Cancer cell-induced tissue inhibitor of metalloproteinase-1 secretion by cancer-associated fibroblasts promotes cancer cell migration

Cancer-associated fibroblasts (CAFs) are one of the major components of the cancer stroma in the tumor microenvironment. The interaction between cancer cells and CAFs (cancer-stromal interaction; CSI) promotes tumor progression, including metastasis. Recently, the tissue inhibitor of metalloproteinase-1 (TIMP-1) was reported to promote cancer cell migration and metastasis, which is contrary to its anticancer role as an inhibitor of matrix metalloproteinase. Moreover, CAF-derived TIMP-1 is reported to regulate CAF activity. In the present study, we investigated the effect of TIMP-1 on colon cancer cell migration in vitro. The TIMP-1 secretion levels from the CAFs and cancer cell lines were comparatively measured to determine the main source of TIMP-1. Furthermore, the effect of CSI on TIMP-1 secretion was investigated using the Transwell co-culture system. Cancer cell migration was evaluated using the wound-healing assay. The results demonstrated that TIMP-1 promoted the migration of LoVo cells, a colon cancer cell line, whereas TIMP-1 neutralization inhibited the enhanced migration. The TIMP-1 levels secreted from the cancer cells were approximately 10 times less than those secreted from the CAFs. TIMP-1 secretion was higher in CAFs co-cultured with cancer cells than in monocultured CAFs. Furthermore, the migration of LoVo cells increased upon co-culturing with the CAFs. TIMP-1 neutralization partially inhibited this enhanced migration. These results suggest that CAFs are the primary source of TIMP-1 and that the TIMP-1 production is enhanced through CSI in the tumor microenvironment, which promotes cancer cell migration.