title: Glioma-derived versican promotes tumor expansion via glioma-associated microglial/macrophages Toll-like receptor 2 signaling.
abstract: Accumulation and infiltration of microglia/brain macrophages around and into glioma tissue promote tumor invasion and expansion. One tumor-promoting mechanism of microglia/brain macrophages is upregulation of membrane type 1 matrix metalloprotease (MT1-MMP), which promotes the degradation of extracellular matrix. MT1-MMP upregulation is induced by soluble factors released by glioma cells activating microglial Toll-like receptor 2 (TLR2).
  
  
  
  Versican identified by proteomics was silenced in glioma cells by short interference RNA and short hairpin RNA approaches and studied in vitro and after injection into mouse brains or organotypic brain slices.
  
  
  
  The splice variants V0/V1 of the endogenous TLR2 ligand versican are highly expressed in mouse and human glioma tissue. Versican-silenced gliomas induced less MT1-MMP expression in microglia both in vitro and in vivo, which resulted in smaller tumors and longer survival rates as compared with controls. Recombinant versican V1 induced significantly higher levels of MT1-MMP in wild-type microglia compared with untreated and treated TLR2 knockout microglial cells. Using glioma-injected organotypic brain slices, we found that the impact of versican signaling on glioma growth depended on the presence of microglia. Moreover, we found that TLR2 expression is upregulated in glioma-associated microglia but not in astrocytes. Additionally, an established TLR2 neutralizing antibody reduced glioma-induced microglial MT1-MMP expression as well as glioma growth ex vivo.
  
  
  
