ArticlePloS one2015
Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 98 papers.
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Who cites it
98 citing papers in PubMed, 141 citations in OpenAlex.
- Special Issue "Molecular Mechanisms and Therapies of Pancreatic Cancer: 2nd Edition".International journal of molecular sciences · 2026Article
- Therapeutic repurposing of old drugs to modulate the tumor immune microenvironment and enhance immunotherapy efficacy.Journal of pharmaceutical analysis · 2026Review
- Clinicopathological and Prognostic Implications of Epithelial-to-Mesenchymal Transition-Related Immunohistochemical Markers in Resectable Pancreatic Cancer: A Retrospective Longitudinal Study.Cancer reports (Hoboken, N.J.) · 2026Article
- The role of metformin in extracellular matrix-based three-dimensional cell culture Models: A mini-review on therapeutic potentials.Biochemistry and biophysics reports · 2026Review
- Immune-Centered Cross-Talk Between Cancer Cells and the Tumor Microenvironment-Implications for Therapy.Cancers · 2026Review
- Review
- Review
- Fibrotic Fortresses and Therapeutic Frontiers: Pancreatic Stellate Cells and the Extracellular Matrix in Pancreatic Cancer.Cancer medicine · 2025Review
- Tumor-associated macrophages (TAMs): Constructing an immunosuppressive microenvironment bridge for pancreatic ductal adenocarcinoma (PDAC).Cancer pathogenesis and therapy · 2025Review
- Cancer associated fibroblasts in cancer development and therapy.Journal of hematology & oncology · 2025Review
- Deciphering mechanical cues in the microenvironment: from non-malignant settings to tumor progression.Biomarker research · 2025Review
- Nimbolide: A Potential Phytochemical Agent in Multimodal Pancreatic Cancer Therapies.Mini reviews in medicinal chemistry · 2025Review
- Chemokines: humble yet mighty players in the tumour microenvironment.Frontiers in immunology · 2025Review
- Current paradigm and futuristic vision on new-onset diabetes and pancreatic cancer research.Frontiers in pharmacology · 2025Review
- The synergistic potential of mechanotherapy and sonopermeation to enhance cancer treatment effectiveness.npj biological physics and mechanics · 2025Review
- The mechanopathology of the tumor microenvironment: detection techniques, molecular mechanisms and therapeutic opportunities.Frontiers in cell and developmental biology · 2025Review
- Enhanced safety and efficacy profile of CD40 antibody upon encapsulation in pHe-triggered membrane-adhesive nanoliposomes.Nanomedicine (London, England) · 2025Article
- Oncolytic Tanapoxvirus Variants Expressing mIL-2 and mCCL-2 Regress Human Pancreatic Cancer Xenografts in Nude Mice.Biomedicines · 2024Article
- Modulating cancer mechanopathology to restore vascular function and enhance immunotherapy.Cell reports. Medicine · 2024Review
- CCK Receptor Inhibition Reduces Pancreatic Tumor Fibrosis and Promotes Nanoparticle Delivery.Biomedicines · 2024Article
38 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 3 institutions in 4 countries.
Funding
Abstract
backgroundPancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor with a dismal prognosis for most patients. Fibrosis and inflammation are hallmarks of tumor desmoplasia. We have previously demonstrated that preventing the activation of pancreatic stellate cells (PSCs) and alleviating desmoplasia are beneficial strategies in treating PDAC. Metformin is a widely used glucose-lowering drug. It is also frequently prescribed to diabetic pancreatic cancer patients and has been shown to associate with a better outcome. However, the underlying mechanisms of this benefit remain unclear. Metformin has been found to modulate the activity of stellate cells in other disease settings. In this study, we examine the effect of metformin on PSC activity, fibrosis and inflammation in PDACs. METHODS/
resultsIn overweight, diabetic PDAC patients and pre-clinical mouse models, treatment with metformin reduced levels of tumor extracellular matrix (ECM) components, in particular hyaluronan (HA). In vitro, we found that metformin reduced TGF-ß signaling and the production of HA and collagen-I in cultured PSCs. Furthermore, we found that metformin alleviates tumor inflammation by reducing the expression of inflammatory cytokines including IL-1β as well as infiltration and M2 polarization of tumor-associated macrophages (TAMs) in vitro and in vivo. These effects on macrophages in vitro appear to be associated with a modulation of the AMPK/STAT3 pathway by metformin. Finally, we found in our preclinical models that the alleviation of desmoplasia by metformin was associated with a reduction in ECM remodeling, epithelial-to-mesenchymal transition (EMT) and ultimately systemic metastasis.
conclusionMetformin alleviates the fibro-inflammatory microenvironment in obese/diabetic individuals with pancreatic cancer by reprogramming PSCs and TAMs, which correlates with reduced disease progression. Metformin should be tested/explored as part of the treatment strategy in overweight diabetic PDAC patients.
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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.