Although Mesenchymal Stem Cells (MSC) has been explored as a new clinically relevant cell type to repair injured tissue, a number of studies have highlighted the important aspect of MSC therapy. Studies have shown that systemically administered MSCs migrate to sites of malignant tumor. The focus of this study was to identify the mechanism of migration of human MSCs into cancerous tissue. First, the effect of cultured medium from cancer cell lines on modulating the migration of MSCs was evaluated, using seven different human colon cancer cell lines. Interestingly, the secretion level of High Mobility Group Box 1 (HMGB1) protein from each cell line affected the migration capacity of MSCs. In addition, recombinant human HMGB1 increased MSC's migration capacity in a dosedependent manner. Finally, 1×10 6 human MSCs were injected subcutaneously into mice (n=14) with colon cancer tumors that secreted high levels of HMGB1. Bioluminescence live image analysis showed that MSCs surrounded the tumors after injection into these mice through day 6. Immunohistochemical analysis using CD90 as a specific antibody revealed the existence of MSCs in and around the tumors as well as the secretion of local HMGB1 from the tumors detected by anti-HMGB1 antibody. These findings are critical in understanding the role of MSCs in development of solid tumors and further, they offer insight that may be useful in therapeutic application of MSCs in the treatment of malignant tumors.