A major risk factor for colon cancer growth and progression is chronic inflammation. We have shown that the MAPK-activated protein kinase 2 (MK2) pathway is critical for colon tumor growth in colitis-associated and spontaneous colon cancer models. This pathway is known to regulate expression of the tumor-promoting cytokines, IL-1, IL-6, and TNF-a. However, little is known about the ability of MK2 to regulate chemokine production. This is the first study to demonstrate this pathway also regulates the chemokines, MCP-1, Mip-1a, and Mip-2a (MMM). We show that these chemokines induce tumor cell growth and invasion in vitro and that MK2 inhibition suppresses tumor cell production of chemokines and reverses the resulting pro-tumorigenic effects. Addition of MMM to colon tumors in vivo significantly enhances tumor growth in control tumors and restores tumor growth in the presence of MK2 inhibition. We also demonstrate that MK2 signaling is critical for chemokine expression and macrophage influx to the colon tumor microenvironment. MK2 signaling in macrophages was essential for inflammatory cytokine/chemokine production, whereas MK2-/- macrophages or MK2 inhibition suppressed cytokine expression. We show that addition of bone marrow-derived macrophages to the tumor microenvironment enhances tumor growth in control tumors and restores tumor growth in tumors treated with MK2 inhibitors, while addition of MK2-/- macrophages had no effect. This is the first study to demonstrate the critical role of the MK2 pathway in chemokine production, macrophage influx, macrophage function, and tumor growth.
|Journal||Frontiers in Immunology|
|State||Published - Sep 21 2018|
Bibliographical noteFunding Information:
We would like to acknowledge Dr. Matthias Gaestel at Hannover Medical School for providing the mice from which the bone marrow-derived macrophages used in this study originated. We would like to thank Dr. Eric Prossnitz (UNMCC) for reading and editing the manuscript. Stephanie Jerman was the recipient of an IRACDA fellowship, K12GM088021.
This work was supported by the by NIH R01CA207051-01, DeGregorio Family Foundation, NIH 8UL1TR000041, the University of New Mexico Clinical and Translational Science Center, and NIH P30CA118100, UNM Cancer Center. AR is a recipient of the T32AI007538-17-21 Predoctoral Fellowship.
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- Colon tumor
ASJC Scopus subject areas
- Immunology and Allergy