scholarly journals Role of tight junctions in the epithelial-to-mesenchymal transition of cancer cells

2020 ◽  
pp. 183503 ◽  
Author(s):  
Daisuke Kyuno ◽  
Akira Takasawa ◽  
Shin Kikuchi ◽  
Ichiro Takemasa ◽  
Makoto Osanai ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tight Junctions ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition

scholarly journals APRIL and BAFF increase breast cancer cell stemness

2017 ◽  
Author(s):  
Vasiliki Pelekanou ◽  
George Notas ◽  
Paraskevi Athanasouli ◽  
Konstantinos Alexakis ◽  
Fotini Kiagiadaki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Breast Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Pluripotency Genes

AbstractRecent advances in cancer immunology revealed immune-related properties of cancer cells as novel promising therapeutic targets. The two TNF superfamily members, APRIL and BAFF even though were primarily studied in lymphocyte maturation, they have also been associated with tumor growth and aggressiveness in a number of solid tumors, including breast cancer. In the present work we studied the effect of APRIL and BAFF on epithelial to mesenchymal transition and migration of breast cancer cells, and their action on the sub-population of cancer stem cells identified by autofluorescence and ALDH activity. Their action on an number of pluripotency genes was examined and breast cancer stem cell ability to form mammospheres was also utilized. The receptor and the signaling pathway involved as well as the role of steroid hormones in their action were also investigated. Our findings show that both APRIL and BAFF increase epithelial to mesenchymal transition and migratory capacity of breast cancer cells, as well as cancer stem cell numbers, by inducing pluripotency genes such as KLF4 and NANOG. These effects are mediated by their common receptor BCMA and the JNK signaling pathway. Interestingly, androgens enhance APRIL transcription and subsequently its pluripotency effect. In conclusion, our data support the significant role of APRIL and BAFF in breast cancer disease progression and provide evidence for a new possible mechanism of therapy resistance, that could be particularly relevant in aromatase inhibitors-treated patients, were local androgen is increased.

scholarly journals Molecular Activation of the Kv11.1 Channel Reprograms EMT in Colon Cancer by Inhibiting TGFβ Signaling via Activation of Calcineurin

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6025
Author(s):  
Najmeh Eskandari ◽  
Vitalyi Senyuk ◽  
Jennifer Moore ◽  
Zane Kalik ◽  
Qiyue Luan ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Vital Role ◽  
Colon Cancer Cells ◽  
Strong Inhibition ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition ◽  
Stimulation Of

Control of ionic gradients is critical to maintain cellular homeostasis in both physiological and pathological conditions, but the role of ion channels in cancer cells has not been studied thoroughly. In this work we demonstrated that activity of the Kv11.1 potassium channel plays a vital role in controlling the migration of colon cancer cells by reversing the epithelial-to-mesenchymal transition (EMT) into the mesenchymal-to-epithelial transition (MET). We discovered that pharmacological stimulation of the Kv11.1 channel with the activator molecule NS1643 produces a strong inhibition of colon cancer cell motility. In agreement with the reversal of EMT, NS1643 treatment leads to a depletion of mesenchymal markers such as SNAIL1, SLUG, TWIST, ZEB, N-cadherin, and c-Myc, while the epithelial marker E-cadherin was strongly upregulated. Investigating the mechanism linking Kv11.1 activity to reversal of EMT into MET revealed that stimulation of Kv11.1 produced a strong and fast inhibition of the TGFβ signaling. Application of NS1643 resulted in de-phosphorylation of the TGFβ downstream effectors R-SMADs by activation of the serine/threonine phosphatase PP2B (calcineurin). Consistent with the role of TGFβ in controlling cancer stemness, NS1643 also produced a strong inhibition of NANOG, SOX2, and OCT4 while arresting the cell cycle in G0/G1. Our data demonstrate that activation of the Kv11.1 channel reprograms EMT into MET by inhibiting TGFβ signaling, which results in inhibition of motility in colon cancer cells.

scholarly journals A flexible network of Vimentin intermediate filaments promotes the migration of amoeboid cancer cells through confined environments

2019 ◽  
Author(s):  
Sara M. Tudor ◽  
Sandrine B. Lavenus ◽  
Jeremy S. Logue
Keyword(s):  
Mechanical Properties ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Human Cancer ◽  
Cell Stiffness ◽  
Mesenchymal Transition ◽  
Human Cancer Cells ◽  
Cell Mechanical Properties ◽  
Metastasis Inhibitor

