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      The generation and use of animal models of osteosarcoma in cancer research

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          Abstract

          Osteosarcoma is the most common malignant bone tumor affecting children and adolescents. Currently, the most common treatment is surgery combined with neoadjuvant chemotherapy. Although the survival rate of patients with osteosarcoma has improved in recent years, it remains poor when the tumor(s) progress and distant metastases develop. Therefore, better animal models that more accurately replicate the natural progression of the disease are needed to develop improved prognostic and diagnostic markers, as well as targeted therapies for both primary and metastatic osteosarcoma. The present review described animal models currently being used in research investigating osteosarcoma, and their characteristics, advantages, and disadvantages. These models may help elucidate the pathogenic mechanism(s) of osteosarcoma and provide evidence to support and develop clinical treatment strategies.

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          Most cited references136

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          Osteosarcoma: Current Treatment and a Collaborative Pathway to Success.

          Osteosarcoma is the bone tumor that most commonly affects children, adolescents, and young adults. Before 1970, treatment primarily included surgical resection. However, the introduction of chemotherapy led to a dramatic improvement in prognosis for patients with localized osteosarcoma; long-term survival rates of less than 20% improved to 65% to 70% after the advent of multiagent chemotherapy regimens. Controversy concerning the ideal combination of chemotherapy agents ensued throughout the last quarter of the 20th century because of conflicting and often nonrandomized data. However, large cooperative group studies and international collaboration have demonstrated that the most effective regimens include the combination of high-dose methotrexate, doxorubicin, and cisplatin (MAP). The introduction of biologic agents such as muramyl tripeptide and the use of additional cytotoxic chemotherapy such as ifosfamide have not definitively improved the survival of patients with osteosarcoma. Collaborative efforts to increase understanding of the biology of osteosarcoma and the use of preclinical models to test novel agents will be critical to identify the path toward improving outcomes for patients. Once promising agents are identified, an international infrastructure exists for clinical trials. Herein, biologic, preclinical, and clinical trial efforts will be described along with future international collaborative strategies to improve outcomes for patients who develop this challenging tumor.
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            Current and future therapeutic approaches for osteosarcoma.

            Current treatment of osteosarcoma includes surgical resection of all gross disease in conjunction with systemic chemotherapy to control micro-metastatic disease. This yields a 5-year event free survival (EFS) of approximately 70% for patients with localized osteosarcoma while patients with metastatic or recurrent disease fare poorly with overall survival rates of less than 20%. Areas covered: This review outlines the current and future approach towards the treatment of osteosarcoma. A literature search was performed utilizing PubMed. Several recent clinical trials are reviewed in detail, as is innovative research evaluating novel agents and surgical techniques which hold promise. Expert commentary: The outcome for patients with osteosarcoma has not changed in several decades. This plateau in survival rates highlights the need for a novel approach towards research. There remains a great deal of interest in utilizing the very high risk population of recurrent osteosarcoma patients to rapidly and sequentially evaluate novel agents to determine if any of these agents hold promise. Several phase II studies are ongoing or in development that offer hope based on intriguing preclinical data. Furthermore, initiatives in obtaining specimens to further explore the genetic and immunological profile behind osteosarcoma will be essential towards identifying novel pathways and targets to exploit.
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              An oncogene-induced DNA damage model for cancer development.

              Of all types of DNA damage, DNA double-strand breaks (DSBs) pose the greatest challenge to cells. One might have, therefore, anticipated that a sizable number of DNA DSBs would be incompatible with cell proliferation. Yet recent experimental findings suggest that, in both precancerous lesions and cancers, activated oncogenes induce stalling and collapse of DNA replication forks, which in turn leads to formation of DNA DSBs. This continuous formation of DNA DSBs may contribute to the genomic instability that characterizes the vast majority of human cancers. In addition, in precancerous lesions, these DNA DSBs activate p53, which, by inducing apoptosis or senescence, raises a barrier to tumor progression. Breach of this barrier by various mechanisms, most notably by p53 mutations, that impair the DNA damage response pathway allows cancers to develop. Thus, oncogene-induced DNA damage may explain two key features of cancer: genomic instability and the high frequency of p53 mutations.
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                Author and article information

                Contributors
                Journal
                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                2352-4820
                2352-3042
                24 March 2023
                March 2024
                24 March 2023
                : 11
                : 2
                : 664-674
                Affiliations
                [a ]Department of Orthopedics, Wuhan Hospital of Traditional Chinese and Western Medicine (Wuhan No.1 Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
                [b ]Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
                [c ]Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, China
                [d ]Hubei Cancer Clinical Study Center, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, China
                Author notes
                []Corresponding author. shaozengwupro@ 123456163.com
                [1]

                These authors contributed equally to this work.

                Article
                S2352-3042(23)00042-9
                10.1016/j.gendis.2022.12.021
                10491873
                37692517
                c6ceb679-d7a6-444c-8f19-1193777f220e
                © 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 license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 27 February 2022
                : 16 December 2022
                Categories
                Review Article

                animal model,cancer,osteosarcoma,pathogenic mechanism,translational research

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