S100B Promotes Glioma Growth through Chemoattraction of Myeloid-Derived Macrophages

Abstract

Purpose S100B is member of a multigenic family of Ca2+-binding proteins that is overexpressed by gliomas. Recently, we demonstrated 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 (TAMs). Experimental Design We stably transfected GL261 glioma cell lines with constructs that overexpressed (S100Bhigh) or underexpressed (S100Blow) S100B and compared their growth characteristics to intracranial wild-type (S100Bwt) tumors. Results Downregulation of S100B in gliomas had no impact on cell division in vitro but abrogated tumor growth in vivo. Interestingly, compared to S100Blow tumors, S100Bwt and S100Bhigh 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, RAGE (receptor for advanced glycation end products), 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 CCL2 was upregulated in S100Bhigh tumors. Furthermore, analysis of TCGA’s glioma data bank demonstrated 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.

RAGE Expression in Tumor-Associated Macrophages Promotes Angiogenesis in Glioma

“…In the current study, however, RAGE expression did not inhibit TAM infiltration in gliomas. This finding is consistent with our recent report demonstrating that S100B-mediated promotion of leukocyte trafficking into gliomas was not dependent on RAGE expression in TME, but mediated through upregulation of CCL2 (32). Similarly, Heijmans et al reported that lack of RAGE in colon polyps did not influence MP trafficking, but instead, caused a marked increase in infiltrating mast cells (33).…”

HMGB1, S100 proteins and other RAGE ligands in cancer - markers, mediators and putative therapeutic targets

“…45,69 ) Chronic lymphatic leukemia Drug resistance in leukemia cells asociated with upregulation of glyoxalase I, HMGB1 levels increased in pts with CLL and HMGB1 concentration associated with absolute lymphocyte cell count, CLL cells passively release HMGB1, release of HMGB1 related to the differentiation of nurse-like cells (NLC), S100A8 promotes (through RAGE activation) autophagy of leukemia cells and contributes to the drug resistance of leukemia cells (ref. 35,47 ) Lymphoma S100A2 expression observed in lymphoma biopsies (ref.…”

“…S100B is overexpressed by gliomas and its downregulation of S100B abrogates tumor growth in vivo and is related to higher infiltration with tumor-associated macrophages, stronger inflammatory response and increased vascularity. As RAGE ablation had no effect on the infiltration of gliomas with tumor-associated macrophages, other pathways (possibly CCL2 expression) may be involved and could be targeted 69 . S100B expression may also be a prognostic marker in malignant melanoma 70 .…”

RAGE Mediates S100A7-Induced Breast Cancer Growth and Metastasis by Modulating the Tumor Microenvironment

“…Phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced pro-inflammatory mediators were shown to be decreased in RAGE-deficient mice (7) which suggests that RAGE expression is involved in sustaining inflammation and skin and pancreatic cancer (1-2,7,9). It has also been well documented that RAGE ligands bind to RAGE and activate its downstream signaling mechanisms that fuel chronic inflammatory conditions leading to neoplastic stage (1,12-13). It is interesting to note that there is very low or no RAGE expression in normal tissues, but enhanced expression in chronic inflammation and cancer (2,10).…”