An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis.
Open accessAbstract
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Bisphosphonates suppress proliferation, adhesion, migration, and survival of endothelial cells in vitro and induce endothelial apoptosis in vivo.
“these agents have also been shown to suppress the proliferation, adhesion, migration, and survival of endothelial cells in vitro (147, 148) while inducing endothelial cell apoptosis in vivo (149).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [149]
Cites
Osteoclast differentiation and activation
Boyle, W. J., Simonet, W. S., & Lacey, D. L. (2003) · Nature · doi:10.1038/nature01658 · Cited by 6,670 · cited 1× · see citing works
“We infer that the susceptibility of macrophages to ZA reflects their lineage relationship to osteoclasts (42, 43), which selectively take up BPs (32, 44).”
BackgroundVisse, R., & Nagase, H. (2003) · Circulation Research · doi:10.1161/01.res.0000070112.80711.3d · Cited by 4,575 · see citing works
Tumorigenesis and the angiogenic switch
Bergers, G., & Benjamin, L. E. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1093 · Cited by 3,559 · see citing works
Tumour-educated macrophages promote tumour progression and metastasis
Pollard, J. W. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1256 · Cited by 3,365 · see citing works
Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis
Bergers, G., Brekken, R., McMahon, G., Vu, T. H., Itoh, T., Tamaki, K., Tanzawa, K., Thorpe, P., Itohara, S., Werb, Z., et al. (2000) · Nature Cell Biology · doi:10.1038/35036374 · Cited by 2,797 · see citing works
Self-citationMatrix Metalloproteinase Inhibitors and Cancer—Trials and Tribulations
Coussens, L. M., Fingleton, B., & Matrisian, L. M. (2002) · Science · doi:10.1126/science.1067100 · Cited by 2,761 · see citing works
Heissig, B., Hattori, K., Dias, S., Friedrich, M., Ferris, B., Hackett, N. R., Crystal, R. G., Besmer, P., Lyden, D. C., Moore, M. A. S., et al. (2002) · Cell · doi:10.1016/s0092-8674(02)00754-7 · Cited by 1,751 · see citing works
Vu, T. H., Shipley, J. M., Bergers, G., Berger, J. E., Helms, J. A., Hanahan, D., Shapiro, S. D., Senior, R. M., & Werb, Z. (1998) · Cell · doi:10.1016/s0092-8674(00)81169-1 · Cited by 1,737 · see citing works
Self-citationHuman papillomavirus types in invasive cervical cancer worldwide: a meta-analysis
Clifford, G. M., Smith, J. S., Plummer, M., Muñóz, N., & Franceschi, S. (2003) · British Journal of Cancer · doi:10.1038/sj.bjc.6600688 · Cited by 1,565 · see citing works
MMP-9 Supplied by Bone Marrow–Derived Cells Contributes to Skin Carcinogenesis
Coussens, L. M., Tinkle, C. L., Hanahan, D., & Werb, Z. (2000) · Cell · doi:10.1016/s0092-8674(00)00139-2 · Cited by 1,306 · see citing works
Self-citationLuckman, S. P., Hughes, D. E., Coxon, F. P., Russell, R. G. G., & Rogers, M. J. (1998) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.1998.13.4.581 · Cited by 1,175 · see citing works
Effects of Angiogenesis Inhibitors on Multistage Carcinogenesis in Mice
Bergers, G., Javaherian, K., Lo, K.-M., Folkman, J., & Hanahan, D. (1999) · Science · doi:10.1126/science.284.5415.808 · Cited by 988 · see citing works
Self-citationInflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis
Coussens, L. M., Raymond, W. W., Bergers, G., Laig-Webster, M., Behrendtsen, O., Werb, Z., Caughey, G. H., & Hanahan, D. (1999) · Genes & Development · doi:10.1101/gad.13.11.1382 · Cited by 946 · cited 4× · see citing works
“from cervices and RT-PCR was performed as previously described (18)”
MethodResultInfluentialSelf-citationHiratsuka, S., Nakamura, K., Iwai, S., Murakami, M., Itoh, T., Kijima, H., Shipley, J. M., Senior, R. M., & Shibuya, M. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00153-8 · Cited by 910 · see citing works
Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice
Hanahan, D., Bergers, G., & Bergsland, E. K. (2000) · Journal of Clinical Investigation · doi:10.1172/jci9872 · Cited by 868 · see citing works
Self-citationWaggoner, S. E. (2003) · The Lancet · doi:10.1016/s0140-6736(03)13778-6 · Cited by 859 · see citing works
Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid.
