Regulation of tumor angiogenesis and mesenchymal–endothelial transition by p38α through TGF-β and JNK signaling
Open accessAbstract
The formation of new blood vessels is essential for normal development, tissue repair and tumor growth. Here we show that inhibition of the kinase p38α enhances angiogenesis in human and mouse colon tumors. Mesenchymal cells can contribute to tumor angiogenesis by regulating proliferation and migration of endothelial cells. We show that p38α negatively regulates an angiogenic program in mesenchymal stem/stromal cells (MSCs), multipotent progenitors found in perivascular locations. This program includes the acquisition of an endothelial phenotype by MSCs mediated by both TGF-β and JNK, and negatively regulated by p38α. Abrogation of p38α in mesenchymal cells increases tumorigenesis, which correlates with enhanced angiogenesis. Using genetic models, we show that p38α regulates the acquisition of an endothelial-like phenotype by mesenchymal cells in colon tumors and damage tissue. Taken together, our results indicate that p38α in mesenchymal cells restrains a TGF-β-induced angiogenesis program including their ability to transdifferentiate into endothelial cells.
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Increased TGF-β expression has been linked to increased microvessel density in certain tumor types.
“It should be noted that increased TGF-β expression has been linked to increased microvessel density in certain tumor types271,272.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [272]
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References 71 · Cited by 142
- Authors
- Batlle, R., Andrés, E., Gonzalez, L., Llonch, E., Igea, A., Gutierrez-Prat, N., Berenguer-Llergo, A., & Nebreda, A. R.
- Affiliations
- Institute for Research in Biomedicine (ES)
- Venue
- Nature Communications
- Published
- 2019-07-11
- Volume
- 10
- Issue
- 1
- Pages
- 3071-3071
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6624205
- OpenAlex
- W2962661158
- Cited by
- 142
- References
- 71
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 17 · 2023: 18 · 2022: 23 · 2021: 45 · 2020: 14 · 2019: 2
- FWCI
- 6.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- University of Pennsylvania
- Ohio State University
- Institute for Research in Biomedicine
- Fundació la Marató de TV3 (20133430)
- Centres de Recerca de Catalunya
- Fundación Olga Torres
- European Commission (ERC 294665, 294665)
- Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya (2017 SGR-557)
- Ministerio de Economía y Competitividad (SAF2016‐81043‐R)
- Agència de Gestió d'Ajuts Universitaris i de Recerca (2017SGR)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- p38α MAPK, tumor angiogenesis, mesenchymal stem cells, TGF-beta signaling, JNK signaling, colon cancer, endothelial transdifferentiation, perivascular stromal cells, carcinogenesis, endothelial cell proliferation and migration
- MeSH terms
- Animals, Azoxymethane, Carcinogens, Colonic Neoplasms, Endothelium, Vascular, Humans, Mice, Inbred C57BL, Mice, Transgenic, Neoplasms, Experimental, Neovascularization, Pathologic, Transforming Growth Factor beta, HT29 Cells, MAP Kinase Signaling System, RNA, Small Interfering, Endothelial Cells, JNK Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 14, Cell Proliferation, Mice, Cell Transdifferentiation, Gene Knockdown Techniques, Epithelial-Mesenchymal Transition, Mesenchymal Stem Cells
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