Immune evasion and promoting of tumor vascular formation are essential for tumor growth and metastasis. Myeloid immune suppressor Gr+CD11b+ cells (MISCs) are significantly increased in peripheral blood, spleens and bone marrow of tumor bearing animals and in cancer patients. Unable to process and present antigens, MISCs do not induce effective anti-tumor responses. Very recently, we have demonstrated a novel tumor-promoting role of these immune cells. MISCs infiltrate into tumors and constitute about 5% of total cells in murine tumors. They promote tumor vascular development through two mechanisms promoting tumor angiogenesis via production of proteases and directly incorporated into tumor endothelium and contributed to tumor vascular formation through vasculogenesis. Consistent with this observation, MISCs decrease expression of a cysteine protease inhibitor, neutrophilic granule protein (NGP). Based on these findings, we hypothesize that concerted protein expression, inclusive of proteases, is a strategy used by MISCs to benefit tumor growth through immune suppression, but also by promotion of tumor vascularization and metastasis. This proposal will characterize the candidate protein function in MISC tumor promoting activity, focusing on NGP. I will also determine the specific role of NGP expression and inhibition of a family of cysteine proteases, cathepsins, in tumor growth and angiogenesis.
My specific aims are (1) to identify the MISC molecular mediators that promote breast cancer growth and metastasis using proteomics and (2) to determine the role of NGP and other potential candidate proteins in MISC in breast cancer growth and metastasis. The invasive and proangiogenic role of MISCs induced by metastatic tumors might constitute a critical mechanism by which tumors subvert their host and increase malignancy. Collectively, this data support our hypothesis that tumor derived MISCs display unique molecular signatures such as enhanced cysteine protease expression and activity that favor tumor progression and invasion. In this study, we will continue to identify molecular signatures in MISCs associated with tumor invasion and metastasis using proteomics and in-vivo bioluminescent imaging. Interventions aimed at targeting these cells may improve anti-tumor immune response and concurrently inhibit breast cancer metastasis.
| Boutte, Angela M; McDonald, W Hayes; Shyr, Yu et al. (2011) Characterization of the MDSC proteome associated with metastatic murine mammary tumors using label-free mass spectrometry and shotgun proteomics. PLoS One 6:e22446 |
| Boutte, Angela M; Friedman, David B; Bogyo, Matthew et al. (2011) Identification of a myeloid-derived suppressor cell cystatin-like protein that inhibits metastasis. FASEB J 25:2626-37 |
