Open AccessFibroblast growth factor signals regulate transforming growth factor‐β‐induced endothelial‐to‐myofibroblast transition of tumor endothelial cells via Elk1
Author(s) -
Akatsu Yuichi,
Takahashi Naoya,
Yoshimatsu Yasuhiro,
Kimuro Shiori,
Muramatsu Tomoki,
Katsura Akihiro,
Maishi Nako,
Suzuki Hiroshi I.,
Inazawa Johji,
Hida Kyoko,
Miyazono Kohei,
Watabe Tetsuro
Publication year - 2019
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12504
Subject(s) - myofibroblast , microbiology and biotechnology , paracrine signalling , transforming growth factor , mesenchymal stem cell , fibroblast growth factor , epithelial–mesenchymal transition , cancer research , tumor microenvironment , fibroblast , biology , transforming growth factor beta , chemistry , transition (genetics) , cell culture , pathology , fibrosis , medicine , tumor cells , biochemistry , receptor , genetics , gene
The tumor microenvironment contains various components, including cancer cells, tumor vessels, and cancer‐associated fibroblasts, the latter of which are comprised of tumor‐promoting myofibroblasts and tumor‐suppressing fibroblasts. Multiple lines of evidence indicate that transforming growth factor‐β ( TGF ‐β) induces the formation of myofibroblasts and other types of mesenchymal (non‐myofibroblastic) cells from endothelial cells. Recent reports show that fibroblast growth factor 2 ( FGF 2) modulates TGF ‐β‐induced mesenchymal transition of endothelial cells, but the molecular mechanisms behind the signals that control transcriptional networks during the formation of different groups of fibroblasts remain largely unclear. Here, we studied the roles of FGF 2 during the regulation of TGF ‐β‐induced mesenchymal transition of tumor endothelial cells ( TEC s). We demonstrated that auto/paracrine FGF signals in TEC s inhibit TGF ‐β‐induced endothelial‐to‐myofibroblast transition (End‐MyoT), leading to suppressed formation of contractile myofibroblast cells, but on the other hand can also collaborate with TGF ‐β in promoting the formation of active fibroblastic cells which have migratory and proliferative properties. FGF 2 modulated TGF ‐β‐induced formation of myofibroblastic and non‐myofibroblastic cells from TEC s via transcriptional regulation of various mesenchymal markers and growth factors. Furthermore, we observed that TEC s treated with TGF ‐β were more competent in promoting in vivo tumor growth than TEC s treated with TGF ‐β and FGF 2. Mechanistically, we showed that Elk1 mediated FGF 2‐induced inhibition of End‐MyoT via inhibition of TGF ‐β‐induced transcriptional activation of α‐smooth muscle actin promoter by myocardin‐related transcription factor‐A. Our data suggest that TGF ‐β and FGF 2 oppose and cooperate with each other during the formation of myofibroblastic and non‐myofibroblastic cells from TEC s, which in turn determines the characteristics of mesenchymal cells in the tumor microenvironment.