  Our results show that versican released from glioma promotes tumor expansion through glioma-associated microglial/macrophage TLR2 signaling and subsequent expression of MT1-MMP. This signaling cascade might be a novel target for glioma therapies.
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.H., O.D.a D., A.H., S.A.W., H.K.); Cancer Genetics and Cellular Stress Responses, Max Delbrück Center for Molecular Medicine, Berlin, Germany (Y.Y.); Mass Spectrometry, Max Delbrück Center for Molecular Medicine, Berlin, Germany (R.J.S., G.D.); Robinson Institute, University of Adelaide, Adelaide, Australia (A.K.K., K.R.D., C.R.); Department of Neuropathology, Charité Medical University, Berlin, Germany (J.L.R., F.L.H.); Department of Neurology and Center for Anatomy, Charité Medical University, Berlin, Germany (S.L.); Department of Neurosurgery, Charité Medical University, 13353 Berlin, Germany (M.S.)Present affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, People's Republic of China (F.H.).
authors.forename: Feng
authors.initials: F
authors.lastname: Hu
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.H., O.D.a D., A.H., S.A.W., H.K.); Cancer Genetics and Cellular Stress Responses, Max Delbrück Center for Molecular Medicine, Berlin, Germany (Y.Y.); Mass Spectrometry, Max Delbrück Center for Molecular Medicine, Berlin, Germany (R.J.S., G.D.); Robinson Institute, University of Adelaide, Adelaide, Australia (A.K.K., K.R.D., C.R.); Department of Neuropathology, Charité Medical University, Berlin, Germany (J.L.R., F.L.H.); Department of Neurology and Center for Anatomy, Charité Medical University, Berlin, Germany (S.L.); Department of Neurosurgery, Charité Medical University, 13353 Berlin, Germany (M.S.)Present affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, People's Republic of China (F.H.).
authors.forename: Omar Dildar
authors.initials: O
authors.lastname: Dzaye
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.H., O.D.a D., A.H., S.A.W., H.K.); Cancer Genetics and Cellular Stress Responses, Max Delbrück Center for Molecular Medicine, Berlin, Germany (Y.Y.); Mass Spectrometry, Max Delbrück Center for Molecular Medicine, Berlin, Germany (R.J.S., G.D.); Robinson Institute, University of Adelaide, Adelaide, Australia (A.K.K., K.R.D., C.R.); Department of Neuropathology, Charité Medical University, Berlin, Germany (J.L.R., F.L.H.); Department of Neurology and Center for Anatomy, Charité Medical University, Berlin, Germany (S.L.); Department of Neurosurgery, Charité Medical University, 13353 Berlin, Germany (M.S.)Present affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, People's Republic of China (F.H.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Hahn
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.H., O.D.a D., A.H., S.A.W., H.K.); Cancer Genetics and Cellular Stress Responses, Max Delbrück Center for Molecular Medicine, Berlin, Germany (Y.Y.); Mass Spectrometry, Max Delbrück Center for Molecular Medicine, Berlin, Germany (R.J.S., G.D.); Robinson Institute, University of Adelaide, Adelaide, Australia (A.K.K., K.R.D., C.R.); Department of Neuropathology, Charité Medical University, Berlin, Germany (J.L.R., F.L.H.); Department of Neurology and Center for Anatomy, Charité Medical University, Berlin, Germany (S.L.); Department of Neurosurgery, Charité Medical University, 13353 Berlin, Germany (M.S.)Present affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, People's Republic of China (F.H.).
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.H., O.D.a D., A.H., S.A.W., H.K.); Cancer Genetics and Cellular Stress Responses, Max Delbrück Center for Molecular Medicine, Berlin, Germany (Y.Y.); Mass Spectrometry, Max Delbrück Center for Molecular Medicine, Berlin, Germany (R.J.S., G.D.); Robinson Institute, University of Adelaide, Adelaide, Australia (A.K.K., K.R.D., C.R.); Department of Neuropathology, Charité Medical University, Berlin, Germany (J.L.R., F.L.H.); Department of Neurology and Center for Anatomy, Charité Medical University, Berlin, Germany (S.L.); Department of Neurosurgery, Charité Medical University, 13353 Berlin, Germany (M.S.)Present affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, People's Republic of China (F.H.).
authors.forename: Rick Joey
authors.initials: RJ
authors.lastname: Scavetta
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.H., O.D.a D., A.H., S.A.W., H.K.); Cancer Genetics and Cellular Stress Responses, Max Delbrück Center for Molecular Medicine, Berlin, Germany (Y.Y.); Mass Spectrometry, Max Delbrück Center for Molecular Medicine, Berlin, Germany (R.J.S., G.D.); Robinson Institute, University of Adelaide, Adelaide, Australia (A.K.K., K.R.D., C.R.); Department of Neuropathology, Charité Medical University, Berlin, Germany (J.L.R., F.L.H.); Department of Neurology and Center for Anatomy, Charité Medical University, Berlin, Germany (S.L.); Department of Neurosurgery, Charité Medical University, 13353 Berlin, Germany (M.S.)Present affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, People's Republic of China (F.H.).
authors.forename: Gunnar
authors.initials: G
authors.lastname: Dittmar
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.H., O.D.a D., A.H., S.A.W., H.K.); Cancer Genetics and Cellular Stress Responses, Max Delbrück Center for Molecular Medicine, Berlin, Germany (Y.Y.); Mass Spectrometry, Max Delbrück Center for Molecular Medicine, Berlin, Germany (R.J.S., G.D.); Robinson Institute, University of Adelaide, Adelaide, Australia (A.K.K., K.R.D., C.R.); Department of Neuropathology, Charité Medical University, Berlin, Germany (J.L.R., F.L.H.); Department of Neurology and Center for Anatomy, Charité Medical University, Berlin, Germany (S.L.); Department of Neurosurgery, Charité Medical University, 13353 Berlin, Germany (M.S.)Present affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, People's Republic of China (F.H.).
authors.forename: Adrian Kamil
authors.initials: AK
authors.lastname: Kaczmarek
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.H., O.D.a D., A.H., S.A.W., H.K.); Cancer Genetics and Cellular Stress Responses, Max Delbrück Center for Molecular Medicine, Berlin, Germany (Y.Y.); Mass Spectrometry, Max Delbrück Center for Molecular Medicine, Berlin, Germany (R.J.S., G.D.); Robinson Institute, University of Adelaide, Adelaide, Australia (A.K.K., K.R.D., C.R.); Department of Neuropathology, Charité Medical University, Berlin, Germany (J.L.R., F.L.H.); Department of Neurology and Center for Anatomy, Charité Medical University, Berlin, Germany (S.L.); Department of Neurosurgery, Charité Medical University, 13353 Berlin, Germany (M.S.)Present affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, People's Republic of China (F.H.).
