When the endothelium scores an own goal: endothelial cells actively augment metastatic extravasation through endothelial-mesenchymal transition

Abstract

Endothelial-mesenchymal transition (EndMT) is an important mechanism during organ development and in certain pathological conditions. For example, EndMT contributes to myofibroblast formation during organ fibrosis, and it has been identified as an important source of cancer-associated fibroblasts, facilitating tumor progression. Recently, EndMT was proposed to modulate endothelial function during intravasation and extravasation of metastatic tumor cells. Evidence suggests that endothelial cells are not passive actors during transendothelial migration (TEM) of cancer cells, as there are profound changes in endothelial junctional protein expression, signaling, permeability, and contractility. This review describes these alterations in endothelial characteristics during TEM of metastatic tumor cells and discusses them in the context of EndMT. EndMT could play an important role during metastatic intravasation and extravasation, a novel hypothesis that may lead to new therapeutic approaches to tackle metastatic disease.

A microfluidic platform for modeling metastatic cancer cell matrix invasion

“…[29,53] This evidence of endothelium-facilitated cancer invasion is consistent with studies of invasion in Transwells and other 3D invasion platforms, which report increased invasion (related to both intravasation and extravasation) for cancer cells co-cultured with HUVECs or treated with HUVEC-conditioned media. [54–58] To confirm the relevance and consistency of our findings with the literature, invasion speeds computed from the reported invasion depths over the 24hr observation time were all within the range of accepted speeds for MDA-MB-231 cells in related in vitro matrix invasion studies. [17,29,53,59] In the investigation to reveal non-chemokine-driven mechanisms for this finding, positive IHC staining for fibronectin on the gel surface following endothelial decellularization confirmed previous reports that endothelial monolayers deposit a fibronectin-containing matrix.…”

A new strategy to measure intercellular adhesion forces in mature cell-cell contacts

“…While, to the best of our knowledge, the latter observation has not been reported before in the context of EndMT, it is known that FA formation at the edges of the cell is important to coordinate EC migration41 and that the acquisition of a migratory phenotype is part of the EndMT process48. Alterations in cell stiffness have been reported both for EMT and EndMT that show different tendencies, some indicating an increase and others a decrease49505152. Although we presume cell type and cell malignancy are contributing factors to this differential effect, a deeper understanding of these processes is still required.…”

MRTFs‐ master regulators of EMT

“…During metastatic extravasation, endothelial cells may undergo a TGF‐β1–dependent EndMT induced by cancer cells to enhance transendothelial migration of metastatic cells. Co‐culture with melanoma cells induced expressional changes in HUVECs characteristic to EndMT; in parallel to the expression of EndMT markers HUVECs also expressed higher levels of MRTF‐A and MRTF‐B mRNA when co‐cultured with melanoma cells, as evidenced in the same gene expression dataset (Krizbai et al, ; Gasparics et al, ).…”