Myeloid-derived suppressor cells

Background Untreatable metastasis, rather than the primary tumor, is the cause of mortality in breast cancer. Myeloid-derived suppressor cells (MDSCs) are hema-topoetic cells that home specifically to the tumors and have a major role in tumor invasion and metastasis and the development of resistance to chemotherapy. MDSCs proliferate in response to tumors and accumulate in the spleen, from which they can be isolated using their Grl and CDllb surface markers. The objective was to use label-free mass spectrometry and shotgun proteomics to characterize MDSCs that associate with two mouse cell lines derived from the same tumor, one from the primary tumor (67NR) and the other from cells that have already metastasized to various organs (4T1). Spectral counting, for quantification, and protein network analysis were used to search for MDSC biomarkers characteristic to metastasis. 

Ochoa, A.C., Zea, A.H., Hernandez, C., and Rodriguez, PC. (2007). Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin. Cancer Res. 13, 721s-726s. 

Dugast, A.S., Haudebourg, T., Coulon, E, Heslan, M., Haspot, R, Poirier, N., Vuillefroy de, S.R., Usal, C., Smit, H., Martinet, B., Thebault, P, Renaudin, K., and Vanhove, B. (2008). Myeloid-derived suppressor cells accumulate in kidney allograft tolerance and specifically suppress effector T cell expansion. J. Immunol. 180, 7898-7906. 

Serahni, P, Meckel, K., Kelso, M., Noonan, K., Califano, J., Koch, W., Dolcetti, L., Bronte, V., and Borrello, I. (2006). Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J. Exp. Med. 203,2691-2702. 

Deshane, J., Zmijewski, J. W., Lnther, R., et al. (2011). Free radical-producing myeloid-derived regulatory cells Potent activators and suppressors of lung inflammation and airway hyperresponsiveness. Mucosal Immunology, 4(5), 503—518. 

Apoptotic cell death is regulated by NO and ONOO" in several cell types including myeloid-derived leukocytes such as neutrophils. The biological effects of NO and ONOO" have been recently reviewed [68]. GEA3162 is able to promote apoptotic cell death in human neutrophils in a caspase-dependent manner [69]. The tumor suppressor p53 is suggested to play a crucial role in apoptosis induced by oxidants. However, functional p53 is not a requirement for ONOO -mediated cell death, as GEA3162 induces mitochondrial permeability in a p53-deficient murine bone marrow cell line, Jaws II. GEA3162 activates caspases 3 and 2 which are important for apoptosis to proceed, with roles for caspases 8 and 9, and p38 MAP kinase [70]. 

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