S100B Promotes Glioma Growth through Chemoattraction of Myeloid-Derived Macrophages

Purpose: S100B is member of a multigenic family of Ca 2+ -binding proteins, which is overexpressed by gliomas. Recently, we showed that low concentrations of S100B attenuated microglia activation through the induction of Stat3. We hypothesized that overexpression of S100B in gliomas could promote tumor growth by modulating the activity of tumor-associated macrophages (TAM). Experimental Design: We stably transfected GL261 glioma cell lines with constructs that overexpressed (S100B high ) or underexpressed (S100B low ) S100B and compared their growth characteristics to intracranial wild-type (S100B wt ) tumors. Results: Downregulation of S100B in gliomas had no impact on cell division in vitro but abrogated tumor growth in vivo . Interestingly, compared to S100B low tumors, S100B wt and S100B high intracranial gliomas exhibited higher infiltration of TAMs, stronger inflammatory cytokine expression, and increased vascularity. To identify the potential mechanisms involved, the expression of the S100B receptor, receptor for advanced glycation end products (RAGE), was evaluated in gliomas. Although S100B expression induced RAGE in vivo , RAGE ablation in mice did not significantly inhibit TAM infiltration into gliomas, suggesting that other pathways were involved in this process. To evaluate other mechanisms responsible for TAM chemoattraction, we then examined chemokine pathways and found that C-C motif ligand 2 (CCL2) was upregulated in S100B high tumors. Furthermore, analysis of The Cancer Genome Atlas9s glioma data bank showed a positive correlation between S100B and CCL2 expression in human proneural and neural glioma subtypes, supporting our finding. Conclusions: These observations suggest that S100B promotes glioma growth by TAM chemoattraction through upregulation of CCL2 and introduces the potential utility of S100B inhibitors for glioma therapy. Clin Cancer Res; 19(14); 3764–75. ©2013 AACR .