Wood, J., Bonjean, K., Ruetz, S., Bellahcène, A., Devy, L., Foidart, J. M., Castronovo, V., & Green, J. R. (2002) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.035295 · Cited by 854 · see citing works
Hamano, Y., Zeisberg, M., Sugimoto, H., Lively, J. C., Maeshima, Y., Yang, C., Hynes, R. O., Werb, Z., Sudhakar, A., & Kalluri, R. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00133-8 · Cited by 560 · see citing works
Rodrı́guez-Manzaneque, J. C., Lane, T. F., Ortega, M.-A., Hynes, R. O., Lawler, J., & Iruela‐Arispe, M. L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.171460498 · Cited by 473 · see citing works
Huang, S. (2002) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/94.15.1134 · Cited by 345 · see citing works
Antitumor effects of bisphosphonates
Green, J. R. (2003) · Cancer · doi:10.1002/cncr.11128 · Cited by 308 · see citing works
Arbeit, J. M., Howley, P. M., & Hanahan, D. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.7.2930 · Cited by 306 · see citing works
Self-citationProgressive squamous epithelial neoplasia in K14-human papillomavirus type 16 transgenic mice
Arbeit, J. M., Münger, K., Howley, P. M., & Hanahan, D. (1994) · Journal of Virology · doi:10.1128/jvi.68.7.4358-4368.1994 · Cited by 304 · see citing works
Self-citationHuman endothelial gelatinases and angiogenesis
Nguyen, M. (2001) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(01)00007-3 · Cited by 300 · see citing works
Guidi, A. J., Abu‐Jawdeh, G. M., Berse, B., Jackman, R. W., Tognazzi, K., Dvorak, H. F., & Brown, L. F. (1995) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/87.16.1237 · Cited by 276 · see citing works
Lopez, T., & Hanahan, D. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00055-7 · Cited by 268 · see citing works
Self-citationVisualization of bisphosphonate-induced caspase-3 activity in apoptotic osteoclasts in vitro
Benford, H. L., McGowan, N. W. A., Helfrich, M., NUTTALL, M. E., & Rogers, M. J. (2001) · Bone · doi:10.1016/s8756-3282(01)00412-4 · Cited by 235 · see citing works
Behrendtsen, O., Alexander, C. M., & Werb, Z. (1992) · Development · doi:10.1242/dev.114.2.447 · Cited by 216 · see citing works
MMP Inhibition and Downregulation by Bisphosphonates
Teronen, O. P., Heikkilä, P., Konttinen, Y. T., Laitinen, M., Salo, T. A., Hanemaaijer, R., TERONEN, A., Maisi, P. S., & Sorsa, T. A. (1999) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1999.tb07702.x · Cited by 200 · see citing works
Angiogenesis: vascular remodeling of the extracellular matrix involves metalloproteinases
Heissig, B., Hattori, K., Friedrich, M., Rafii, S., & Werb, Z. (2003) · Current Opinion in Hematology · doi:10.1097/00062752-200303000-00007 · Cited by 188 · see citing works
Zoledronate Sensitizes Endothelial Cells to Tumor Necrosis Factor-induced Programmed Cell Death
Bezzi, M., Hasmim, M., Bieler, G., Dormond, O., & Rüegg, C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m308114200 · Cited by 139 · see citing works
Dobbs, S. P., Hewett, P., Johnson, I., Carmichael, J., & Murray, J. (1997) · British Journal of Cancer · doi:10.1038/bjc.1997.571 · Cited by 139 · see citing works
Molecular pathways regulating mobilization of marrow-derived stem cells for tissue revascularization
Rabbany, S. Y., Heissig, B., Hattori, K., & Rafii, S. (2003) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(03)00021-2 · Cited by 133 · see citing works
Oades, G. M., Senaratne, S. G., Clarke, I., et al. (2003) · The Journal of Urology · doi:10.1097/01.ju.0000070685.34760.5f · Cited by 133 · see citing works
Senaratne, S. G., Mansi, J., & Colston, K. W. (2002) · British Journal of Cancer · doi:10.1038/sj.bjc.6600297 · Cited by 131 · see citing works
