Role Of Stromal Cell Derived Factor 1(SDF-1) And Tumor Infiltrating Immune Cells In Breast Cancer Invasion And Metastasis

Background Stromal cell derived factor 1(SDF-1) stimulates survival and growth of breast cancer cells in a paracrine fashion. However, epigenetic silencing of SDF-1 induces their reduced expression and increases the metastatic potential of cancer cells. We therefore speculate different roles of endogenous and exogenous SDF-1 on EMT status of breast tumor cells. Various types of tumor-infiltrating immune cells, including both effector cells with anti-tumor activity and regulatory immune-suppressing cells, could be chemo-attracted by SDF-1 and may either promote or inhibit the growth of tumors, showing distinct prognostic values in breast cancer.Material and Methods Expression levels of SDF-1 at genetic and protein level were analyzed by RT-PCR and ELISA. Western blot and quantitative real-time RT-PCR was used to evaluate the EMT status of breast cancer cell lines after stimulation or transfecting the plasmid of SDF-1. The invasiveness and expression of chemokine receptors CXCR4 and CXCR7 was compared between the SDF-1 re-expression MDA-MB-231 and wild type control. Formalin-Fixed, Paraffin-Embedded blocks from a cohort of 119 patients diagnosed with breast cancer and received primary surgery at Ruijin Hospital between 2004 and 2008 were achieved. SDF-1, CXCR4, CXCR7 expression of the tumors and CD8, FOXP3 and PD-1 positive immune cells were studied. Their interactions and correlation with clinicopathologic features and patientoutcome were analyzed.Results Reduced expression of SDF-1 was found in more malignant cell lines. While exogenous SDF-1 promoted EMT of tumor cells, a mesenchymal epithelial transition(MET) change was shown during the process of SDF-1 re-expression. Furthermore, patients with grade 3 or triple negative breast cancers were found to have less SDF-1 expression in tumors. Furthermore, no correlation was found between SDF-1 expression and the number of certain type of immune cells. The number of FOXP3 and PD-1 cells increased in patients with high risk factors. More PD-1+ cells and lower CD8/PD-1 ratio were both associated with poorer patient outcome.Conclusions Endogenous and exogenous SDF-1 were found to have opposite roles on EMT status of breast tumor cells. Therapies that boost SDF-1 levels may prove to be a potentially effective treatment for breast cancer. In tumor microenvironment, multiple layers of both cellular and molecular immune suppression mechanisms exist. Targeting the immune checkpoint PD-1 pathway as well as depletion of Tregs may be a feasible approach to treat patients with breast cancer and warrants further investigation.