Fibroblast growth factor signals regulate transforming growth factor‐β‐induced endothelial‐to‐myofibroblast transition of tumor endothelial cells via Elk1

Abstract

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.

TGF-β-Induced Endothelial to Mesenchymal Transition in Disease and Tissue Engineering

“…Recently, FGF2 was shown to not only inhibit TGF-β-induced endothelial-to-myofibroblast transition (End-MyoT) mediated via the transcription factor ELK1, but also promoted the formation of active fibroblastic cells with migratory and proliferative characteristics. This revealed the opposing and cooperative action between FGF and TGF-β signaling during the modulation of different mesenchymal cell phenotypes (Akatsu et al, 2019). In mouse embryos with ECs deficient in β-catenin, the cardiac cushion had fewer cells, suggesting that β-catenin in ECs is needed for efficient EndMT and invasion of the mesenchymal cells into the cardiac jelly to form cardiac septa and valves.…”

Tumor Endothelial Heterogeneity in Cancer Progression

“…Conversely, recent studies demonstrated that ECs resist specific conversion to alpha-SMA+ myofibroblast-like cells when the cells are challenged with TGFβ through secretion of bFGF [83]. TGFβ and bFGF could oppose and cooperate with each other during EndMT via Elk1 [84]. These data suggest that EndMT is another mechanism producing TEC heterogeneity.…”

TNF‐α enhances TGF‐β‐induced endothelial‐to‐mesenchymal transition via TGF‐β signal augmentation

“…2 We recently reported that transforming growth factor-β (TGF-β) induced the transition from tumor ECs (TECs) to α-smooth muscle actin (αSMA)-positive mesenchymal cells (myofibroblasts), which induced tumor formation more potently than αSMA-negative TEC-derived mesenchymal cells. 5 In addition to formation of CAFs during EndMT, loss of the endothelial barrier of the tumor vasculature can be observed, suggesting an important role of EndMT in facilitating metastatic dissemination. Thus, effective targeting of EndMT is likely to result in the development of novel anti-cancer therapies.…”