Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/ijms22031046
Keywords
glioblastoma; tumor microenvironment; transforming growth factor beta; fibroblast activation protein; seprase; regulation of expression; Smad2; signaling
Funding
- Ministry of Health of the Czech Republic [1531379A]
- Ministry of Education, Youth and Sports of the Czech Republic of the EATRIS-CZ [LM2015064]
- project Center of Tumor Ecology - Operational Program Research, Development and Education of the Ministry of Education, Youth and Sports, Czech Republic [CZ.02.1.01/0.0/0.0/16_019/0000785]
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The study demonstrates a significant positive correlation between TGFbeta and FAP in glioblastomas, with TGFbeta-1 promoting FAP expression in various cell types present in the glioblastoma microenvironment. The effect is mediated by TGFbeta-1 secreted by glioma cells and involves activation of FAP gene transcription.
The proline-specific serine protease fibroblast activation protein (FAP) can participate in the progression of malignant tumors and represents a potential diagnostic and therapeutic target. Recently, we demonstrated an increased expression of FAP in glioblastomas, particularly those of the mesenchymal subtype. Factors controlling FAP expression in glioblastomas are unknown, but evidence suggests that transforming growth factor beta (TGFbeta) can trigger mesenchymal changes in these tumors. Here, we investigated whether TGFbeta promotes FAP expression in transformed and stromal cells constituting the glioblastoma microenvironment. We found that both FAP and TGFbeta-1 are upregulated in glioblastomas and display a significant positive correlation. We detected TGFbeta-1 immunopositivity broadly in glioblastoma tissues, including tumor parenchyma regions in the immediate vicinity of FAP-immunopositive perivascular stromal cells. Wedemonstrate for the first time that TGFbeta-1 induces expression of FAP in non-stem glioma cells, pericytes, and glioblastoma-derived endothelial and FAP(+) mesenchymal cells, but not in glioma stem-like cells. In glioma cells, this effect is mediated by the TGFbeta type I receptor and canonical Smad signaling and involves activation of FAP gene transcription. We further present evidence of FAP regulation by TGFbeta-1 secreted by glioma cells. Our results provide insight into the previously unrecognized regulation of FAP expression by autocrine and paracrine TGFbeta-1 signaling in a broad spectrum of cell types present in the glioblastoma microenvironment.
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