The central findings from the current study provided strong evidence linking MD2-TLR4 to colon cancer growth: i) MD2 was upregulated in human colon cancer tissue, mouse colon cancer tissue in model of colitis-associated colon cancer, and colon cancer cell lines; ii) MD2 blockade prevented LPS-induced motility and invasiveness of colon cancer cells; iii) MD2 blockade significantly reduced colon cancer cell metastasis to lungs and growth in colitis-associated colon cancer, and iv) MD2 blockade abrogated NF-κB activation in mouse tumor tissue and LPS-stimulated colon cancer cells. Here, TLR4 is linked to colitis.