Abstract
The emergence of disseminated metastases remains the primary cause of mortality in cancer patients. Formation of the pre-metastatic niche (PMN), which precedes the establishment of tumor lesions, is critical for metastases. Bone marrow-derived myeloid cells (BMDCs) are indispensable for PMN formation. Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells that accumulate in patients with cancer and appear in the early PMN. The mechanisms by which MDSCs establish the pre-metastatic microenvironment in distant organs are largely unknown, although MDSCs play an essential role in metastasis. Here, we summarize the key factors associated with the recruitment and activation of MDSCs in the PMN and review the mechanisms by which MDSCs regulate PMN formation and evolution. Finally, we predict the potential value of MDSCs in PMN detection and therapy.
Highlights
Metastasis remains the leading cause of cancer-related death
In patients with hepatocellular carcinoma, Endoplasmic reticulum (ER) stress promote Lysyl oxidase (LOX)-1+CD15+ GMDSCs expansion and suppress T cell proliferation through reactive oxygen species (ROS)/arginase 1 (Arg-1)(79). These results suggest that significant ER stress in a tumor-bearing host might induce pre-metastatic niche (PMN) formation mediated by enhancement of LDL receptor-1 (LOX-1)+CD15+ G-Myeloid-derived suppressor cells (MDSCs) -mediated suppression
The presented findings show that MDSCderived transforming growth factor-β (TGF-β), S100A8/A9, vascular endothelial growth factor (VEGF), and exosomes promote PMN formation and metastasis through crosslinking with the immune system, fibroblasts, endothelial cells, and hepatic stellate cells
Summary
Metastasis remains the leading cause of cancer-related death. Decades of investigations into cancer metastasis have focused largely on the causes of oncogenic transformation and the incipient emergence of tumors, Stephen Paget proposed the seed-and-soil hypothesis in 1889 [1]. Monocyte chemoattractant protein 1 (MCP1) recruits PMN-MDSCs to the pre-metastatic lung and suppresses NK cell function, which promotes the formation of an immunosuppressive PMN [21].BMDCs express CCL2 to attract MDSCs via CCR2 in hedgehog-induced skin tumors [67]. PMN formation and evolution in original or distant organs remain to be elucidated, MDSCs clearly play an immunosuppressive role through secreting Arg-1, NOS2, IL10, COX2, ROS, TGF-β, PGE2, and IDO, sequestrating active site cysteine, decreasing L-selectin expression, and many other pathways [32].
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