Interleukin-6 expression by interactions between gynecologic cancer cells and human mesenchymal stem cells promotes epithelial-mesenchymal transition.

Epithelial-to-mesenchymal transition (EMT) facilitates the invasion and metastasis of cancer cells. EMT seems to be mediated by the interaction between cancer cells and human mesenchymal stem cells (hMSCs) in the tumor microenvironment. The present study is intended to identify specific cytokines as potent inducers of EMT associated hMSCs-tumor interactions. We used ovarian cancer cell lines (SKOV-3 and IGROV-1), endometrial cancer cell line (Ishikawa) and hMSCs (bone marrow MSC, amniotic membrane MSC and decidua MSC). The expressions of EMT markers (E-cadherin, Snail, Twist and N-cadherin) were analyzed using quantitative RT-PCR, immunofluorescence and western blot analysis. Matrix metalloproteinases (MMP-2 and MMP-9), Matrigel invasion assay, and wound healing assay were used to analyze cell migration and invasion. Gynecologic cancer cells directly co-cultured with hMSCs had contact-dependent altered morphology and growth patterns. IL-6 was elevated in all co-cultures using a human cytokine array. After IL-6 treatment of cancer cell lines, RT-PCR and western blot analysis indicated a decrease in an epithelial marker and an increase in mesenchymal markers. Also, cancer cells with IL-6 significantly increase in MMP-2 and MMP-9 and significantly enhance the migration ability compared to untreated cells (P<0.05), as shown by wound healing assay. On Matrigel invasion assay, treated cells displayed significantly increased invasiveness compared to untreated cancer cells. Gyneocologic cancer cells exposed to IL-6 acquired mesenchymal properties that facilitated metastasis and invasion by promoting EMT. The present study suggests that IL-6 of the tumor microenvironment has a critical role in oncogenic EMT.