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Medicine in the early twenty-first century: paradigm and anticipation - EPMA position paper 2016

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      A new initiative on precision medicine.

      President Obama has announced a research initiative that aims to accelerate progress toward a new era of precision medicine, with a near-term focus on cancers and a longer-term aim to generate knowledge applicable to the whole range of health and disease.
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        Precision medicine--personalized, problematic, and promising.

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          The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase.

          Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia. Tumour-secreted proteins play a crucial role in these interactions and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis, independent of RANK ligand, which disrupts normal bone homeostasis leading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications.
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            Author and article information

            Affiliations
            [1 ]European Association for Predictive, Preventive and Personalised Medicine, Brussels, Belgium
            [2 ]Radiologic Department, Rheinische Friedrich-Wilhelms-University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany
            [3 ]Breast Cancer Research Centre, Rheinische Friedrich-Wilhelms-University of Bonn, Bonn, Germany
            [4 ]Augusta University, Augusta, GA USA
            [5 ]Department of Surgery, School of Medicine, Augusta University, Augusta, GA USA
            [6 ]Dipartimento di Scienze Biomediche e Chirurgico Specialistiche, Università di Ferrara, Via Fossato di Mortara, 64A, 44121 Ferrara, Italy
            [7 ]Institute for Advanced Study, Technische Universität München, Garching bei München, Germany
            [8 ]School of Medical Sciences, Edith Cowan University, Perth, Australia
            [9 ]Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China
            [10 ]WHO Expert Panel (Member), Geneva, Switzerland
            [11 ]Global Health Epidemiology Reference Group (GHERG), Edinburgh, UK
            [12 ]Clinical hospital “Pheophania” of State Affairs Department, Kyiv, Ukraine
            [13 ]Zabolotny Institute of Microbiology and Virology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
            [14 ]European Medical Association, Brussels, Belgium
            Contributors
            Olga.Golubnitschaja@ukb-uni-bonn.de
            BBABAN@gru.edu
            bnlgnn@unife.it
            wei.wang@ecu.edu.au
            rostbubnov@gmail.com
            marko.kapalla@gmail.com
            kurt_krapfenbauer@yahoo.de
            MMOZAFFA@gru.edu
            vincenzo@emanet.org
            Journal
            EPMA J
            EPMA J
            The EPMA Journal
            BioMed Central (London )
            1878-5077
            1878-5085
            25 October 2016
            25 October 2016
            2016
            : 7
            5078893
            72
            10.1186/s13167-016-0072-4
            © The Author(s). 2016

            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.

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