Biomedical Sciences ETDs

Publication Date

Summer 7-2017

Abstract

Colorectal cancer (CRC) is the third most common malignancy in the United States for men and women. A major risk factor for CRC development and progression is inflammation, in particular the inflammatory cytokines IL-1, IL-6, and TNF-α. These proteins promote critical cancer functions, such as proliferation, invasion, survival, and migration. Control of inflammation is one potential area of therapeutic intervention for some cancers. Because signaling of these cytokines overlaps in many of the same pathways, targets upstream of protein production could prove an effective strategy to reduce inflammation. MAPK-activated protein kinase 2 (MK2) pathway controls production of these cytokines within the MAPK p38 pathway. By investigating the role of MK2 signaling in CRC, we demonstrate that MK2 is a critical protein in the initiation and progression of colitis-associated and spontaneous CRC. MK2-/- mice have much lower expression of IL-1, IL-6, and TNF-α than wild-type mice, indicating that MK2 is the primary regulator of these cytokines in a colitis-associated model of CRC. MK2 blockade also decreased cytokine-producing macrophage populations, which are an important source of inflammatory cytokines that support tumor growth. MK2-/- mice are completely protected against neoplasms. MK2 is thus a crucial component of CRC development that regulates intestinal macrophage populations. Addition of wild-type macrophages to mice in the CRC model increased cytokines in both wild-type and MK2 mice, and tumor burden in wild-type mice. Pharmacological inhibition of MK2 in wild-type mice after neoplasms developed caused complete regression in the majority of mice. MK2 is thus implicated as a critical signaling pathway throughout tumor initiation and development in a colitis-associated model of CRC. To address MK2’s participation in an invasive model of CRC, a syngeneic cell line was used to develop tumors. Cells treated with MK2 inhibitor developed smaller tumors and produced approximately 80% less MK2-induced cytokines than controls. Treatment of cells with MK2-induced cytokines induced MK2 signaling, and restoring MK2-induced cytokines to tumor cells treated with MK2 inhibitor restored tumor burden and cytokines. These data support the existence of an inflammatory feedback cycle that drives CRC. MK2 inhibition is effective in multiple models, and offers a potential therapeutic target.

Keywords

MK2, colorectal cancer, inflammation, macrophages, cytokines, cancer

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Ellen Beswick

Second Committee Member

Michelle Ozbun

Third Committee Member

Xuexian Yang

Fourth Committee Member

Bryce Chackerian

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