ArticleThe Journal of clinical investigation2004
An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis.
Article in The Journal of clinical investigation, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00892242 (Perioperative Treatment With Zoledronic Acid in Patients With Resectable Pancreas Cancer), which is not on this map. Cited by 293 papers, 2 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Perioperative Treatment With Zoledronic Acid in Patients With Resectable Pancreas Cancer
Who cites it
293 citing papers in PubMed, 2 syntheses or guidelines pooled it, 609 citations in OpenAlex.
- Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of seven randomized controlled trials.International journal of clinical oncology · 2014Pooled it
- Osteoporosis drug therapy strategies in the setting of disease-modifying agents for autoimmune disease.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2013Pooled it
- Trial
- Neutrophils in cancer.Nature reviews. Cancer · 2026Review
- The pivotal role of macrophages in tumorigenesis and pioneering cancer immunotherapy across pre-clinical and clinical frontiers.Journal of cancer research and clinical oncology · 2026Review
- TAMs in the Gynecological Tumor Microenvironment: Insights from Cross-Cancer Studies for Immunotherapy.Cancers · 2026Review
- Tumor-Associated Macrophages as Therapeutic Targets: Deciphering Interaction Networks and Advancing Clinical Translation.MedComm · 2026Review
- Review
- The Roles of the Membrane-Anchored Glycoprotein RECK in Animal Development, Tumor Suppression, and Beyond.Life (Basel, Switzerland) · 2026Review
- Advancing adoptive T cell therapy in ovarian cancer: barriers, innovations, and emerging platforms.Journal for immunotherapy of cancer · 2026Review
- When treatment backfires: Dopamine agonist-induced CSF leaks in prolactinomas - Case series and systematic review.Brain & spine · 2026Review
- Reversing diabetic wound stagnation: macrophage polarization dysregulation as a therapeutic linchpin from pathogenesis to precision interventions.Burns & trauma · 2026Review
- Monocyte-Macrophage Lineages in Cancer: Biology, Plasticity, and Therapeutic Targeting.Cancer biome and targeted therapy · 2026Article
- Synthesis and Evaluation of Radiogallium-Labeled Peptide Probes for In Vivo Imaging of Legumain Activity.Molecules (Basel, Switzerland) · 2025Article
- Dual roles and therapeutic targeting of tumor-associated macrophages in tumor microenvironments.Signal transduction and targeted therapy · 2025Review
- Macrophage regulation of tumor cell dormancy and the dormant niche: an overview in solid tumors.Cancer metastasis reviews · 2025Review
- HPV16-Expressing Tumors Release Multiple IL1 Ligands to Orchestrate Systemic Immunosuppression Whose Disruption Enables Efficacy of a Therapeutic Vaccine.Cancer discovery · 2025Article
- Bisphosphonates with high bone-resorption-capacity promote osteonecrosis of the jaw development after tooth extraction in mice.Journal of bone and mineral metabolism · 2025Article
- Synergistic effects of sequential treatment with doxorubicin and zoledronic acid on anticancer effects in estrogen receptor-negative breast cancer cells.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Ultrasound-assisted synthesis of new bisphosphonate-betulin conjugates and preliminary evaluation of their cytotoxic activity.RSC advances · 2025Article
233 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.