MAPKAP Kinase-2 Drives Expression of Angiogenic Factors by Tumor-Associated Macrophages in a Model of Inflammation-Induced Colon Cancer

Abstract

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.

MK2 Expression Promotes Non-Small Cell Lung Cancer Cell Death and Predicts Survival

“…One possible explanation for our data diverging from previously published work is that many of these utilized different cancer types (i.e. intestinal tumors) or murine models (61)(62)(63)(64)(65). However, in patient derived data from TCGA, we note a significant association with improved 2-year survival in lung adenocarcinoma with high MK2 expression, Figure 5 Our data clearly show that a non-kinase function of MK2 is responsible for the observed sensitization to cell death, Figure 9.…”

“…Interestingly, the majority of data showing a role for MK2 in cancers focus on MK2 kinase activity and its role in tumor development (61)(62)(63)(64). In a novel murine model of NSCLC that generates MK2-proficient and MK2-deficient tumors within the same animal, Morandell et al show that MK2-proficient tumor area is consistently greater than MK2-deficient tumor area (65).…”

Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): From Mechanism to Therapy and Prognosis

“…IL-10 stimulates macrophages to secrete the soluble factors MMP-2 and MMP-9, which effectively promote cancer cellinduced angiogenesis in vivo [84]. By adoptive transfer of WT macrophages into MK2 KO mice, Suarez-Lopez, L. et al demonstrated that MK2 signaling/angiogenesis is inherent in macrophages; MK2 regulates CXCL12 expression in TAMs, promoting angiogenesis and progression of cancer cells [85]. Luput, L. and his team demonstrated that TAMs can enhance the expression of angiogenic proteins in the TME by regulating the activity of NADPH oxidase, which maintains the redox status and angiogenic capacity in the TME of CRC [64].…”

Inflammatory Bowel Disease and Risk of Colorectal Cancer: An Overview From Pathophysiology to Pharmacological Prevention

“…A recent work demonstrated for the first time, using a mouse model of IBD-CRC, that the M2 macrophage polarization could be altered by genetic inactivation of the MAPK-activated protein kinase 2 (MK2), resulting in delayed tumor progression (Suarez-Lopez et al, 2020).…”