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.

Chemokine CXCL12 in neurodegenerative diseases: an SOS signal for stem cell-based repair

“…Tumor-secreted CXCL12 recruits peripheral endothelial progenitors to mitotic neovasculature, where the microenvironment influences the differentiation of endothelial progenitors [76]. Consistent with these findings, CXCL12 enhances the release of VEGF from CSCs, leading to tumor-growth-induced angiogenesis [77]. These studies suggest that tumor-associated CXCL12 is an important niche signal for the growth of GBM CSCs (Figure 3).…”

Glioma‐derived macrophage migration inhibitory factor (MIF) promotes mast cell recruitment in a STAT5‐dependent manner

“…Immunofluorescent staining was carried out as described elsewhere (Lindberg et al., 2009; Polajeva et al., 2011) employing primary antibodies against human MC tryptase, hTPS (sc‐33676) and pSTAT5 (sc‐11671, Santa Cruz Biotech, Santa Cruz, USA) and chicken anti‐goat Alexa 488 and donkey anti‐mouse Alexa 555 (Invitrogen, Carlsbad, USA) as secondary antibodies. Identification and quantification of human MCs co‐expressing pSTAT5 was performed.…”

“…Neutralizing experiments were performed in triplicates as described previously (Polajeva et al., 2011) using two MIF antibody concentrations (50 and 0.5 μg/ml; R&D Systems, Abingdon, UK) and control IgG (50 μg/ml; R&D Systems, Abingdon, UK). The selection of concentration range for MIF neutralizing antibodies was based on previous publications (Bernhagen et al., 2007; Ferro et al., 2008).…”

“…At the same time, the prognostic value of MC infiltration into tumors is controversial, since related inflammatory processes can either facilitate or hinder tumor development, depending on the setting. We were the first to report that gliomas also contain MCs (Polajeva et al., 2011). Moreover, we presented evidence suggesting that chemotactic infiltration of MCs into glioma is facilitated by the CXCL12/CXCR4 axis, where CXCL12 is a chemoattractant produced by the glioma itself.…”

Role of Notch, SDF-1 and Mononuclear Cells Recruitment in Angiogenesis

“…It was shown that CXCR4 is expressed on eosinophils [86] and concentrations of SDF-1 correlates with eosinophil recruitment [87]. It is known that SDF-1/CXCR4 signaling has pivotal role in mast cell (MC) recruitment in tumor tissue [88] and that MC produce proangiogenic chemokines in response to SDF-1 [89]. CXCR4+ dendritic cells (DC) promote angiogenesis during embryo implantation in mice [90] and CXCR4 is known as a critical chemokine receptor for migration of plasmacytoid DC [91].…”