β2-Microglobulin Induces Epithelial to Mesenchymal Transition and Confers Cancer Lethality and Bone Metastasis in Human Cancer Cells

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.

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Human Cancer Cells Express Slug-based Epithelial-Mesenchymal Transition Gene Signature Obtained in Vivo

Nature Precedings ◽

10.1038/npre.2011.6243.1 ◽

2011 ◽

Author(s):

Jessica Kandel ◽

Dimitris Anastassiou ◽

Viktoria Rumjantseva ◽

Wei-yi Cheng ◽

Jianzhong Huang ◽

...

Keyword(s):

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Human Cancer ◽

Gene Signature ◽

Mesenchymal Transition ◽

Human Cancer Cells

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EMT reversal in human cancer cells after IR knockdown in hyperinsulinemic mice

Endocrine Related Cancer ◽

10.1530/erc-16-0142 ◽

2016 ◽

Vol 23 (9) ◽

pp. 747-758 ◽

Cited By ~ 14

Author(s):

Zara Zelenko ◽

Emily Jane Gallagher ◽

Irini Markella Antoniou ◽

Deepali Sachdev ◽

Anupma Nayak ◽

...

Keyword(s):

Insulin Receptor ◽

Cancer Cells ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Human Cancer ◽

Mortality Data ◽

Primary Tumors ◽

Mesenchymal Transition ◽

Insulin Resistant ◽

Human Cancer Cells

Type 2 diabetes (T2D) is associated with increased cancer risk and cancer-related mortality. Data herein show that we generated an immunodeficient hyperinsulinemic mouse by crossing theRag1−/−mice, which have no mature B or T lymphocytes, with the MKR mouse model of T2D to generate theRag1−/−(Rag/WT) andRag1−/−/MKR+/+(Rag/MKR) mice. The female Rag/MKR mice are insulin resistant and have significantly higher nonfasting plasma insulin levels compared with the Rag/WT controls. Therefore, we used these Rag/MKR mice to investigate the role of endogenous hyperinsulinemia on human cancer progression. In this study, we show that hyperinsulinemia in the Rag/MKR mice increases the expression of mesenchymal transcription factors,TWIST1andZEB1, and increases the expression of the angiogenesis marker, vascular endothelial growth factor A (VEGFA). We also show that silencing the insulin receptor (IR) in the human LCC6 cancer cells leads to decreased tumor growth and metastases, suppression of mesenchymal markers vimentin, SLUG, TWIST1 and ZEB1, suppression of angiogenesis markers,VEGFAandVEGFD, and re-expression of the epithelial marker, E-cadherin. The data in this paper demonstrate that IR knockdown in primary tumors partially reverses the growth-promoting effects of hyperinsulinemia as well as highlighting the importance of the insulin receptor signaling pathway in cancer progression, and more specifically in epithelial–mesenchymal transition.

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MicroRNA-21 inhibitor potentiates anti-tumor effect of radiation therapy in vitro and in vivo

Tumor Microenvironment and Therapy ◽

10.2478/tumor-2014-0001 ◽

2014 ◽

Vol 2 (1) ◽

pp. 1-13 ◽

Cited By ~ 3

Author(s):

Bong Jun Cho ◽

Hans H. Kim ◽

David J Lee ◽

Eun Jung Choi ◽

Yeo Hyun Hwang ◽

...

Keyword(s):

Radiation Therapy ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Human Cancer ◽

