Colorectal cancer (CRC) development and progression is associated with chronic inflammation. We have identified the MAPK-activated protein kinase 2 (MK2) pathway as a primary mediator of inflammation in CRC. MK2 signaling promotes production of proinflammatory cytokines IL-1β, IL-6 and TNF-α. These cytokines have been implicated in tumor growth, invasion and metastasis. For the first time, we investigate whether MK2 inhibition can improve outcome in two mouse models of CRC. In our azoxymethane/dextran sodium sulfate (AOM/DSS) model of colitis-associated CRC, MK2 inhibitor treatment eliminated murine tumor development. Using the implanted, syngeneic murine CRC cell line CT26, we observe significant tumor volume reduction following MK2 inhibition. Tumor cells treated with MK2 inhibitors produced 80% less IL-1β, IL-6 and TNF-α and demonstrated decreased invasion. Replenishment of downstream proinflammatory MK2-mediated cytokines (IL-1β, IL-6 and TNF-α) to tumors led to restoration of tumor proliferation and rapid tumor regrowth. These results demonstrate the importance of MK2 in driving proinflammatory cytokine production, its relevance to in vivo tumor proliferation and invasion. Inhibition of MK2 may represent an attractive therapeutic target to suppress tumor growth and progression in patients.

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Radiation therapy (RT) is a cornerstone of treatment in the management of head and neck squamous cell carcinomas (HNSCC), yet treatment failure and disease recurrence are common. The p38/MK2 pathway is activated in response to cellular stressors, including radiation, and promotes tumor inflammation in a variety of cancers. We investigated MK2 pathway activation in Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Hypercoagulable state is linked to cancer progression; however, the precise role of the coagulation cascade is poorly described. Herein, we examined the contribution of a hypercoagulative state through the administration of intravenous Coagulation Factor Xa (FXa), on the growth of solid human tumors and the experimental metastasis of the B16F10 melanoma in mouse models. FXa increased solid tumor volume and lung, liver, kidney and lymph node metastasis of tail-vein injected B16F10 cells. Concentrating on the metastasis model, upon coadministration of the anticoagulant Dalteparin, lung metastasis was significantly reduced, and no metastasis was observed in other organs. FXa did not directly alter proliferation, migration or invasion of cancer cells in vitro. Alternatively, FXa upon endothelial cells promoted cytoskeleton contraction, disrupted membrane VE-Cadherin pattern, heightened endothelial-hyperpermeability, increased inflammatory adhesion molecules and enhanced B16F10 adhesion under flow conditions. Microarray analysis of endothelial cells treated with FXa demonstrated elevated expression of inflammatory transcripts. Accordingly, FXa treatment increased immune cell infiltration in mouse lungs, an effect reduced by dalteparin. Taken together, our results suggest that FXa increases B16F10 metastasis via endothelial cell activation and enhanced cancer cell-endothelium adhesion advocating that the coagulation system is not merely a bystander in the process of cancer metastasis.