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      The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities

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          Abstract

          The evolutionarily conserved Wnt signaling pathway plays a central role in development and adult tissue homeostasis across species. Wnt proteins are secreted, lipid-modified signaling molecules that activate the canonical (β-catenin dependent) and non-canonical (β-catenin independent) Wnt signaling pathways. Cellular behaviors such as proliferation, differentiation, maturation, and proper body-axis specification are carried out by the canonical pathway, which is the best characterized of the known Wnt signaling paths. Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues. This includes but is not limited to embryonic, hematopoietic, mesenchymal, gut, neural, and epidermal stem cells. Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties. Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders. Not surprisingly, aberrant Wnt signaling is also associated with a wide variety of diseases, including cancer. Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation, epithelial–mesenchymal transition, and metastasis. Altogether, advances in the understanding of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway. Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt, this review aims to summarize the current knowledge of Wnt signaling in stem cells, aberrations to the Wnt pathway associated with diseases, and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.

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          Accessories to the crime: functions of cells recruited to the tumor microenvironment.

          Mutationally corrupted cancer (stem) cells are the driving force of tumor development and progression. Yet, these transformed cells cannot do it alone. Assemblages of ostensibly normal tissue and bone marrow-derived (stromal) cells are recruited to constitute tumorigenic microenvironments. Most of the hallmarks of cancer are enabled and sustained to varying degrees through contributions from repertoires of stromal cell types and distinctive subcell types. Their contributory functions to hallmark capabilities are increasingly well understood, as are the reciprocal communications with neoplastic cancer cells that mediate their recruitment, activation, programming, and persistence. This enhanced understanding presents interesting new targets for anticancer therapy. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Wnt/beta-catenin signaling: components, mechanisms, and diseases.

            Signaling by the Wnt family of secreted glycolipoproteins via the transcriptional coactivator beta-catenin controls embryonic development and adult homeostasis. Here we review recent progress in this so-called canonical Wnt signaling pathway. We discuss Wnt ligands, agonists, and antagonists, and their interactions with Wnt receptors. We also dissect critical events that regulate beta-catenin stability, from Wnt receptors to the cytoplasmic beta-catenin destruction complex, and nuclear machinery that mediates beta-catenin-dependent transcription. Finally, we highlight some key aspects of Wnt/beta-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis, and discuss potential therapeutic implications.
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              Identification of c-MYC as a target of the APC pathway.

              The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that is inactivated in most colorectal cancers. Mutations of APC cause aberrant accumulation of beta-catenin, which then binds T cell factor-4 (Tcf-4), causing increased transcriptional activation of unknown genes. Here, the c-MYC oncogene is identified as a target gene in this signaling pathway. Expression of c-MYC was shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c-MYC promoter. These results provide a molecular framework for understanding the previously enigmatic overexpression of c-MYC in colorectal cancers.
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                Author and article information

                Contributors
                Journal
                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                2352-4820
                2352-3042
                22 July 2023
                May 2024
                22 July 2023
                : 11
                : 3
                : 101026
                Affiliations
                [a ]School of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
                [b ]Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
                [c ]Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
                [d ]Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
                [e ]Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
                [f ]Department of Clinical Laboratory Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
                [g ]Department of Orthopaedic Surgery, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
                [h ]Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
                [i ]Department of Neurology, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong 523475, China
                Author notes
                []Corresponding author. Molecular Oncology Laboratory, The University of Chicago Medical Center, 5841 South Maryland Avenue, MC3079, Chicago, IL 60637, USA. Fax: +1 773 834 4598. tche@ 123456uchicago.edu
                [∗∗ ]Corresponding author. Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, 5841 S. Maryland Ave., Rm. J-641, MC 6035, Chicago, IL 60637, USA. Fax: +1 773 702 1634. rreid@ 123456surgery.bsd.uchicago.edu
                [1]

                These authors contributed equally to the work.

                Article
                S2352-3042(23)00294-5 101026
                10.1016/j.gendis.2023.04.042
                10825312
                38292186
                a590a401-9f09-4190-af42-320d340428c0
                © 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 23 August 2022
                : 18 March 2023
                : 12 April 2023
                Categories
                Review Article

                β-catenin,cancer,canonical wnt,disease,non-canonical wnt,stem cells,targeted therapy,wnt signaling

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