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Citations to this article

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

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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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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 Total
Citations: 5 9 10 15 15 10 10 9 12 10 18 19 23 22 23 20 15 10 7 8 1 271
Citation information
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Citations to this article in year 2009 (15)

Title and authors Publication Year
Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes the vasculature
Federica Maione, Fabiola Molla, Claudia Meda, Roberto Latini, Lorena Zentilin, Mauro Giacca, Giorgio Seano, Guido Serini, Federico Bussolino, Enrico Giraudo
Journal of Clinical Investigation 2009
Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway
M Coscia, E Quaglino, M Iezzi, C Curcio, F Pantaleoni, C Riganti, I Holen, H Mönkkönen, M Boccadoro, G Forni, P Musiani, A Bosia, F Cavallo, M Massaia
Journal of Cellular and Molecular Medicine 2009
Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2009
Revisiting the seed and soil in cancer metastasis
M Mendoza, C Khanna
The International Journal of Biochemistry & Cell Biology 2009
High-density gene expression analysis of tumor-associated macrophages from mouse mammary tumors
LS Ojalvo, W King, D Cox, JW Pollard
The American Journal of Pathology 2009
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AC Hirbe, AJ Roelofs, DH Floyd, H Deng, SN Becker, LG Lanigan, AJ Apicelli, Z Xu, JL Prior, MC Eagleton, D Piwnica-Worms, MJ Rogers, K Weilbaecher
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JR Garbow, AC Santeford, JR Anderson, JA Engelbach, JM Arbeit
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Y Kawasaki, S Tsuji, K Muroya, S Furukawa, Y Shibata, M Okuno, S Ohwada, T Akiyama
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Ahn GO, Brown JM
Cell cycle (Georgetown, Tex.) 2009
The Science and Practice of Bone Health in Oncology: Managing Bone Loss and Metastasis in Patients With Solid Tumors
Lipton A, Uzzo R, Amato RJ, Ellis GK, Hakimian B, Roodman GD, Smith MR
Journal of the National Comprehensive Cancer Network : JNCCN 2009
When neighbourhood matters: tumour microenvironment.
Pérez-Moreno M
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 2009

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