Zhao, Y.-G., Xiao, A.-Z., Newcomer, R. G., Park, H. I., Kang, T., Chung, L. W. K., Swanson, M. G., Zhau, H. E., Kurhanewicz, J. V., & Sang, Q. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210975200 · Cited by 129 · see citing works
Hahn-Dantona, E. A., RAMOS‐DeSIMONE, N., Sipley, J. D., Nagase, H., French, D. L., & Quigley, J. P. (1999) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1999.tb07696.x · Cited by 100 · see citing works
Pathophysiologic interactions in skeletal metastasis
Orr, F. W., Lee, J., Duivenvoorden, W., & Singh, G. (2000) · Cancer · doi:10.1002/1097-0142(20000615)88:12+ · Cited by 79 · see citing works
Antagonistic Effects of Different Classes of Bisphosphonates in Osteoclasts and Macrophages In Vitro
Frith, J. C., & Rogers, M. J. (2003) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2003.18.2.204 · Cited by 77 · see citing works
Trappen, P. O. V., Ryan, A., Carroll, M., Lecœur, C., Goff, L. K., Gyselman, V. G., Young, B. D., Lowe, D. G., Pepper, M. S., Shepherd, J. H., et al. (2002) · British Journal of Cancer · doi:10.1038/sj.bjc.6600471 · Cited by 71 · see citing works
TIMP-1 Alters Susceptibility to Carcinogenesis
Rhee, J.-S., Diaz, R. J., Korets, L. V., Hodgson, J., & Coussens, L. M. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-2445 · Cited by 64 · see citing works
Khapli, S. M., Mangashetti, L. S., Yogesha, S. D., & Wani, M. R. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.1.142 · Cited by 63 · see citing works
A novel non-containing-nitrogen bisphosphonate inhibits both in vitro and in vivo angiogenesis
Hamma‐Kourbali, Y., Benedetto, M. D., Ledoux, D., Oudar, O., Leroux, Y., Lecouvey, M., & Kraemer, M. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.09.083 · Cited by 62 · see citing works
Davidson, B., Goldberg, I., Kopolovic, J., et al. (1999) · Gynecologic Oncology · doi:10.1006/gyno.1998.5285 · Cited by 59 · see citing works
Valleala, H., Hanemaaijer, R., Mandelin, J. M., et al. (2003) · Life Sciences · doi:10.1016/s0024-3205(03)00657-x · Cited by 55 · see citing works
Cohen, M. H., Dagher, R. N., Griebel, D. J., Ibrahim, A., Martin, A. A., Scher, N. S., Sokol, G. H., Williams, G. A., & Pazdur, R. (2002) · The Oncologist · doi:10.1634/theoncologist.7-5-393 · Cited by 53 · see citing works
Nair, S. A., Karunagaran, D., Nair, M. B., et al. (2003) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-002-0411-9 · Cited by 49 · see citing works
Bergers, G., & Hanahan, D. (2002) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2002.67.293 · Cited by 29 · see citing works
Self-citationCombined modality therapy in the treatment of gynecologic malignancies
Engleman, M. A. (2003) · Seminars in Oncology · doi:10.1016/s0093-7754(03)00275-6 · Cited by 7 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Macrophage plasticity and polarization: in vivo veritas
Sica, A., & Mantovani, A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59643 · Cited by 6,335 · see citing works
Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment
Hanahan, D., & Coussens, L. M. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.022 · Cited by 4,632 · see citing works
Self-citationDistinct role of macrophages in different tumor microenvironments
Lewis, C. E., & Pollard, J. W. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-4005 · Cited by 2,225 · see citing works
Microenvironmental regulation of tumour angiogenesis
De Palma, M., Biziato, D., & Petrova, T. V. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.51 · Cited by 1,847 · see citing works
Erez, N., Truitt, M., Olson, P., & Hanahan, D. (2010) · Cancer Cell · doi:10.1016/j.ccr.2009.12.041 · Cited by 1,515 · see citing works
Self-citationLin, Y., Xu, J., & Lan, H. (2019) · Journal of Hematology & Oncology · doi:10.1186/s13045-019-0760-3 · Cited by 1,398 · see citing works
The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages.
