Endothelial-to-Mesenchymal Transition (EndoMT): Roles in Tumorigenesis, Metastatic Extravasation and Therapy Resistance

Abstract

Cancer cells evolve in a very complex tumor microenvironment, composed of several cell types, among which the endothelial cells are the major actors of the tumor angiogenesis. Today, these cells are also characterized for their plasticity, as endothelial cells have demonstrated their potential to modify their phenotype to differentiate into mesenchymal cells through the endothelial-to-mesenchymal transition (EndoMT). This cellular plasticity is mediated by various stimuli including transforming growth factor-β (TGF-β) and is modulated dependently of experimental conditions. Recently, emerging evidences have shown that EndoMT is involved in the development and dissemination of cancer and also in cancer cell to escape from therapeutic treatment. In this review, we summarize current updates on EndoMT and its main induction pathways. In addition, we discuss the role of EndoMT in tumorigenesis, metastasis, and its potential implication in cancer therapy resistance.

Figure 1

Phenotypic modifications during EndoMT. TGF-β (transforming growth factor-β); ROS (reactive oxygen species); VE cadherin (vascular endothelial cadherin); vWF (vonWillebrand factor); FSP-1 (fibroblast-specific protein-1); α-SMA (α-smooth muscle actin).

Figure 2

Transforming growth factor-β- (TGF-β-) induced EndoMT. Upon stimulation by TGF-β1, -2, or -3, type-2 TGF-β receptors phosphorylate ALK5 (type-1 TGF-B receptor) and associate into a heterotetrameric structure which induce Smad-2/3/4 complex formation and translocation to the nucleus. Stimulation by TGF-β1 or -3 induces a paracrine loop toward a TGF-β2 stimulation. Smad-7 acts as an inhibitor of Smad association and serves as a negative retro control. TGF-β signaling also induces phosphorylation of ERK 1/2 (extracellular signal-regulated kinases 1/2) and p38 MAPK (p38 mitogen-activated protein kinase). The BMP receptors can also trigger upon stimulation by the BMP ligand canonical Smad pathway and non-canonical ERK pathway. Inside the nucleus, all actors involved stimulate the activity of the transcription factor, mainly Snail, Slug, and Twist, thus initiating EndoMT by promoting transcription of mesenchymal markers and diminishing transcription of endothelial markers. TGF-β signaling crosstalk with several others pathways, including Notch which promotes ERK 1/2 activity and Akt2 isoform activity which will then inhibit GSK-3β. GSK-3β, ERK, PI3K, P38, and also CDK4 can phosphorylate Smad-2 and -3 on specific residues in its linker region (in red) promoting Smad signaling in a canonical-independent manner. However, it is worth to note that some studies report the inhibiting effect of linker region phosphorylation, and that the specific effects of this phosphorylation site seem to be cell-type dependent.

Figure 3

Wnt induction of EndoMT. Wnt bound the extracellular part of the Frizzled receptor, while LRP5/6 serves as co-receptors. This causes the complex Axin-GSK-3β to bind to the cytoplasmic tail of LRP5/6. Therefore, this complex is no longer able to assure the degradation of β-catenin, which accumulates in the cytoplasm and translocates into the nucleus to stimulate the activity of transcription factors of the TCF/LEF families. The Wnt pathway crosstalk with several other pathways: Akt 2 can phosphorylate and thus inhibit GSK-3β. Moreover, RSK phosphorylation ERK 1/2-dependent RSK phosphorylation leads to inhibition of GSK-3β.

Figure 4

Notch induction of EndoMT. Notch receptors' family interacts with diverse ligands via a cell-to-cell contact mechanism. The signal is mediated by the Notch intracellular domain (NICD) through the nucleus to activate a complex of inducers (RBPJ/CBF1/Su(H)) which in turn activates the transcription of genes implicated in EndoMT. This complex also stabilizes the Snail protein. The Notch pathway crosstalks with several other pathways: NICD increases the Akt 2 expression which inhibits GSK-3β. NICD also activates ERK 1/2, which activates RSK leading to GSK-3β downregulation. The nuclear Notch complex also interacts with β-catenin, increasing its transcription activity.