Epithelial Mesenchymal-like Transition Research Articles

Enzymatic Activity of CD73 Modulates Invasion of Gliomas via Epithelial-Mesenchymal Transition-Like Reprogramming.

Glioblastoma (GBM) is the most aggressive malignant primary brain tumour in adulthood. Despite strong research efforts current treatment options have a limited impact on glioma stem-like cells (GSCs) which contribute to GBM formation, progression and chemoresistance. Invasive growth of GSCs is in part associated with epithelial–mesenchymal-like transition (EMT), a mechanism associated with CD73 in several cancers. Here, we show that CD73 regulates the EMT activator SNAIL1 and further investigate the role of enzymatic and non-enzymatic CD73 activity in GBM progression. Reduction of CD73 protein resulted in significant suppression of GSC viability, proliferation and clonogenicity, whereas CD73 enzymatic activity exhibited negative effects only on GSC invasion involving impaired downstream adenosine (ADO) signalling. Furthermore, application of phosphodiesterase inhibitor pentoxifylline, a potent immunomodulator, effectively inhibited ZEB1 and CD73 expression and significantly decreased viability, clonogenicity, and invasion of GSC in vitro cultures. Given the involvement of adenosine and A3 adenosine receptor in GSC invasion, we investigated the effect of the pharmacological inhibition of A3AR on GSC maintenance. Direct A3AR inhibition promoted apoptotic cell death and impaired the clonogenicity of GSC cultures. Taken together, our data indicate that CD73 is an exciting novel target in GBM therapy. Moreover, pharmacological interference, resulting in disturbed ADO signalling, provides new opportunities to innovate GBM therapy.

S-Nitrosocaptopril prevents cancer metastasis in vivo by creating the hostile bloodstream microenvironment against circulating tumor cells.

A perfect microenvironment facilitates the activated circulating tumor cells (CTCs) to spark the adhesion-invasion-extravasation metastatic cascade in their premetastatic niche. Platelet-CTC interaction contributes to the progression of tumor malignancy by protecting CTCs from shear stress and immunological assault, aiding CTCs entrapment in the capillary bed, enabling CTCs to successfully exit the bloodstream and enter the tissue, inducing epithelial-mesenchymal-like transition (EMT), and assisting in the establishment of metastatic foci. To prevent the cascade from sparking, we show that, the multifunctional S-nitrosocaptopril (CapNO) acts on both CTCs and platelets to interrupt platelet/CTCs interplay and adhesion to endothelium, thus inhibiting CTC-based pulmonary metastasis in vivo. The activated platelets cloak cancer HT29 cells, resulting in HT29-exhibiting platelet biomarkers CD61 and P-selectin positive. CapNO inhibits both sialyl Lewisx (Slex) expression on HT29 and ADP-induced activation of platelets through P-selectin- and GPIIb/IIIa-dependent mechanisms, confirmed by the corresponding antibody assay. CapNO inhibits platelet- or interleukin (IL)-1β-mediated adhesion between HT29 and endothelial cells, and micrometastatic formation in the lungs of immunocompetent syngeneic mouse models. CapNO have also shown the effects of vasodilation, anticoagulation, inhibition of matrix metalloproteinase-2 (MMP2) expression on cancer cells, and inhibition of cell adhesion molecules (CAMs) expression on vascular endothelium. Due to a series of the beneficial effects of CapNO, CTCs remain exposed to the hostile bloodstream environment and are vulnerable to death induced by shear stress and immune elimination. This new discovery provides a basis for CapNO used for cancer metastatic chemoprevention, and might suggest regulation of the CTCs bloodstream microenvironment as a new avenue for cancer metastatic prevention.

Abstract 288: TGF-beta induced epithelial-to-mesenchymal transition is attenuated when the MNK/eIF4E pathway is functionally impaired.

Abstract The epithelial-mesenchymal-like transition (EMT) is a process enabling epithelial cells to gain the motile characteristics of mesenchymal cells, in a manner resembling metastasis. TGF-beta, via well-defined transcriptional mechanisms, is considered a master regulator of EMT. However, the idea that TGF-beta can regulate the translational machinery to drive EMT remains largely unexplored. The eukaryotic translation initiation factor eIF4E is known to be overexpressed in breast cancer, has been linked to increased invasiveness, and is a promising target for the treatment of breast cancer. Our hypothesis is that phosphorylation of eIF4E stimulated by TGF-beta is required for inducing EMT and metastasis in breast cancer. Our novel preliminary data show that TGF-beta can stimulate eIF4E phosphorylation as normal mammary epithelial cells become mesenchymal. Silencing of eIF4E attenuates molecular and behavioral changes associated with EMT. Moreover, decreasing eIF4E levels can impair TGF-beta induced migration and invasion of ErbB2-expressing breast cancer cells. In keeping with a role of phosphorylated eIF4E in driving the metastatic phenotype, we show that chemically and genetically inhibiting the eIF4E kinase MNK1 attenuates TGF-beta-stimulated EMT. We hypothesized that the expression of master regulators of EMT could be restricted when the eIF4E/MNK pathway is functionally impaired, which prompted us to look at the expression of Twist and Snail in TGF-beta treated eIF4E- and MNK- silenced cells. Our data shows that TGF-beta-induced Snail protein expression, but not mRNA level, is repressed when the MNK/eIF4E pathway is functionally impaired. Our results indicate that MNK and eIF4E are essential for EMT and suggest that therapeutic inhibition of MNK/eIF4E pathway may be a useful strategy for the control of tumor invasion and metastasis. Citation Format: Sonia V. del Rincon, Bonnie Huor, Elaine Ngan, Luca Petruccelli, Peter Siegel, Wilson H. Miller, Jr. TGF-beta induced epithelial-to-mesenchymal transition is attenuated when the MNK/eIF4E pathway is functionally impaired. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 288. doi:10.1158/1538-7445.AM2013-288