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.
Highlights
Gliomas are the most frequent primary brain tumors of adults that are classified into grades I–IV based on malignancy
Immune infiltration of gliomas was recognized as one of the processes following the development of advanced gliomas, and it has been demonstrated that gliomas are infiltrated by microglia, CD4 and CD8 T lymphocytes, and natural killer (NK) cells [4,5]
In previous studies it has been shown that the absence of either of the key tumor suppressors Ink4a or Arf in Ntv-a and Gtv-a transgenic mice yields tumors upon infection with the combination of RCASKRas + RCAS-Akt
Summary
Gliomas are the most frequent primary brain tumors of adults that are classified into grades I–IV based on malignancy. Hallmarks of glioma include disruption of the blood brain barrier (BBB) and aberrant invasiveness. Disruption of the BBB occurs in high-grade gliomas, is associated with abnormal neovasculature and extreme vessel leakiness, which promote expansion of GBM [2]. At the site of tumor growth, is a potent cancer promoter and results in induction of angiogenesis, tissue remodeling and immune modulation. Many human cancers, including gliomas, instruct and maintain a complex inflammatory program that, among other effects, triggers rapid recruitment of inflammatory cells to the tumor site. The exact contribution of the immune system in tumorigenesis is still not clear
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