Metformin against TGFβ-induced epithelial-to-mesenchymal transition (EMT): From cancer stem cells to aging-associated fibrosis
Open accessAbstract
Transforming Growth Factor-b (TGFb) is a major driving force of the Epithelial-to-Mesenchymal (EMT) genetic program, which becomes overactive in the pathophysiology of many age-related human diseases. TGFb-driven EMT is sufficient to generate migrating cancer stem cells by directly linking the acquisition of cellular motility with the maintenance of tumor-initiating (stemness) capacity. Chronic diseases exhibiting excessive fibrosis can be caused by repeated and sustained infliction of TGFb-driven EMT, which increases collagen and extracellular matrix synthesis. Pharmacological prevention and/or reversal of TGFb-induced EMT may therefore have important clinical applications in the management of cancer metastasis as well as in the prevention and/or treatment of end-state organ failures. Earlier studies from our group have revealed that clinically-relevant concentrations of the biguanide derivative metformin, the most widely used oral agent to lower blood glucose concentration in patients with type 2 diabetes and metabolic syndrome, notably decreased both the self-renewal and the proliferation of trastuzumab-refractory breast cancer stem cell populations. Given that: a.) tumor-initiating cancer stem cells display a significant enrichment in the expression of basal/mesenchymal or myoepithelial markers, including an increased secretion of TGFb; b.) metformin treatment impedes the ontogeny of generating the stem cell phenotype by transcriptionally repressing key drivers of the EMT genetic program (e.g. ZEB1, TWIST1, SNAIL2 [Slug], TGFbs), we recently hypothesized that prevention of TGFb-induced EMT might represent a common molecular mechanism underlying the anti-cancer stem cells and anti-fibrotic actions of metformin. Remarkably, metformin exposure not only impedes TGFb-promoted loss of the epithelial marker E-cadherin in MCF-7 breast cancer cells but it prevents further TGF-induced cell scattering and accumulation of the mesenchymal marker vimentin in Madin-Darby canine kidney (MDCK) cells. We now propose that metformin, by weakening the ability of TGFb signaling to fully induce mesenchymal cell states in a variety of pathological processes including fibrosis (e.g. chronic renal disease, non-alcoholic steatohepatitis, heart failure or sclerosis) and malignant progression (and likely by reducing TGFb-regulated inflammation and immune responses -inflamm-aging-), molecularly behaves as a bona fide anti-aging modality.
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Animal experiments have elucidated the mechanisms underlying these epidemiological findings, i.e., inhibition of epithelial-to-mesenchymal transition (which is implicated in metastasis).
“inhibition of epithelial-to-mesenchymal transition(265), (which is implicated in metastasis);”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [265]
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- Authors
- Cufí, S., Vazquez-Martin, A., Oliveras-Ferraros, C., Martin-Castillo, B., Joven, J., & Menendez, J. A.
- Affiliations
- Institut Català d'Oncologia (ES)
- Institut de Recerca Biomèdica Catalunya Sud (ES)
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2010-11-15
- Volume
- 9
- Issue
- 22
- Pages
- 4461-4468
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- OpenAlex
- W2090836265
- Cited by
- 216
- References
- 35
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 4 · 2023: 5 · 2022: 5 · 2021: 8 · 2020: 18 · 2019: 13 · 2018: 14 · 2017: 22 · 2016: 21 · 2015: 21 · 2014: 16 · 2013: 17 · 2012: 24
- FWCI
- 7.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministerio de Ciencia e Innovación
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- metformin, TGF-beta, epithelial-mesenchymal transition, cancer stem cells, breast cancer, E-cadherin, vimentin, ZEB1, TWIST1, Snail2, anti-aging, inflammation, chronic kidney disease, nonalcoholic steatohepatitis, heart failure, sclerosis, biguanides
- MeSH terms
- Animals, Breast Neoplasms, Dogs, Female, Fibrosis, Humans, Hypoglycemic Agents, Metformin, Neoplastic Stem Cells, Signal Transduction, Cadherins, Transforming Growth Factor beta, Cellular Senescence, Cell Line, Tumor, Epithelial-Mesenchymal Transition
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