Myeloid-Derived Suppressor Cells Promote Metastasis in Breast Cancer After the Stress of Operative Removal of the Primary Cancer

Abstract

Objective: To investigate the role of myeloid-derived suppressor cells (MDSC) in cancer progression after the stress of operative removal and the potential treatment value of MDSC depletion.Summary Background Data: Surgery is the most important treatment strategy in breast cancer. Recent research has provided evidence that operations may promote cancer metastases under some circumstances.Methods: A mouse model of breast cancer (administration of the murine breast cancer 4T1 cells subcutaneously) and the stress of operation were used to compare immune responses and survival outcomes. Flow cytometry was performed to detect the expression of CD11b and Gr1 MDSCs in tumor tissues and lung metastases. Cytokine levels were detected with three-color flow cytometry and enzyme-linked immunosorbent assay (ELISA). MDSCs were isolated and co-cultured with 4T1 cells to identify any morphological change with immunofluorescence. The anti Gr-1 antibody was used to detect the function of the anti-Gr1 treatment in breast cancer.Results: The operative stress impaired the overall survival, leading to an increased number of MDSCs that preferentially infiltrated the tumor microenvironment and promoted tumor metastasis. In both in vitro and in vivo assays, MDSCs induced the epithelial-mesenchymal transition (EMT) of tumor cells through the up-regulation of TGF-beta1, VEGF, and IL-10. Furthermore, a treatment strategy of MDSC depletion was found to reduce pulmonary metastases after operations.Conclusions: The stress of operation could impair the overall survival in mice. The infiltrated MDSCs appear to induce EMT of tumor cells and increase metastases through the up-regulation of TGF-beta1, VEGF, and IL-10 levels. MDSC depletion could be a promising treatment strategy to prevent immune evasion after operations.

Chronic stress promotes EMT-mediated metastasis through activation of STAT3 signaling pathway by miR-337-3p in breast cancer

“…Previous studies revealed the negative targeting relationship between miR-337-3p and JAK2/STAT3 and further demonstrated that STAT3 is directly targeted by miR-337-3p 21 , 22 . Additionally, accumulating evidence has validated that miRNAs expression is often dysregulated by stress in cancer, such as chronic stress 23 , heat stress 24 , and surgical stress 25 . The rapid development of sequencing technology enables the detection of genetic changes in mutated cells, which promote the understanding for cancer biology 26 , 27 .…”

Transcriptomic Analyses of Myeloid-Derived Suppressor Cell Subsets in the Circulation of Colorectal Cancer Patients

“…Tumor-infiltrating immune cells, including myeloid cells, provide an immune-subversive environment for tumor development and progression through the activation of various signaling cascades ( 34 ). It has been reported that the MDSC subset, I-MDSCs, favors tumor progression by expanding T H 17 cells within the TME, rather than suppressing T cells ( 35 ).…”

Role of Tumor-Associated Myeloid Cells in Breast Cancer

“…In a previously reported mouse model injected with breast cancer cell line (4T1), among the recruited bone marrow-derived CD11b+Gr1+ myeloid progenitor cells in premetastatic lung, CD11b + Ly6C high monocytic MDSCs secreted versican, an extracellular matrix proteoglycan, thus triggering the EMT, increases tumor cell proliferation, and accelerates metastasis [ 149 ]. MDSCs in breast cancer show increased secretion of TGF-β, VEGF, and IL-10, which induces EMT and metastasis [ 150 ]. TNBC is characterized by ΔNp63 upregulation, which activates CXCL2 and CCL22 and MDSC recruitment.…”