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

J Clin Invest. 2004 Sep;114(5):623-33. doi: 10.1172/JCI22087.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Cell Movement / drug effects
  • Cervical Intraepithelial Neoplasia / blood supply*
  • Cervical Intraepithelial Neoplasia / enzymology
  • Cervical Intraepithelial Neoplasia / pathology
  • Diphosphonates / pharmacology*
  • Enzyme Activation / drug effects
  • Female
  • Humans
  • Imidazoles / pharmacology*
  • Macrophage Activation / drug effects
  • Macrophages / drug effects*
  • Macrophages / enzymology
  • Macrophages / pathology
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors*
  • Mice
  • Mice, Transgenic
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / enzymology
  • Neovascularization, Pathologic / pathology
  • Uterine Cervical Neoplasms / blood supply*
  • Uterine Cervical Neoplasms / drug therapy
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / pathology
  • Vascular Endothelial Growth Factors / metabolism
  • Zoledronic Acid

Substances

  • Angiogenesis Inhibitors
  • Diphosphonates
  • Imidazoles
  • Matrix Metalloproteinase Inhibitors
  • Vascular Endothelial Growth Factors
  • Zoledronic Acid
  • Matrix Metalloproteinase 9