Regulation of tumor angiogenesis and mesenchymal–endothelial transition by p38α through TGF-β and JNK signaling

• Published in: Nature communications 2019-07, Vol.10 (1), p.3071-18, Article 3071
• Main Authors: Batlle, Raquel, Andrés, Eva, Gonzalez, Lorena, Llonch, Elisabet, Igea, Ana, Gutierrez-Prat, Núria, Berenguer-Llergo, Antoni, Nebreda, Angel R.
• Format: Article
• Language: English
• Subjects: 13; 13/100; 13/106; 13/51; 13/95; 14/1; 14/19; 14/63; 38; 38/61; 38/77; 59; 631/532/2074; 631/67/2328; 631/80/86; 64; 64/110; Angiogenesis; Animals; Azoxymethane - administration & dosage; Azoxymethane - toxicity; Blood vessels; Carcinogens - administration & dosage; Carcinogens - toxicity; Cell migration; Cell Proliferation; Cell Transdifferentiation; Colon; Colonic Neoplasms - pathology; Colorectal cancer; Endothelial cells; Endothelial Cells - pathology; Endothelium, Vascular - cytology; Endothelium, Vascular - pathology; Epithelial-Mesenchymal Transition; Gene Knockdown Techniques; HT29 Cells; Humanities and Social Sciences; Humans; JNK Mitogen-Activated Protein Kinases - metabolism; Kinases; MAP Kinase Signaling System; Mesenchymal Stem Cells - metabolism; Mesenchymal Stem Cells - pathology; Mesenchyme; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitogen-Activated Protein Kinase 14 - genetics; Mitogen-Activated Protein Kinase 14 - metabolism; multidisciplinary; Neoplasms, Experimental - chemically induced; Neoplasms, Experimental - pathology; Neovascularization, Pathologic - pathology; Phenotypes; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Stem cells; Stromal cells; Transforming Growth Factor beta - metabolism; Tumorigenesis; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10946-y

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. Mesenchymal cells contribute to tumor angiogenesis by regulating proliferation and migration of endothelial cells. Here, the authors show that mesenchymal stem cells also have the ability to acquire an endothelial phenotype upon TGF-β stimulation via the downstream kinase JNK, and that p38α negatively regulates this process.