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MAPKAP Kinase-2 Drives Expression of Angiogenic Factors by Tumor-Associated Macrophages in a Model of Inflammation-Induced Colon Cancer
Name
fimmu-11-607891.pdf
Description
Published version
Size
1.85 MB
Format
Adobe PDF
Checksum (MD5)
c54351e6eebe3119e5fd11584ffeb1a3
Author(s)
Suarez-Lopez, Lucia
Kong, Yi Wen
Sriram, Ganapathy
Patterson, Jesse C
Rosenberg, Samantha
Morandell, Sandra
Haigis, Kevin M
Yaffe, Michael B
Date Issued
2021
Journal
Frontiers in Immunology
Publisher
Frontiers Media SA
Version
Final published version
Abstract
© Copyright © 2021 Suarez-Lopez, Kong, Sriram, Patterson, Rosenberg, Morandell, Haigis and Yaffe. Chronic inflammation increases the risk for colorectal cancer through a variety of mechanisms involving the tumor microenvironment. MAPK-activated protein kinase 2 (MK2), a major effector of the p38 MAPK stress and DNA damage response signaling pathway, and a critical regulator of pro-inflammatory cytokine production, has been identified as a key contributor to colon tumorigenesis under conditions of chronic inflammation. We have previously described how genetic inactivation of MK2 in an inflammatory model of colon cancer results in delayed tumor progression, decreased tumor angiogenesis, and impaired macrophage differentiation into a pro-tumorigenic M2-like state. The molecular mechanism responsible for the impaired angiogenesis and tumor progression, however, has remained contentious and poorly defined. Here, using RNA expression analysis, assays of angiogenesis factors, genetic models, in vivo macrophage depletion and reconstitution of macrophage MK2 function using adoptive cell transfer, we demonstrate that MK2 activity in macrophages is necessary and sufficient for tumor angiogenesis during inflammation-induced cancer progression. We identify a critical and previously unappreciated role for MK2-dependent regulation of the well-known pro-angiogenesis factor CXCL-12/SDF-1 secreted by tumor associated-macrophages, in addition to MK2-dependent regulation of Serpin-E1/PAI-1 by several cell types within the tumor microenvironment.
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
10.3389/fimmu.2020.607891
