Open AccessTGF-β induces oncofetal fibronectin, which in turn modulates TGF-β superfamily signaling in endothelial cells
Author(s) -
Elisa Ventura,
Michael Weller,
Will Macnair,
Katja Eschbach,
Christian Beisel,
Cinzia Cordazzo,
Manfred Claassen,
Luciano Zardi,
Isabel Burghardt
Publication year - 2017
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.209619
Subject(s) - biology , angiogenesis , transforming growth factor , fibronectin , cd31 , microbiology and biotechnology , transforming growth factor beta , alternative splicing , immunoglobulin superfamily , signal transduction , smad , cancer research , cell adhesion molecule , extracellular matrix , gene isoform , gene , genetics
Gene splicing profiles are frequently altered in cancer, and the splice variants of fibronectin (FN) containing the extra-domains A (EDA) and B (EDB) referred to as EDA+FN and EDB+FN are highly up-regulated in tumor vasculature. TGF-β signaling has been attributed a pivotal role in glioblastoma, with TGF-β promoting angiogenesis and vessel remodeling. By immunohistochemical 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 patients’ tumors using the markers CD31 and alpha-smooth muscle actin (αSMA) 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 trend of positive correlation in the expression of EDA+FN and EDB+FN with molecules associated with TGF-β signaling. Further, TGF-β induced EDA+FN and EDB+FN in human cerebral microvascular endothelial cells and glioblastoma-derived endothelial cells in a SMAD3/SMAD4-dependent manner. In turn, FN modulated TGF-β superfamily signaling in endothelial cells via the EDA and EDB domains, pointing towards a bidirectional influence between oncofetal FN and TGF-β superfamily signaling.