The ILK-MMP9-MRTF axis is crucial for EndMT differentiation of endothelial cells in a tumor microenvironment

Abstract

Increasing evidence indicates that the tumor microenvironment is a critical factor supporting cancer progression, chemoresistance and metastasis. Recently, cancer-associated fibroblasts (CAFs) have been recognized as a crucial tumor stromal component promoting cancer growth and invasiveness via modulation of the extracellular matrix (ECM) structure, tumor metabolism and immune reprogramming. One of the main sources of CAFs are endothelial cells undergoing the endothelial-mesenchymal transition (EndMT). EndMT is mainly promoted by the Transforming Growth Factor-β (TGF-β) family secreted by tumor cells, though the role of particular members in EndMT regulation remains poorly understood. Our findings demonstrate that TGF-β2 induces mesenchymal transdifferentiation of human microvascular endothelial cells (HMEC-1 cells) to CAF-like cells in association with elongated cell morphology, modulation of stress fiber organization, higher α-SMA protein levels and activation of RhoA and Rac-1 pathways. Such regulation is similar to that observed in cells maintained using conditioned medium from invasive colorectal cancer cell line culture. Furthermore, TGF-β2 stimulation resulted in myocardin-related transcription factor (MRTF) activation and upregulation. Our results demonstrate for the first time that such interaction is sufficient for integrin-linked kinase (ILK) overexpression. ILK upregulation also enhanced MRTF activation via RhoA and Rac-1-MMP9 via inside-out integrin activation. Herein, we propose a new ILK-MMP9-MRTF axis that appears to be critical for EndMT differentiation of endothelial to CAF-like cells. Thus, it might be an attractive target for cancer treatment.

Valproic Acid Induces Endothelial-to-Mesenchymal Transition-Like Phenotypic Switching

“…However, in the heart following injury BNP facilitates neutrophil infiltration and increases the MMP-9 activity, which is the second most up-regulated gene in the qPCR array after VPA treatment to HUVECs. Furthermore, MMP-9 appears to be critical for TGFβ-mediated EndMT differentiation of endothelial to CAF-like cells ( Ciszewski et al, 2017 ). This suggests that BNP and MMP-9 both play role in the processes of extracellular matrix remodeling and wound-healing ( Nakatani et al, 2018 ), which is related to EndMT and fibrosis ( Chen and Frangogiannis, 2013 ).…”

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

“…CAFs secrete TGF-β to promote cancer invasion and metastasis (Xiao et al, 2015). Other CAF-derived factors, such as EGF, FGF, and matrix metalloproteinases (MMPs), have been identified as contributors of cancer progression that promote proliferation and invasion (Mendelsohn and Baselga, 2000;Katoh and Nakagama, 2014;Ciszewski et al, 2017). Interestingly, CAFs may also play a role in awakening dormant cells to induce metastasis (De Wever et al, 2014).…”

TGF-β-Induced Endothelial-Mesenchymal Transition in Fibrotic Diseases

“…Mechanosensitive transcription factors were also found to be involved in EMT. It has been shown that cytoskeletal reorganization leads to MRTF nuclear translocation and induction of epithelial to mesenchymal/myofibroblast transition [ 123 , 124 ]. The transcriptional co-factors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) were shown to promote TGF-β signaling via retaining activated Smad2/3 in the nucleus [ 125 , 126 , 127 ].…”