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      Perspectives of small molecule inhibitors of activin receptor-like kinase in anti-tumor treatment and stem cell differentiation

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          Abstract

          Activin receptor-like kinases (ALKs), members of the type I activin receptor family, belong to the serine/threonine kinase receptors of the transforming growth factor-β (TGF-β) superfamily. ALKs mediate the roles of activin/TGF-β in a wide variety of physiological and pathological processes, ranging from cell differentiation and proliferation to apoptosis. For example, the activities of ALKs are associated with an advanced tumor stage in prostate cancer and the chondrogenic differentiation of mesenchymal stem cells. Therefore, potent and selective small molecule inhibitors of ALKs would not only aid in investigating the function of activin/TGF-β, but also in developing treatments for these diseases via the disruption of activin/TGF-β. In recent studies, several ALK inhibitors, including LY-2157299, SB-431542 and A-83-01, have been identified and have been confirmed to affect stem cell differentiation and tumor progression in animal models. This review discusses the therapeutic perspective of small molecule inhibitors of ALKs as drug targets in tumor and stem cells.

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          Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development.

          Charles E. Murry, Gordon Keller (2008)
          The potential to generate virtually any differentiated cell type from embryonic stem cells (ESCs) offers the possibility to establish new models of mammalian development and to create new sources of cells for regenerative medicine. To realize this potential, it is essential to be able to control ESC differentiation and to direct the development of these cells along specific pathways. Embryology has offered important insights into key pathways regulating ESC differentiation, resulting in advances in modeling gastrulation in culture and in the efficient induction of endoderm, mesoderm, and ectoderm and many of their downstream derivatives. This has led to the identification of new multipotential progenitors for the hematopoietic, neural, and cardiovascular lineages and to the development of protocols for the efficient generation of a broad spectrum of cell types including hematopoietic cells, cardiomyocytes, oligodendrocytes, dopamine neurons, and immature pancreatic beta cells. The next challenge will be to demonstrate the functional utility of these cells, both in vitro and in preclinical models of human disease.
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            Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells.

            Laurent David, Christine Mallet, Sabine Mazerbourg … (2007)
            ALK1 is an endothelial-specific type I receptor of the TGFbeta receptor family whose heterozygous mutations cause hereditary hemorrhagic telangiectasia type 2. Although TGFbeta1 and TGFbeta3 have been shown to bind ALK1 under specific experimental conditions, they may not represent the physiological ligands for this receptor. In the present study, we demonstrate that BMP9 induces the phosphorylation of Smad1/5/8 in microvascular endothelial cells, and this phosphorylation lasts over a period of 24 hours. BMP9 also activates the ID1 promoter-derived BMP response element (BRE) in a dose-dependent manner (EC50 = 45 +/- 27 pg/mL), and this activation is abolished by silencing ALK1 expression or addition of ALK1 extracellular domain. Overexpression of endoglin increases the BMP9 response, whereas silencing of both BMPRII and ActRIIA expressions completely abolishes it. BMP10, which is structurally close to BMP9, is also a potent ALK1 ligand. Finally, we demonstrate that BMP9 and BMP10 potently inhibit endothelial cell migration and growth, and stimulate endothelial expression of a panel of genes that was previously reported to be activated by the constitutively active form of ALK1. Taken together, our results suggest that BMP9 and BMP10 are two specific ALK1 ligands that may physiologically trigger the effects of ALK1 on angiogenesis.
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              Development of definitive endoderm from embryonic stem cells in culture.

              Marion Kennedy, Atsushi Kubo, Katsunori Shinozaki … (2004)
              The cellular and molecular events regulating the induction and tissue-specific differentiation of endoderm are central to our understanding of the development and function of many organ systems. To define and characterize key components in this process, we have investigated the potential of embryonic stem (ES) cells to generate endoderm following their differentiation to embryoid bodies (EBs) in culture. We found that endoderm can be induced in EBs, either by limited exposure to serum or by culturing in the presence of activin A (activin) under serum-free conditions. By using an ES cell line with the green fluorescent protein (GFP) cDNA targeted to the brachyury locus, we demonstrate that endoderm develops from a brachyury(+) population that also displays mesoderm potential. Transplantation of cells generated from activin-induced brachyury(+) cells to the kidney capsule of recipient mice resulted in the development of endoderm-derived structures. These findings demonstrate that ES cells can generate endoderm in culture and, as such, establish this differentiation system as a unique murine model for studying the development and specification of this germ layer.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Med Rep
                Journal ID (iso-abbrev): Mol Med Rep
                Title: Molecular Medicine Reports
                Publisher: D.A. Spandidos
                ISSN (Print): 1791-2997
                ISSN (Electronic): 1791-3004
                Publication date (Print): June 2019
                Publication date (Electronic): 30 April 2019
                Publication date PMC-release: 30 April 2019
                Volume: 19
                Issue: 6
                Pages: 5053-5062
                Affiliations
                [1 ]Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
                [2 ]Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
                Author notes
                Correspondence to: Professor Zhonghui Liu or Dr Yan Qi, Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, Jilin 130021, P.R. China, E-mail: liuzh@ 123456jlu.edu.cn , E-mail: qiyan@ 123456jlu.edu.cn
                Article
                Publisher ID: mmr-19-06-5053
                DOI: 10.3892/mmr.2019.10209
                PMC ID: 6522871
                PubMed ID: 31059090
                SO-VID: bb185a21-1857-4954-bbcd-59328569509b
                Copyright © Copyright: © Cui et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                Date received : 06 September 2018
                Date accepted : 21 March 2019
                Categories
                Subject: Review

                Keywords: activin receptor-like kinases,inhibitor,cancer,stem cells
                Data availability:
                Keywords: activin receptor-like kinases, inhibitor, cancer, stem cells

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