Allavena, P., Sica, A., Solinas, G., Porta, C., & Mantovani, A. (2008) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2007.07.004 · Cited by 1,044 · see citing works
Macrophages in Tumor Microenvironments and the Progression of Tumors
Hao, N.-B., Lü, M.-H., Fan, Y.-H., Cao, Y.-L., Zhang, Z.-R., & Yang, S.-M. (2012) · Clinical and Developmental Immunology · doi:10.1155/2012/948098 · Cited by 1,003 · see citing works
Kearns, A. E., Khosla, S., & Kostenuik, P. J. (2008) · Endocrine Reviews · doi:10.1210/er.2007-0014 · Cited by 824 · see citing works
Chen, Q., Zhang, X. H.-F., & Massagué, J. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.08.025 · Cited by 619 · see citing works
Cancer related inflammation: the macrophage connection
Sica, A., Allavena, P., & Mantovani, A. (2008) · Cancer Letters · doi:10.1016/j.canlet.2008.03.028 · Cited by 601 · see citing works
Harnessing tumor‐associated macrophages as aids for cancer immunotherapy
Li, X., Liu, R., Su, X., Pan, Y., Han, X., Shao, C., & Shi, Y. (2019) · Molecular Cancer · doi:10.1186/s12943-019-1102-3 · Cited by 364 · see citing works
Role of the tumor microenvironment in tumor progression and the clinical applications (Review)
YUAN, Y., JIANG, Y.-C., SUN, C.-K., & CHEN, Q.-M. (2016) · Oncology Reports · doi:10.3892/or.2016.4660 · Cited by 320 · see citing works
Angiogenic Role of LYVE-1–Positive Macrophages in Adipose Tissue
Cho, C.-H., Jun Koh, Y., Han, J., Sung, H.-K., Jong Lee, H., Morisada, T., Schwendener, R. A., Brekken, R. A., Kang, G., Oike, Y., et al. (2007) · Circulation Research · doi:10.1161/01.res.0000259564.92792.93 · Cited by 309 · see citing works
Osteoclasts are important for bone angiogenesis
Cackowski, F. C., Anderson, J. L., Patrene, K. D., Choksi, R. J., Shapiro, S. D., Windle, J. J., Blair, H. C., & Roodman, G. D. (2010) · Blood · doi:10.1182/blood-2009-08-237628 · Cited by 188 · see citing works
Joyce, J. A., Freeman, C., Meyer-Morse, N., Parish, C. R., & Hanahan, D. (2005) · Oncogene · doi:10.1038/sj.onc.1208602 · Cited by 163 · see citing works
Self-citationGenome Editing Abrogates Angiogenesis in Vivo
Huang, X., Zhou, G., Wu, W., Duan, Y., Ma, G., Song, J., Xiao, R., Vandenberghe, L., Zhang, F., D’Amore, P. A., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00140-3 · Cited by 142 · see citing works
The dual roles of homeobox genes in vascularization and wound healing
Kachgal, S., Mace, K. A., & Boudreau, N. J. (2012) · Cell Adhesion & Migration · doi:10.4161/cam.22164 · Cited by 72 · see citing works
Park, J.-H., Rasch, M. G., Qiu, J., Lund, I. K., & Egeblad, M. (2015) · Neoplasia · doi:10.1016/j.neo.2015.04.003 · Cited by 29 · see citing works
- Authors
- Giraudo, E., Inoue, M., & Hanahan, D.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Hanahan, Douglas
- Venue
- Journal of Clinical Investigation
- Published
- 2004-09-01
- Volume
- 114
- Issue
- 5
- Pages
- 623-633
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC514591
- OpenAlex
- W2158739925
- Cited by
- 700
- References
- 49
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 23 · 2023: 23 · 2022: 21 · 2021: 29 · 2020: 24 · 2019: 18 · 2018: 14 · 2017: 23 · 2016: 22 · 2015: 35 · 2014: 55 · 2013: 43 · 2012: 47
- FWCI
- 12.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- zoledronic acid, bisphosphonates, MMP-9, macrophages, angiogenesis, cervical cancer, cervical intraepithelial neoplasia, anti-angiogenic therapy, vascular endothelial growth factor, angiogenic switch, apoptosis, HPV16, MMP-9 inhibitors
- MeSH terms
- Zoledronic Acid, Animals, Cell Movement, Uterine Cervical Dysplasia, Uterine Cervical Neoplasms, Diphosphonates, Enzyme Activation, Female, Humans, Imidazoles, Macrophage Activation, Macrophages, Mice, Transgenic, Neovascularization, Pathologic, Angiogenesis Inhibitors, Matrix Metalloproteinase 9, Vascular Endothelial Growth Factors, Mice, Matrix Metalloproteinase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
