Reference SummaryGiraudo E, J Clin Invest 2004 Sep;114(5):623-33

Title

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

Authors

Giraudo E; Inoue M; Hanahan D

Journal

J Clin Invest

Volume

114

Issue

5

Year

2004

Pages

623-33

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.

Links

J:92599 – MGI References
15343380 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
FVB.Cg-Tg(KRT14-HPV16)wt1Dh Uterus - Cervix cervical intraepithelial neoplasia (CIN)
  • 17beta-estradiol (E2)
Uterus - Cervix

observed

FVB.Cg-Tg(KRT14-HPV16)wt1Dh Uterus - Cervix cervical intraepithelial neoplasia (CIN)
  • 17beta-estradiol (E2)
  • batimastat (BB-94)
Uterus - Cervix

observed

FVB.Cg-Tg(KRT14-HPV16)wt1Dh Uterus - Cervix cervical intraepithelial neoplasia (CIN)
  • 17beta-estradiol (E2)
  • batimastat (BB-94)
Uterus - Cervix

observed

FVB.Cg-Tg(KRT14-HPV16)wt1Dh Uterus - Cervix cervical intraepithelial neoplasia (CIN)
  • 17beta-estradiol (E2)
  • zoledronic acid
Uterus - Cervix

observed

FVB/N Uterus - Cervix cervical intraepithelial neoplasia (CIN)
  • 17beta-estradiol (E2)
Uterus - Cervix

0

FVB/N-Mmp2tm1Ito Tg(KRT14-HPV16)wt1Dh Uterus - Cervix cervical intraepithelial neoplasia (CIN)
  • 17beta-estradiol (E2)
Uterus - Cervix

observed

FVB/N-Mmp9tm1Tvu Tg(KRT14-HPV16)wt1Dh Uterus - Cervix cervical intraepithelial neoplasia (CIN)
  • 17beta-estradiol (E2)
Uterus - Cervix

observed

FVB.Cg-Tg(KRT14-HPV16)wt1Dh Uterus - Cervix squamous cell carcinoma
  • 17beta-estradiol (E2)
Uterus - Cervix

very high - 90

FVB.Cg-Tg(KRT14-HPV16)wt1Dh Uterus - Cervix squamous cell carcinoma
  • 17beta-estradiol (E2)
  • batimastat (BB-94)
Uterus - Cervix

observed

FVB.Cg-Tg(KRT14-HPV16)wt1Dh Uterus - Cervix squamous cell carcinoma
  • 17beta-estradiol (E2)
  • zoledronic acid
Uterus - Cervix

observed - very high

FVB/N Uterus - Cervix squamous cell carcinoma
  • 17beta-estradiol (E2)
Uterus - Cervix

0

FVB/N-Mmp2tm1Ito Tg(KRT14-HPV16)wt1Dh Uterus - Cervix squamous cell carcinoma
  • 17beta-estradiol (E2)
Uterus - Cervix

very high

FVB/N-Mmp9tm1Tvu Tg(KRT14-HPV16)wt1Dh Uterus - Cervix squamous cell carcinoma
  • 17beta-estradiol (E2)
Uterus - Cervix

moderate