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Tumor-derived lactadherin as a potential factor responsible for pro-invasive polarization of glioma-associated microglia and macrophages

Pszczolkowska Dominika#, Kijewska Magdalena#, Ellert-Miklaszewska Aleksandra#, Kaminska Bozena#

# Nencki Institute of Experimental Biology, Polish Academy of Science, 3 Pasteur St, 02-093 Warsaw

Malignant gliomas are fast-growing, heterogeneous, invasive brain tumors strongly infiltrated by non-tumor cells. Glioma attracts immune cells, in particular microglia/macrophages (GAMs) and re-program these cells into immunosupresive, tumor-supporting cells. Factors responsible for shaping tumor microenvironment in gliomas are poorly known. We analysed glioma secretome and identified lactadherin (Mfge8) in microglia-activating fraction. Mfge8 is αvβ3/αvβ5 integrin ligand able to interact with receptors present on GAMs and thus could be involved in pro-invasive polarization of these cells. Moreover Mfge8 is overexpressed in glioma cells, but not in non-transformed astrocytes.
C6 glioma cells stably expressing shRNA specific to lactadherin (shMfge8) and negative shRNA (shNeg) were implanted into striatum of Wistar rats. There was no difference in proliferation and viability of C6 cells, C6 shMfge8 and C6 shNeg in vitro, that proves negligible effect of autocrine Mfge8 production on tumor cell growth. Knockdown of Mfge8 resulted in reduction of tumor volume. Immunochemical analysis of brain sections revealed similar number of infiltrating GAMs (Iba1 staining), but reduced number of arginase 1 expressing cells in Mfge8-depleated tumors. However, silencing of Mfge8 does not change blood vessels density in Mfge8-depleted tumors. Our results suggest that lactadherin is important factor in glioma microenvironment shaping and its targeting could be a new therapeutic strategy

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