title: Mast cell accumulation in glioblastoma with a potential role for stem cell factor and chemokine CXCL12.
abstract: Glioblastoma multiforme (GBM) is the most common and malignant form of glioma with high mortality and no cure. Many human cancers maintain a complex inflammatory program triggering rapid recruitment of inflammatory cells, including mast cells (MCs), to the tumor site. However, the potential contribution of MCs in glioma has not been addressed previously. Here we report for the first time that MCs infiltrate KRas+Akt-induced gliomas, using the RCAS/TV-a system, where KRas and Akt are transduced by RCAS into the brains of neonatal Gtv-a- or Ntv-a transgenic mice lacking Ink4a or Arf. The most abundant MC infiltration was observed in high-grade gliomas of Arf-/- mice. MC accumulation could be localized to the vicinity of glioma-associated vessels but also within the tumor mass. Importantly, proliferating MCs were detected, suggesting that the MC accumulation was caused by local expansion of the MC population. In line with these findings, strong expression of stem cell factor (SCF), i.e. the main MC growth factor, was detected, in particular around tumor blood vessels. Further, glioma cells expressed the MC chemotaxin CXCL12 and MCs expressed the corresponding receptor, i.e. CXCR4, suggesting that MCs could be attracted to the tumor through the CXCL12/CXCR4 axis. Supporting a role for MCs in glioma, strong MC infiltration was detected in human glioma, where GBMs contained significantly higher MC numbers than grade II tumors did. Moreover, human GBMs were positive for CXCL12 and the infiltrating MCs were positive for CXCR4. In conclusion, we provide the first evidence for a role for MCs in glioma.
authors.affiliation: Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Jelena
authors.initials: J
authors.lastname: Põlajeva
authors.forename: Anna M
authors.initials: AM
authors.lastname: Sjösten
authors.forename: Nina
authors.initials: N
authors.lastname: Lager
authors.forename: Marianne
authors.initials: M
authors.lastname: Kastemar
authors.forename: Ida
authors.initials: I
authors.lastname: Waern
authors.forename: Irina
authors.initials: I
authors.lastname: Alafuzoff
authors.forename: Anja
authors.initials: A
authors.lastname: Smits
authors.forename: Bengt
authors.initials: B
authors.lastname: Westermark
authors.forename: Gunnar
authors.initials: G
authors.lastname: Pejler
authors.forename: Lene
authors.initials: L
authors.lastname: Uhrbom
authors.forename: Elena
authors.initials: E
authors.lastname: Tchougounova
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D019089:Stem Cell Factor / Q000378:metabolism*
chemical_list: C417743:Cdkn2a protein, mouse; D054377:Chemokine CXCL12; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019718:Receptors, CXCR4; D019089:Stem Cell Factor; D051057:Proto-Oncogene Proteins c-akt; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)