Combined Treatment ◽

A549 Cells ◽

Specific Inhibitor ◽

Tumor Burden ◽

Mesenchymal Transition ◽

Human Cancer Cells

AbstractMicroRNA-21 (miR-21) plays important roles in carcinogenesis and is highly expressed in diverse human cancers. We evaluated the potential of targeting miRNA-21 to overcome the radioresistance of human cancer cells having an activated EGFR2-associated signaling and also aimed to elucidate the mechanisms of radiosensitization, and the effect on epithelial- mesenchymal transition (EMT). Ectopic overexpression of miR-21 up-regulated EGFR/HER2-associated signaling and increased radioresistance of a panel of human cancer cells (U251, U87, and A549 cells). In contrast, a specific inhibitor of miR-21 attenuated this signaling and radiosensitized a panel of human cancer cells. Inhibition of miR-21 was associated with persistent γH2AX foci formation. Inhibition of miR-21 decreased the typical features of EMT, such as invasion and migration and vascular tube formation. Treatment with anti-miR-21 decreased tumor burden in nude mice bearing intracranial U251 xenografts compared to controls. Combined treatment of anti-miR-21 and radiation further decreased tumor burden compared to each treatment alone. In summary, miR-21 is an important onco-miR, which confers radioresistance and diverse features of EMT. Inhibition of miR-21 could be a potential strategy for improving the efficacy of radiation therapy via unique modulation of pro-survival signaling implicated in radiation response and EMT.

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Abstract 343: Inhibitory effect of oncolytic adenovirus on transforming growth factor- β-induced epithelial-mesenchymal transition in human cancer cells

10.1158/1538-7445.am2012-343 ◽

2012 ◽

Author(s):

Yuuri Hashimoto ◽

Hiroshi Tazawa ◽

Yasuo Urata ◽

Shunsuke Kagawa ◽

Toshiyoshi Fujiwara

Keyword(s):

Growth Factor ◽

Cancer Cells ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Human Cancer ◽

Transforming Growth Factor Β ◽

Inhibitory Effect ◽

Oncolytic Adenovirus ◽

Mesenchymal Transition ◽

Human Cancer Cells

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Epithelial-Mesenchymal Transition Stimulates Human Cancer Cells to Extend Microtubule-based Invasive Protrusions and Suppresses Cell Growth in Collagen Gel

PLoS ONE ◽

10.1371/journal.pone.0053209 ◽

2012 ◽

Vol 7 (12) ◽

pp. e53209 ◽

Cited By ~ 45

Author(s):

Jun Oyanagi ◽

Takashi Ogawa ◽

Hiroki Sato ◽

Shouichi Higashi ◽

Kaoru Miyazaki

Keyword(s):

Cell Growth ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Human Cancer ◽

Collagen Gel ◽

Mesenchymal Transition ◽

Human Cancer Cells

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A chemical screen based on an interruption of zebrafish gastrulation identifies the HTR2C inhibitor Pizotifen as a suppressor of EMT-mediated metastasis

eLife ◽

10.7554/elife.70151 ◽

2021 ◽

Vol 10 ◽

Author(s):

Joji Nakayama ◽

Lora Tan ◽

Yan Li ◽

Boon Cher Goh ◽

Shu Wang ◽

...

Keyword(s):

Wnt Signaling ◽

Cancer Cells ◽

High Throughput Screening ◽

Serotonin Receptor ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Human Cancer ◽

Metastatic Progression ◽

Mesenchymal Transition ◽

Chemical Screen

Metastasis is responsible for approximately 90% of cancer-associated mortality but few models exist that allow for rapid and effective screening of anti-metastasis drugs. Current mouse models of metastasis are too expensive and time consuming to use for rapid and high-throughput screening. Therefore, we created a unique screening concept utilizing conserved mechanisms between zebrafish gastrulation and cancer metastasis for identification of potential anti-metastatic drugs. We hypothesized that small chemicals that interrupt zebrafish gastrulation might also suppress metastatic progression of cancer cells and developed a phenotype-based chemical screen to test the hypothesis. The screen used epiboly, the first morphogenetic movement in gastrulation, as a marker and enabled 100 chemicals to be tested in five hours. The screen tested 1280 FDA-approved drugs and identified Pizotifen, an antagonist for serotonin receptor 2C (HTR2C) as an epiboly-interrupting drug. Pharmacologic and genetic inhibition of HTR2C suppressed metastatic progression in a mouse model. Blocking HTR2C with Pizotifen restored epithelial properties to metastatic cells through inhibition of Wnt-signaling. In contrast, HTR2C induced epithelial to mesenchymal transition (EMT) through activation of Wnt-signaling and promoted metastatic dissemination of human cancer cells in a zebrafish xenotransplantation model. Taken together, our concept offers a novel platform for discovery of anti-metastasis drugs.

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