice bearing SCC (T0; 5 months old) treated with ZA for 1 month (T1) in a RT showed a 57% decrease in tumor volume (n = 15 control, n = 10 ZA-treated). Values are mean ± SEM. **P < 0.01; #P < 0.001. P values were calculated using the Wilcoxon test. Tumor volume and histological scores were determined as described in Methods. Scale bar: 50 μm.