title: Distinctive responses of brain tumor cells to TLR2 ligands.
abstract: Malignant brain tumor mass contains significant numbers of infiltrating glial cells that may intimately interact with tumor cells and influence cancer treatments. Understanding of characteristic discrepancies between normal GLIA and tumor cells would, therefore, be valuable for improving anticancer therapeutics. Here, we report distinct differences in toll-like receptors (TLR)-2-mediated responses between normal glia and primary brain tumor cell lines. We found that tyrosine phosphorylation of STAT1 by TLR2 ligands and its downstream events did not occur in mouse, rat, or human brain tumor cell lines, but were markedly induced in normal primary microglia and astrocytes. Using TLR2-deficient, interferon (IFN)-γ-deficient, and IFNγ-receptor-1-deficient mice, we revealed that the impaired phosphorylation of STAT1 might be linked with defective TLR2 system in tumor cells, and that a TLR2-dependent pathway, not IFNγ-receptor machinery, might be critical for tyrosine STAT1 phosphorylation by TLR2 ligands. We also found that TLR2 and its heterodimeric partners, TLR1 and 6, on brain tumor cells failed to properly respond to TLR2 ligands, and representative TLR2-dependent cellular events, such as inflammatory responses and cell death, were not detected in brain tumor cells. Similar results were obtained in in vitro and in vivo experiments using orthotopic mouse and rat brain tumor models. Collectively, these results suggest that primary brain tumor cells may exhibit a distinctive dysfunction of TLR2-associated responses, resulting in abnormal signaling and cellular events. Careful targeting of this distinctive property could serve as the basis for effective therapeutic approaches against primary brain tumors.
authors: Cancer Immunology Branch, National Cancer Center, Goyang, Korea.
authors: Hee Jung
authors: HJ
authors: Yoon
authors: Sae-Bom
authors: SB
authors: Jeon
authors: Han Seok
authors: HS
authors: Koh
authors: Jae-Young
authors: JY
authors: Song
authors: Sang Soo
authors: SS
authors: Kim
authors: In-Hoo
authors: IH
authors: Kim
authors: Eun Jung
authors: EJ
authors: Park
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D007371:Interferon-gamma; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000473:pathology*; D009457:Neuroglia / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D008024:Ligands; D017471:Receptors, Interferon; D051195:Toll-Like Receptor 2; D000096743:Interferon gamma Receptor; C493486:Tlr2 protein, mouse
keywords: STAT1; TLR2; astrocytes; brain tumor; microglia