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      Fighting Thyroid Cancer with Microgravity Research

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          Abstract

          Microgravity in space or simulated by special ground-based devices provides an unusual but unique environment to study and influence tumour cell processes. By investigating thyroid cancer cells in microgravity for nearly 20 years, researchers got insights into tumour biology that had not been possible under normal laboratory conditions: adherently growing cancer cells detach from their surface and form three-dimensional structures. The cells included in these multicellular spheroids (MCS) were not only altered but behave also differently to those grown in flat sheets in normal gravity, more closely mimicking the conditions in the human body. Therefore, MCS became an invaluable model for studying metastasis and developing new cancer treatment strategies via drug targeting. Microgravity intervenes deeply in processes such as apoptosis and in structural changes involving the cytoskeleton and the extracellular matrix, which influence cell growth. Most interestingly, follicular thyroid cancer cells grown under microgravity conditions were shifted towards a less-malignant phenotype. Results from microgravity research can be used to rethink conventional cancer research and may help to pinpoint the cellular changes that cause cancer. This in turn could lead to novel therapies that will enhance the quality of life for patients or potentially develop new preventive countermeasures.

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          Most cited references103

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          Regulation of the actin cytoskeleton in cancer cell migration and invasion.

          Malignant cancer cells utilize their intrinsic migratory ability to invade adjacent tissues and the vasculature, and ultimately to metastasize. Cell migration is the sum of multi-step processes initiated by the formation of membrane protrusions in response to migratory and chemotactic stimuli. The driving force for membrane protrusion is localized polymerization of submembrane actin filaments. Recently, several studies revealed that molecules that link migratory signals to the actin cytoskeleton are upregulated in invasive and metastatic cancer cells. In this review, we summarize recent progress on molecular mechanisms of formation of invasive protrusions used by tumor cells, such as lamellipodia and invadopodia, with regard to the functions of key regulatory proteins of the actin cytoskeleton; WASP family proteins, Arp2/3 complex, LIM-kinase, cofilin, and cortactin.
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            3D tumor spheroid models for in vitro therapeutic screening: a systematic approach to enhance the biological relevance of data obtained

            The potential of a spheroid tumor model composed of cells in different proliferative and metabolic states for the development of new anticancer strategies has been amply demonstrated. However, there is little or no information in the literature on the problems of reproducibility of data originating from experiments using 3D models. Our analyses, carried out using a novel open source software capable of performing an automatic image analysis of 3D tumor colonies, showed that a number of morphology parameters affect the response of large spheroids to treatment. In particular, we found that both spheroid volume and shape may be a source of variability. We also compared some commercially available viability assays specifically designed for 3D models. In conclusion, our data indicate the need for a pre-selection of tumor spheroids of homogeneous volume and shape to reduce data variability to a minimum before use in a cytotoxicity test. In addition, we identified and validated a cytotoxicity test capable of providing meaningful data on the damage induced in large tumor spheroids of up to diameter in 650 μm by different kinds of treatments.
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              Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation.

              Here, we have studied the activity of a novel protein-tyrosine kinase inhibitor that is selective for the Src family of tyrosine kinases. We have focused our study on the effects of this compound on T cell receptor-induced T cell activation, a process dependent on the activity of the Src kinases Lck and FynT. This compound is a nanomolar inhibitor of Lck and FynT, inhibits anti-CD3-induced protein-tyrosine kinase activity in T cells, demonstrates selectivity for Lck and FynT over ZAP-70, and preferentially inhibits T cell receptor-dependent anti-CD3-induced T cell proliferation over non-T cell receptor-dependent phorbol 12-myristate 13-acetate/interleukin-2 (IL-2)-induced T cell proliferation. Interestingly, this compound selectively inhibits the induction of the IL-2 gene, but not the granulocyte-macrophage colony-stimulating factor or IL-2 receptor genes. This compound offers a useful new tool for examining the role of the Lck and FynT tyrosine kinases versus ZAP-70 in T cell activation as well as the role of other Src family kinases in receptor function.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                24 May 2019
                May 2019
                : 20
                : 10
                : 2553
                Affiliations
                [1 ]Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, 39120 Magdeburg, Germany; marcus.krueger@ 123456med.ovgu.de (M.K.); daniela.melnik@ 123456med.ovgu.de (D.M.); sascha.kopp@ 123456med.ovgu.de (S.K.); christoph.buken@ 123456gmx.de (C.B.); markus.wehland@ 123456med.ovgu.de (M.W.); manfred.infanger@ 123456med.ovgu.de (M.I.)
                [2 ]Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark; jaysaha@ 123456biomed.au.dk (J.S.); corydon@ 123456biomed.au.dk (T.J.C.)
                [3 ]Max Planck Institute of Biochemistry, 82152 Martinsried, Germany; jbauer@ 123456biochem.mpg.de
                [4 ]Institute of Aerospace Medicine, Gravitational Biology, German Aerospace Center (DLR), Linder Höhe, 51147 Cologne, Germany; ruth.hemmersbach@ 123456dlr.de
                [5 ]Department of Ophthalmology, Aarhus University Hospital, 8200 Aarhus N, Denmark
                [6 ]Gravitational Biology and Translational Regenerative Medicine, Faculty of Medicine and Mechanical Engineering, Otto von Guericke University, 39120 Magdeburg, Germany
                Author notes
                [* ]Correspondence: dgg@ 123456biomed.au.dk ; Tel.: +45-8716-7693; Fax: +45-8612-8804
                Author information
                https://orcid.org/0000-0003-1120-0246
                Article
                ijms-20-02553
                10.3390/ijms20102553
                6566201
                31137658
                49a06d82-a218-4a23-8d69-7960fe19ee22
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 17 April 2019
                : 23 May 2019
                Categories
                Review

                Molecular biology
                three-dimensional growth,spheroids,aggressiveness,metastasis,signal transduction,cytokines,target

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