authors.forename: Kylie R
authors.initials: KR
authors.lastname: Dunning
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.H., O.D.a D., A.H., S.A.W., H.K.); Cancer Genetics and Cellular Stress Responses, Max Delbrück Center for Molecular Medicine, Berlin, Germany (Y.Y.); Mass Spectrometry, Max Delbrück Center for Molecular Medicine, Berlin, Germany (R.J.S., G.D.); Robinson Institute, University of Adelaide, Adelaide, Australia (A.K.K., K.R.D., C.R.); Department of Neuropathology, Charité Medical University, Berlin, Germany (J.L.R., F.L.H.); Department of Neurology and Center for Anatomy, Charité Medical University, Berlin, Germany (S.L.); Department of Neurosurgery, Charité Medical University, 13353 Berlin, Germany (M.S.)Present affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, People's Republic of China (F.H.).
authors.forename: Carmela
authors.initials: C
authors.lastname: Ricciardelli
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.H., O.D.a D., A.H., S.A.W., H.K.); Cancer Genetics and Cellular Stress Responses, Max Delbrück Center for Molecular Medicine, Berlin, Germany (Y.Y.); Mass Spectrometry, Max Delbrück Center for Molecular Medicine, Berlin, Germany (R.J.S., G.D.); Robinson Institute, University of Adelaide, Adelaide, Australia (A.K.K., K.R.D., C.R.); Department of Neuropathology, Charité Medical University, Berlin, Germany (J.L.R., F.L.H.); Department of Neurology and Center for Anatomy, Charité Medical University, Berlin, Germany (S.L.); Department of Neurosurgery, Charité Medical University, 13353 Berlin, Germany (M.S.)Present affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, People's Republic of China (F.H.).
authors.forename: Jan L
authors.initials: JL
authors.lastname: Rinnenthal
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.H., O.D.a D., A.H., S.A.W., H.K.); Cancer Genetics and Cellular Stress Responses, Max Delbrück Center for Molecular Medicine, Berlin, Germany (Y.Y.); Mass Spectrometry, Max Delbrück Center for Molecular Medicine, Berlin, Germany (R.J.S., G.D.); Robinson Institute, University of Adelaide, Adelaide, Australia (A.K.K., K.R.D., C.R.); Department of Neuropathology, Charité Medical University, Berlin, Germany (J.L.R., F.L.H.); Department of Neurology and Center for Anatomy, Charité Medical University, Berlin, Germany (S.L.); Department of Neurosurgery, Charité Medical University, 13353 Berlin, Germany (M.S.)Present affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, People's Republic of China (F.H.).
authors.forename: Frank L
authors.initials: FL
authors.lastname: Heppner
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.H., O.D.a D., A.H., S.A.W., H.K.); Cancer Genetics and Cellular Stress Responses, Max Delbrück Center for Molecular Medicine, Berlin, Germany (Y.Y.); Mass Spectrometry, Max Delbrück Center for Molecular Medicine, Berlin, Germany (R.J.S., G.D.); Robinson Institute, University of Adelaide, Adelaide, Australia (A.K.K., K.R.D., C.R.); Department of Neuropathology, Charité Medical University, Berlin, Germany (J.L.R., F.L.H.); Department of Neurology and Center for Anatomy, Charité Medical University, Berlin, Germany (S.L.); Department of Neurosurgery, Charité Medical University, 13353 Berlin, Germany (M.S.)Present affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, People's Republic of China (F.H.).
authors.forename: Seija
authors.initials: S
authors.lastname: Lehnardt
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.H., O.D.a D., A.H., S.A.W., H.K.); Cancer Genetics and Cellular Stress Responses, Max Delbrück Center for Molecular Medicine, Berlin, Germany (Y.Y.); Mass Spectrometry, Max Delbrück Center for Molecular Medicine, Berlin, Germany (R.J.S., G.D.); Robinson Institute, University of Adelaide, Adelaide, Australia (A.K.K., K.R.D., C.R.); Department of Neuropathology, Charité Medical University, Berlin, Germany (J.L.R., F.L.H.); Department of Neurology and Center for Anatomy, Charité Medical University, Berlin, Germany (S.L.); Department of Neurosurgery, Charité Medical University, 13353 Berlin, Germany (M.S.)Present affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, People's Republic of China (F.H.).
authors.forename: Michael
authors.initials: M
authors.lastname: Synowitz
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.H., O.D.a D., A.H., S.A.W., H.K.); Cancer Genetics and Cellular Stress Responses, Max Delbrück Center for Molecular Medicine, Berlin, Germany (Y.Y.); Mass Spectrometry, Max Delbrück Center for Molecular Medicine, Berlin, Germany (R.J.S., G.D.); Robinson Institute, University of Adelaide, Adelaide, Australia (A.K.K., K.R.D., C.R.); Department of Neuropathology, Charité Medical University, Berlin, Germany (J.L.R., F.L.H.); Department of Neurology and Center for Anatomy, Charité Medical University, Berlin, Germany (S.L.); Department of Neurosurgery, Charité Medical University, 13353 Berlin, Germany (M.S.)Present affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, People's Republic of China (F.H.).
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Wolf
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany (F.H., O.D.a D., A.H., S.A.W., H.K.); Cancer Genetics and Cellular Stress Responses, Max Delbrück Center for Molecular Medicine, Berlin, Germany (Y.Y.); Mass Spectrometry, Max Delbrück Center for Molecular Medicine, Berlin, Germany (R.J.S., G.D.); Robinson Institute, University of Adelaide, Adelaide, Australia (A.K.K., K.R.D., C.R.); Department of Neuropathology, Charité Medical University, Berlin, Germany (J.L.R., F.L.H.); Department of Neurology and Center for Anatomy, Charité Medical University, Berlin, Germany (S.L.); Department of Neurosurgery, Charité Medical University, 13353 Berlin, Germany (M.S.)Present affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, People's Republic of China (F.H.).
authors.forename: Helmut
authors.initials: H
authors.lastname: Kettenmann
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D053675:Versicans / Q000378:metabolism*
chemical_list: C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C508323:Vcan protein, mouse; D053675:Versicans; D020781:Matrix Metalloproteinase 1
keywords: MT1-MMP; TLR2; glioma; microglia/brain macrophages; versican