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Bone Metastasis Bone Metastasis: Mechanisms, Therapies and Biomarkers Philippe Clézardin, Rob Coleman, Margherita Puppo, Penelope Ottewell, Edith Bonnelye, Frédéric Paycha, Cyril Confavreux, Ingunn Holen To cite this version: Philippe Clézardin, Rob Coleman, Margherita Puppo, Penelope Ottewell, Edith Bonnelye, et al.. Bone Metastasis: Mechanisms, Therapies and Biomarkers. Physiological Reviews, American Physiological Society, In press, 10.1152/physrev.00012.2019. hal-03102895 HAL Id: hal-03102895 https://hal.archives-ouvertes.fr/hal-03102895 Submitted on 7 Jan 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 1 Bone Metastasis: mechanisms, therapies and biomarkers. 2 Philippe Clézardin,1,2 Rob Coleman,2 Margherita Puppo,2 Penelope Ottewell,2 Edith Bonnelye,1 Frédéric 3 Paycha,3 Cyrille B. Confavreux,1,4 Ingunn Holen.2 4 5 1 INSERM, Research Unit UMR_S1033, LyOS, Faculty of Medicine Lyon-Est, University of Lyon 1, 6 Lyon, France. 7 2 Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK. 8 3 Service de Médecine Nucléaire, Hôpital Lariboisière, Paris, France. 9 4 Service de Rhumatologie Sud, CEMOS - Centre Expert des Métastases Osseuses, Centre Hospitalier 10 Lyon Sud, Hospices Civils de Lyon, Lyon, France. 11 12 Abbreviated title: bone metastasis 13 Key words: metastatic niche, dormancy, invasion, aerobic glycolysis, immunosurveillance, 14 osteomimicry, osteoclast, osteoblast, osteocyte, bisphosphonate, denosumab, non-coding RNA 15 16 Corresponding author: 17 Prof Philippe Clézardin 18 INSERM, UMR_S1033, UFR de Médecine Lyon-Est, 7 Rue Guillaume Paradin, 19 69372 Lyon cedex 08, France 20 (Tel.: +33 478785737; e-mail: [email protected]) 21 Department of Oncology and Metabolism, The Medical School, Beech Hill Road, Sheffield S10 2RX, UK 22 (Tel.: +44 1142229242; e-mail: [email protected]) 23 1 Downloaded from journals.physiology.org/journal/physrev at INSERM (193.054.110.061) on December 29, 2020. 24 I. Introduction ........................................................................................................................... 5 25 II. Bone metastasis incidence and consequences for bone health ...................................... 6 26 A. Common ground - bone metastasis in different cancer types ....................................... 6 27 B. Cancer-related skeletal complications ........................................................................... 8 28 III. Taking over the neighborhood - Bone colonization by tumor cells .................................. 9 29 A. Preparing the soil – the concept of the metastatic niche ............................................... 10 30 B. Mechanisms of tumor cell extravasation and homing to the bone marrow .................... 13 31 1. 32 ............................................................................................................................... Tumo 33 r cell extravasation ................................................................................................ 13 34 2. 35 ............................................................................................................................... Homi 36 ng .......................................................................................................................... 15 37 C. Hiding in plain sight – Tumor cell dormancy and dormant cell reactivation 38 mechanisms in bone marrow niches ............................................................................. 17 39 1. Tumor cell interactions with cells from bone marrow niches .................................. 18 40 2. Tumor cell dormancy ............................................................................................. 22 41 3. Dormant cell reactivation ....................................................................................... 24 42 IV. Fitting in - Adaptation of tumor cells to the bone marrow microenvironment ................. 25 43 V. Disrupting the balance - Tumor-induced bone destruction ............................................... 28 44 A. Factors promoting osteoclast-mediated bone resorption .............................................. 28 45 B. Factors suppressing osteoblast-mediated bone formation ............................................ 30 46 C. Osteocytes – silent partners with a role to play .............................................................. 32 47 D. The fertile soil - contribution of the bone matrix ............................................................. 35 48 VI. Too much of a good thing - tumor-derived factors regulating osteosclerosis ................ 37 49 A. Factors promoting osteoblast-mediated bone formation ............................................... 37 50 B. Factors suppressing osteoclast-mediated bone resorption ........................................... 40 51 VII. Contribution of bone marrow cells to tumor development – multiple 52 interactions beyond the vicious cycle ................................................................................. 41 53 A. The immune cells of the bone microenvironment .......................................................... 42 54 1. Immune cells inhibiting local tumor growth in the bone microenvironment ............. 42 55 2. Immunosuppressive cells promoting local tumor growth in the bone 56 microenvironment ................................................................................................... 44 57 B. Nerve cells .................................................................................................................... 50 58 C. Adipocytes .................................................................................................................... 52 2 Downloaded from journals.physiology.org/journal/physrev at INSERM (193.054.110.061) on December 29, 2020. 59 VIII. Fueling expansion - Reprogramming energy metabolism 60 to facilitate bone metastasis progression ........................................................................... 56 61 IX. Blocking bone deconstruction - Current therapies for the treatment of 62 bone metastasis .................................................................................................................... 58 63 A. Inhibiting bone resorption by targeting osteoclasts ....................................................... 60 64 1. Bisphosphonates ................................................................................................... 60 65 2. Anti-RANKL: denosumab ...................................................................................... 66 66 3. Novel antiresorptive agents ................................................................................... 70 67 B. Promoting bone formation by targeting osteoblasts ...................................................... 76 68 1. Agents blocking WNT inhibitors ............................................................................. 76 69 2. Endothelin-1 receptor inhibitors ............................................................................. 76 70 3. Androgen inhibitors ............................................................................................... 77 71 4. Activin A inhibitors ................................................................................................. 77 72 C. Targeting the bone matrix and the microenvironment ................................................... 78 73 1. Bone targeted radiopharmaceuticals ..................................................................... 78 74 2. Agents targeting nerve- or bone-derived growth factors ........................................ 80 75 X. The value of bone turnover biomarkers in bone metastasis ............................................. 80 76 A. Bone formation markers ................................................................................................. 81 77 B. Bone resorption markers ............................................................................................... 83 78 C. Insights from markers not associated with bone turnover ............................................. 86 79 XI. Conclusion ............................................................................................................................. 87 80 XII. References ............................................................................................................................. 89 81 82 3 Downloaded from journals.physiology.org/journal/physrev at INSERM (193.054.110.061) on December 29, 2020. 83 84 Abstract: 85 Skeletal metastases are frequent complications of many cancers, causing bone complications 86 (fractures, bone pain, disability), which negatively affect the patient’s quality of life. Here, we first 87 discuss the burden of skeletal complications in cancer bone metastasis. We then describe the 88 pathophysiology of bone metastasis. Bone metastasis is a multistage process; long before the 89 development of clinically detectable metastases, circulating tumor cells settle and enter a dormant state 90 in normal vascular and endosteal niches
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