Uterine smooth muscle cells increase invasive ability of endometrial carcinoma cells through tumor–stromal interaction

The incidence of lymph node metastasis by endometrial carcinoma (EMCA) increases with the depth of myometrial invasion, and this depth of invasion has been found to have a major impact on the outcome. In the present study, we assessed the effect of tumor–stromal interactions on the invasive behavior of EMCA cells and examined the involvement of SDF-1alpha/CXCL12-CXCR4 in the interaction of EMCA cells and uterine smooth muscle cells (UtSMCs). We investigated whether SDF-1alpha/CXCL12 produced and secreted from UtSMCs induces EMCA cell migration by using 5 human EMCA cell lines such as AMEC and RL95 cells. The SDF-1alpha/CXCL12 concentration in conditioned medium (CM) of UtSMCs(was 4,120 ± 530 pg/ml. Treatments with CM of UtSMCs and plated UtSMCs significantly induced both AMEC and RL95 cell migration. The induced cell migrations were significantly inhibited by CXCR4 mAb (12G5) and CXCR4 antagonist (AMD3100) pre-treatments. Treatments with UtSMCs CM to AMEC and RL95 cells stimulated Akt phosphorylation in a time-dependent manner. Pre-treatment of AMEC and RL95 cells with wortmannin as a PI3K inhibitor significantly inhibited UtSMCs CM-induced cell migration. The SDF-1alpha/CXCL12-CXCR4 chemokine axis between UtSMCs and EMCA played an important role in the muscular infiltration of endometrial cancer through activation of PI3K-Akt signaling pathway. Suppression of this pathway could be an effective target for the treatment of early uterine body cancer in particular.