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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: 6 9 10 15 15 10 10 9 12 10 18 19 23 22 23 20 15 10 7 8 1 272
Citation information
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Citations to this article in year 2017 (12)

Title and authors Publication Year
Macrophage infiltration and genetic landscape of undifferentiated uterine sarcomas
Joanna Przybyl, Magdalena Kowalewska, Anna Quattrone, Barbara Dewaele, Vanessa Vanspauwen, Sushama Varma, Sujay Vennam, Aaron Newman, Michal Swierniak, Elwira Bakula-Zalewska, Janusz Siedlecki, Mariusz Bidzinski, Jan Cools, Matt van de Rijn, Maria Debiec-Rychter
JCI Insight 2017
Immunopathogenesis of HPV-Associated Cancers and Prospects for Immunotherapy
S Smola
Viruses 2017
Microenvironmental regulation of tumour angiogenesis
MD Palma, D Biziato, TV Petrova
Nature Reviews Cancer 2017
Zoledronic acid renders human M1 and M2 macrophages susceptible to Vδ2+ γδ T cell cytotoxicity in a perforin-dependent manner
DW Fowler, J Copier, AG Dalgleish, MD Bodman-Smith
Cancer Immunology, Immunotherapy 2017
Translational Significance for Tumor Metastasis of Tumor-Associated Macrophages and Epithelial–Mesenchymal Transition
W Song, R Mazzieri, T Yang, GC Gobe
Frontiers in immunology 2017
The role of toll-like receptor 4 in tumor microenvironment
J Li, F Yang, F Wei, X Ren
Oncotarget 2017
Circulating tumor cell interactions with macrophages: implications for biology and treatment
G Hamilton, B Rath
Translational Lung Cancer Research 2017
Genome editing abrogates angiogenesis in vivo
X Huang, G Zhou, W Wu, Y Duan, G Ma, J Song, R Xiao, L Vandenberghe, F Zhang, PA DAmore, H Lei
Nature Communications 2017
CD163 as a marker of M2 macrophage, contribute to predicte aggressiveness and prognosis of Kazakh esophageal squmous cell carcinoma
JM Hu, K Liu, JH Liu, XL Jiang, XL Wang, YZ Chen, SG Li, H Zou, LJ Pang, CX Liu, XB Cui, L Yang, J Zhao, XH Shen, JF Jiang, WH Liang, XL Yuan, F Li
Oncotarget 2017
Bisphosphonates hinder osteoblastic/osteoclastic differentiation in the maxillary sinus mucosa-derived stem cells
J Zhang, J Park, JW Lee, YD Kwon, EC Kim
Clinical Oral Investigations 2017
[Research progress on bisphosphonate-related osteonecrosis of the jaws].
Jian P, Qizhang W, Jiyuan L
Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology 2017
The roles of microglia/macrophages in tumor progression of brain cancer and metastatic disease.
Wu SY, Watabe K
2017

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