Metformin Inhibits Metastatic Breast Cancer Progression and Improves Chemosensitivity by Inducing Vessel Normalization via PDGF-B Downregulation
Open accessAbstract
BACKGROUND: Vascular maturity and functionality are closely associated with tumor progression and chemosensitivity. The antidiabetic agent metformin has shown its ability to inhibit tumor angiogenesis in metastatic breast cancer models. However, it remains unclear if or how metformin remodels the abnormal vasculature of metastatic breast cancer, while inhibiting angiogenesis. METHODS: Metastatic breast cancer models were constructed to compare microvessel density (MVD), vascular maturity and function, lung metastasis and chemosensitivity in metformin-treated or untreated mice. Protein array assay and transcriptome sequencing were performed for genetic screening. Lentiviral shRNA-PDGF-B transfection was used for observing the contribution of PDGF-B knockdown to metformin's vascular effects. RESULTS: Metastatic breast cancers were characterized by an excessively angiogenic, immature and morphologically abnormal vasculature. Compared to control, metformin significantly reduced MVD, leakage and hypoxia, and increased vascular mural cells coverage and perfusion, namely, "vessel normalization". Metformin at human blood concentrations had no direct effect on the migration and proliferation of cancer cells. Based on that, reduced lung metastasis of the primary tumor and improved chemosensitization by metformin were assumed to be mediated via metformin's vascular effects. Further results of genetic screening and in vivo experiments showed that the downregulation of platelet-derived growth factor B (PDGF-B) greatly contributed to the metformin-induced vessel normalization. CONCLUSIONS: These findings provide pre-clinical evidences for the vascular mechanism of metformin-induced metastasis inhibition and the chemosensitization of metastatic breast cancers.
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Many in vitro studies have used mM concentrations of metformin to demonstrate an anti-proliferative action in tumor cells in culture.
“However, many in vitro studies have used mM concentrations of metformin to demonstrate an anti-proliferative action in tumor cells in culture [see (114, 115); Table 2].”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [115]
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- Authors
- Wang, J.-C., Li, G.-Y., Wang, B., Han, S.-X., Sun, X., Jiang, Y.-N., Shen, Y.-W., Zhou, C., Feng, J., Lu, S.-Y., Liu, J.-L., Wang, M.-D., & Liu, P.-J.
- Affiliations
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- Venue
- Journal of Experimental & Clinical Cancer Research
- Published
- 2019-06-04
- Volume
- 38
- Issue
- 1
- Pages
- 235-235
- ISSN
- 0392-9078 (ISSN-L)
- 1756-9966
- PMC
- PMC6549289
- OpenAlex
- W2948510422
- Cited by
- 138
- References
- 67
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 22 · 2023: 24 · 2022: 27 · 2021: 22 · 2020: 14 · 2019: 5
- FWCI
- 5.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Experimental & Clinical Cancer Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Young Scientists Fund (No.81602502, No.81602638)
- Shaanxi Provincial Science and Technology Department (No.2017SF017, No.2016SF196)
- Natural Science Foundation of Shaanxi Province (No.2016JM8125)
- Xi’an Jiaotong University (No. xjj2016104)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- metformin, metastatic breast cancer, vessel normalization, PDGF-B, tumor angiogenesis, chemosensitivity, lung metastasis, vascular maturation, microvessel density, tumor hypoxia, vascular leakage
- MeSH terms
- Animals, Antineoplastic Agents, Breast Neoplasms, Cell Movement, Disease Models, Animal, Female, Humans, Metformin, Models, Biological, Neoplasm Staging, Neovascularization, Pathologic, Prognosis, Gene Expression Regulation, Neoplastic, Disease Progression, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-sis, Gene Expression Profiling, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice
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