Abstract
Abstract The complement system is a vital part of the innate immune system which plays a critical role in immune surveillance and inflammatory processes. Malignant and host cells express various complement inhibitory proteins on their surface to protect against complement mediated cytotoxicity. Imbalanced complement activation triggers inflammation and alters the tumor microenvironment. Complement activation has been shown to induce proliferation and migration of breast, ovarian and lung cancer cells. At this time, the expression and functional role of the complement cascade in glioblastoma (GBM) remain elusive. Here, we investigated the role of complement proteins and their receptor expression in human primary glioma stem-like cells (GSCs) and human GBM tissues. Western blot data demonstrated a high level of expression of central complement components and their receptors in GSCs. RT-PCR data further confirmed the high expression of complement genes which was similar or higher to normal human astrocytes (HA), a cell with high baseline expression levels of complement genes. Flow cytometry analysis revealed that almost 95% of GSCs expressed the anaphylatoxin complement receptors C3aR and C5aR on their cell surfaces which was consistent with our immunohistochemistry analysis of freshly resected GBM tissues. Furthermore, anaphylatoxin C5a exposure increased the proliferation of a subgroup of GSCs while reduced in another subset. Interestingly, C5a exposure was found to increase the expression of various pro-inflammatory markers in GSCs with reduced proliferation. Fluorescence-activated cell sorting (FACS) analysis of freshly isolated human GBM tissue revealed predominant expression of C5aR on cancer cells (CD11b-/CD45- cells) rather than on immune cells. RT-PCR analysis also demonstrated high expression levels of complement genes with concomitant decrease in complement inhibitory genes in human GBM tissue. Evaluation of the differential role of the complement system in GSCs along with their role in in vivo glioma models is ongoing.
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