AbstractThe spread of tumor cells to distant sites is promoted by their ability to switch between mesenchymal and amoeboid (bleb-based) migration. Because of this, inhibitors of metastasis must account for each motility mode. To this end, here we determine the precise role of the Vimentin intermediate filament system in regulating the migration of amoeboid human cancer cells. Vimentin is a classic marker of epithelial to mesenchymal transition and is therefore, an ideal target for a metastasis inhibitor. However, the role of Vimentin in amoeboid migration has not been determined. Since amoeboid, leader bleb-based migration occurs in confined spaces and Vimentin is known to be a major determinant of cell mechanical properties, we hypothesized that a flexible Vimentin network is required for fast amoeboid migration. This was tested using our PDMS slab-based approach for the confinement of cells, RNAi, over-expression, pharmacological treatments, and measurements of cell stiffness. In contrast to Vimentin RNAi, inducing the bundling of Vimentin was found to inhibit fast amoeboid migration and proliferation. Importantly, these effects were independent of changes in actomyosin contractility. Collectively, our data supports a model whereby the perturbation of cell mechanical properties by Vimentin bundling inhibits the invasive properties of cancer cells.

scholarly journals A flexible network of vimentin intermediate filaments promotes migration of amoeboid cancer cells through confined environments

2020 ◽  
Vol 295 (19) ◽  
pp. 6700-6709 ◽  
Author(s):  
Sandrine B. Lavenus ◽  
Sara M. Tudor ◽  
Maria F. Ullo ◽  
Karl W. Vosatka ◽  
Jeremy S. Logue
Keyword(s):  
Mechanical Properties ◽  
Cancer Cells ◽  
Intermediate Filament ◽  
Epithelial To Mesenchymal Transition ◽  
Human Cancer ◽  
Cell Stiffness ◽  
Mesenchymal Transition ◽  
Cell Mechanical Properties ◽  
Vimentin Intermediate Filament

Tumor cells can spread to distant sites through their ability to switch between mesenchymal and amoeboid (bleb-based) migration. Because of this difference, inhibitors of metastasis must account for each migration mode. However, the role of vimentin in amoeboid migration has not been determined. Because amoeboid leader bleb–based migration (LBBM) occurs in confined spaces and vimentin is known to strongly influence cell-mechanical properties, we hypothesized that a flexible vimentin network is required for fast amoeboid migration. To this end, here we determined the precise role of the vimentin intermediate filament system in regulating the migration of amoeboid human cancer cells. Vimentin is a classic marker of epithelial-to-mesenchymal transition and is therefore an ideal target for a metastasis inhibitor. Using a previously developed polydimethylsiloxane slab–based approach to confine cells, RNAi-based vimentin silencing, vimentin overexpression, pharmacological treatments, and measurements of cell stiffness, we found that RNAi-mediated depletion of vimentin increases LBBM by ∼50% compared with control cells and that vimentin overexpression and simvastatin-induced vimentin bundling inhibit fast amoeboid migration and proliferation. Importantly, these effects were independent of changes in actomyosin contractility. Our results indicate that a flexible vimentin intermediate filament network promotes LBBM of amoeboid cancer cells in confined environments and that vimentin bundling perturbs cell-mechanical properties and inhibits the invasive properties of cancer cells.

scholarly journals Role of E2Fs and mitotic regulators controlled by E2Fs in the epithelial to mesenchymal transition

2019 ◽  
Vol 244 (16) ◽  
pp. 1419-1429
Author(s):  
Shirley Jusino ◽  
Harold I Saavedra
Keyword(s):  
Epithelial Cells ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Centrosome Amplification ◽  
Mesenchymal Transition

The epithelial-to-mesenchymal transition (EMT) is a complex cellular process in which epithelial cells acquire mesenchymal properties. EMT occurs in three biological settings: development, wound healing and fibrosis, and tumor progression. Despite occurring in three independent biological settings, EMT signaling shares some molecular mechanisms that allow epithelial cells to de-differentiate and acquire mesenchymal characteristics that confer cells invasive and migratory capacity to distant sites. Here we summarize the molecular mechanism that delineates EMT and we will focus on the role of E2 promoter binding factors (E2Fs) in EMT during tumor progression. Since the E2Fs are presently undruggable due to their control in numerous pivotal cellular functions and due to the lack of selectivity against individual E2Fs, we will also discuss the role of three mitotic regulators and/or mitotic kinases controlled by the E2Fs (NEK2, Mps1/TTK, and SGO1) in EMT that can be useful as drug targets. Impact statement The study of the epithelial to mesenchymal transition (EMT) is an active area of research since it is one of the early intermediates to invasion and metastasis—a state of the cancer cells that ultimately kills many cancer patients. We will present in this review that besides their canonical roles as regulators of proliferation, unregulated expression of the E2F transcription factors may contribute to cancer initiation and progression to metastasis by signaling centrosome amplification, chromosome instability, and EMT. Since our discovery that the E2F activators control centrosome amplification and mitosis in cancer cells, we have identified centrosome and mitotic regulators that may represent actionable targets against EMT and metastasis in cancer cells. This is impactful to all of the cancer patients in which the Cdk/Rb/E2F pathway is deregulated, which has been estimated to be most cancer patients with solid tumors.

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