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      Current status and perspectives of patient-derived xenograft models in cancer research

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          Abstract

          Cancers remain a major public health problem worldwide, which still require profound research in both the basic and preclinical fields. Patient-derived xenograft (PDX) models are created when cancerous cells or tissues from patients’ primary tumors are implanted into immunodeficient mice to simulate human tumor biology in vivo, which have been extensively used in cancer research. The routes of implantation appeared to affect the outcome of PDX research, and there has been increasing applications of patient-derived orthotopic xenograft (PDOX) models. In this review, we firstly summarize the methodology to establish PDX models and then go over recent application and function of PDX models in basic cancer research on the areas of cancer characterization, initiation, proliferation, metastasis, and tumor microenvironment and in preclinical explorations of anti-cancer targets, drugs, and therapeutic strategies and finally give our perspectives on the future prospects of PDX models.

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          Most cited references 114

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          LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs

          While recent studies indicated roles of long non-coding RNAs (lncRNAs) in physiologic aspects of cell-type determination and tissue homeostasis 1 yet their potential involvement in regulated gene transcription programs remain rather poorly understood. Androgen receptor (AR) regulates a large repertoire of genes central to the identity and behavior of prostate cancer cells 2 , and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy 3 . Here, we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 and PCGEM1, bind successively to the AR and strongly enhance both ligand-dependent and ligand-independent AR-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the C-terminally acetylated AR on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the DOT1L-mediated methylated AR N-terminus. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited Pygopus2 PHD domain proves to enhance selective looping of AR-bound enhancers to target gene promoters in these cells. In “resistant” prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full length AR, causing ligand-independent activation of the AR transcriptional program and cell proliferation. Conditionally-expressed short hairpin RNA (shRNA) targeting of these lncRNAs in castration-resistant prostate cancer (CRPC) cell lines strongly suppressed tumor xenograft growth in vivo. Together, these results suggest that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumors.
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            VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents.

            Ideally, an oncolytic virus will replicate preferentially in malignant cells, have the ability to treat disseminated metastases, and ultimately be cleared by the patient. Here we present evidence that the attenuated vesicular stomatitis strains, AV1 and AV2, embody all of these traits. We uncover the mechanism by which these mutants are selectively attenuated in interferon-responsive cells while remaining highly lytic in 80% of human tumor cell lines tested. AV1 and AV2 were tested in a xenograft model of human ovarian cancer and in an immune competent mouse model of metastatic colon cancer. While highly attenuated for growth in normal mice, both AV1 and AV2 effected complete and durable cures in the majority of treated animals when delivered systemically.
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              Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance.

              Cytotoxic chemotherapy is effective in debulking tumour masses initially; however, in some patients tumours become progressively unresponsive after multiple treatment cycles. Previous studies have demonstrated that cancer stem cells (CSCs) are selectively enriched after chemotherapy through enhanced survival. Here we reveal a new mechanism by which bladder CSCs actively contribute to therapeutic resistance via an unexpected proliferative response to repopulate residual tumours between chemotherapy cycles, using human bladder cancer xenografts. Further analyses demonstrate the recruitment of a quiescent label-retaining pool of CSCs into cell division in response to chemotherapy-induced damages, similar to mobilization of normal stem cells during wound repair. While chemotherapy effectively induces apoptosis, associated prostaglandin E2 (PGE2) release paradoxically promotes neighbouring CSC repopulation. This repopulation can be abrogated by a PGE2-neutralizing antibody and celecoxib drug-mediated blockade of PGE2 signalling. In vivo administration of the cyclooxygenase-2 (COX2) inhibitor celecoxib effectively abolishes a PGE2- and COX2-mediated wound response gene signature, and attenuates progressive manifestation of chemoresistance in xenograft tumours, including primary xenografts derived from a patient who was resistant to chemotherapy. Collectively, these findings uncover a new underlying mechanism that models the progressive development of clinical chemoresistance, and implicate an adjunctive therapy to enhance chemotherapeutic response of bladder urothelial carcinomas by abrogating early tumour repopulation.
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                Author and article information

                Contributors
                Lai_yunxin@gibh.ac.cn
                Wei_xinru@gibh.ac.cn
                lin_shouheng@gibh.ac.cn
                Qin_le@gibh.ac.cn
                Cheng_lin@gibh.ac.cn
                li_peng@gibh.ac.cn
                Journal
                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central (London )
                1756-8722
                12 May 2017
                12 May 2017
                2017
                : 10
                Affiliations
                [1 ]ISNI 0000000119573309, GRID grid.9227.e, Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, , Chinese Academy of Sciences, ; Guangzhou, 510530 China
                [2 ]ISNI 0000000119573309, GRID grid.9227.e, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, , Chinese Academy of Sciences, ; Guangzhou, 510530 China
                [3 ]ISNI 0000 0000 8653 1072, GRID grid.410737.6, Department of Abdominal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University of Guangzhou Medical University, , Guangzhou Medical University, ; Guangzhou, Guangdong 510095 China
                Article
                470
                10.1186/s13045-017-0470-7
                5427553
                28499452
                e68ce4d0-52eb-48a9-b535-3300080474c7
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81522002
                Award Recipient :
                Funded by: Strategic Priority Research Program of the Chinese Academy of Sciences
                Award ID: XDB19030205
                Award Recipient :
                Funded by: Natural Science Fund for Distinguished Young Scholars of Guangdong Province
                Award ID: 2014A030306028
                Award Recipient :
                Funded by: Guangdong Provincial Applied Science and Technology Research& Development Program
                Award ID: 2016B020237006
                Award Recipient :
                Funded by: Guangdong Provincial Outstanding Young Scholars Award
                Award ID: 2014TQ01R068
                Award Recipient :
                Funded by: Frontier and key technology innovation special grant from the Department of Science and Technology of Guangdong province
                Award ID: 2016B030229006
                Award Recipient :
                Funded by: the Guangdong Provincial Research and Commercialization Program
                Award ID: 2014B090901044
                Award Recipient :
                Funded by: Guangzhou Science Technology and Innovation Commission Project
                Award ID: 201504010016
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2017

                Oncology & Radiotherapy

                pdx models, basic, preclinical, cancer research, drugs

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