期刊
JOURNAL OF CELL SCIENCE
卷 131, 期 1, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.209619
关键词
TGF-beta; EDA plus FN; EDB plus FN; Glioblastoma
类别
资金
- program Highly Specialized Medicine (HSM) 2 of the Canton of Zurich, Switzerland [KFS-3305-08-2013]
- Swiss Cancer League/Oncosuisse [KFS-3305-08-2013]
- EMDO STIFTUNG Zurich [808]
- University of Zurich (UZH Foundation)
- SystemsX.ch
- Swiss initiative for systems biology
Gene splicing profiles are frequently altered in cancer, and the splice variants of fibronectin (FN) that contain the extra-domains A (EDA) or B (EDB), referred to as EDA+FN or EDB+FN, are highly upregulated in tumor vasculature. Transforming growth factor beta (TGF-beta) signaling has been attributed a pivotal role in glioblastoma, with TGF-beta promoting angiogenesis and vessel remodeling. By using immunohistochemistry staining, we observed that the oncofetal FN isoforms EDA+FN and EDB+FN are expressed in glioblastoma vasculature. Ex vivo single-cell gene expression profiling of tumors by using CD31 and alpha-smooth muscle actin (alpha SMA) as markers for endothelial cells, and pericytes and vascular smooth muscle cells (VSMCs), respectively, confirmed the predominant expression of FN, EDA+FN and EDB+FN in the vascular compartment of glioblastoma. Specifically, within the CD31-positive cell population, we identified a positive correlation between the expression of EDA+FN and EDB+FN, and of molecules associated with TGF-beta signaling. Further, TGF-beta induced EDA+FN and EDB+FN in human cerebral microvascular endothelial cells and glioblastoma-derived endothelial cells in a SMAD3- and SMAD4-dependent manner. In turn, we found that FN modulated TGF-beta superfamily signaling in endothelial cells via the EDA and EDB, pointing towards a bidirectional influence of oncofetal FN and TGF-beta superfamily signaling.
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