Abstract |
Chronic inflammation is a major risk factor for colorectal cancer. The p38/ MAPKAP Kinase 2 (MK2) kinase axis controls the synthesis of proinflammatory cytokines that mediate both chronic inflammation and tumor progression. Blockade of this pathway has been previously reported to suppress inflammation and to prevent colorectal tumorigenesis in a mouse model of inflammation-driven colorectal cancer, by mechanisms that are still unclear. Here, using whole-animal and tissue-specific MK2 KO mice, we show that MK2 activity in the myeloid compartment promotes tumor progression by supporting tumor neoangiogenesis in vivo. Mechanistically, we demonstrate that MK2 promotes polarization of tumor-associated macrophages into protumorigenic, proangiogenic M2-like macrophages. We further confirmed our results in human cell lines, where MK2 chemical inhibition in macrophages impairs M2 polarization and M2 macrophage-induced angiogenesis. Together, this study provides a molecular and cellular mechanism for the protumorigenic function of MK2.
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Authors | Lucia Suarez-Lopez, Ganapathy Sriram, Yi Wen Kong, Sandra Morandell, Karl A Merrick, Yuliana Hernandez, Kevin M Haigis, Michael B Yaffe |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 115
Issue 18
Pg. E4236-E4244
(05 01 2018)
ISSN: 1091-6490 [Electronic] United States |
PMID | 29666270
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Intracellular Signaling Peptides and Proteins
- Neoplasm Proteins
- MAP-kinase-activated kinase 2
- Protein Serine-Threonine Kinases
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Topics |
- Animals
- Colorectal Neoplasms
(blood supply, epidemiology, genetics, pathology)
- Intracellular Signaling Peptides and Proteins
(genetics, metabolism)
- Macrophages
(enzymology, pathology)
- Mice
- Mice, Knockout
- Neoplasm Proteins
(genetics, metabolism)
- Neovascularization, Pathologic
(enzymology, genetics, pathology)
- Protein Serine-Threonine Kinases
(genetics, metabolism)
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