title: S100B promotes glioma growth through chemoattraction of myeloid-derived macrophages.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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 Atlas's 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.
authors.affiliation: Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, Shandong Province, PR China.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Wang
authors.forename: Leying
authors.initials: L
authors.lastname: Zhang
authors.forename: Ian Y
authors.initials: IY
authors.lastname: Zhang
authors.forename: Xuebo
authors.initials: X
authors.lastname: Chen
authors.forename: Anna
authors.initials: A
authors.lastname: Da Fonseca
authors.forename: Shihua
authors.initials: S
authors.lastname: Wu
authors.forename: Hui
authors.initials: H
authors.lastname: Ren
authors.forename: Sam
authors.initials: S
authors.lastname: Badie
authors.forename: Sam
authors.initials: S
authors.lastname: Sadeghi
authors.forename: Mao
authors.initials: M
authors.lastname: Ouyang
authors.forename: Charles D
authors.initials: CD
authors.lastname: Warden
authors.forename: Behnam
authors.initials: B
authors.lastname: Badie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002210:Caprylates / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000378:metabolism; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D002633:Chemotaxis; D004789:Enzyme Activation; D005910:Glioma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology; D009368:Neoplasm Transplantation; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D047368:Tumor Burden; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D002210:Caprylates; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D002630:Chemotactic Factors; C459360:ONO2506; D000067759:Receptor for Advanced Glycation End Products; D064568:S100 Calcium Binding Protein beta Subunit; C579159:S100b protein, mouse