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Lungu O, Toscani D, Giuliani N. Mechanistic insights into bone destruction in multiple myeloma: Cellular and molecular perspectives. J Bone Oncol 2025; 51:100668. [PMID: 40124903 PMCID: PMC11928850 DOI: 10.1016/j.jbo.2025.100668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 02/21/2025] [Accepted: 02/21/2025] [Indexed: 03/25/2025] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy that leads to significant bone destruction, resulting in debilitating pain and skeletal-related events. The pathophysiology of osteolytic bone destruction in MM involves complex interactions between malignant plasma cells (PCs) and the bone marrow (BM) microenvironment. This review aims to provide a comprehensive synthesis of the cellular and molecular pathways underlying MM-associated bone disease. We discuss the role of osteoclast (OC), osteoblast (OB), osteocytes, along with the complex interactions between immune cells and the BM microenvironment in shaping disease progression. Additionally, we explore the molecular signaling pathways involved in bone disease as well as the influence of inflammatory cytokines, and the role of the metabolic alterations that characterize the MM BM. We also explore novel therapeutic strategies targeting these pathways to improve clinical outcomes. Understanding these mechanisms is crucial for the development of more effective treatments to prevent bone damage in MM patients.
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Affiliation(s)
- Oxana Lungu
- Laboratory of Hematology, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Denise Toscani
- Laboratory of Hematology, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Nicola Giuliani
- Laboratory of Hematology, Department of Medicine and Surgery, University of Parma, Parma, Italy
- Hematology and BMT Unit, “Azienda Ospedaliero-Universitaria di Parma”, Parma, Italy
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2
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Anloague A, Sabol HM, Kaur J, Khan S, Ashby C, Schinke C, Barnes CL, Alturkmani F, Ambrogini E, Gundesen MT, Lund T, Amstrup AK, Andersen TL, Diaz-delCastillo M, Roodman GD, Bellido T, Delgado-Calle J. A novel CCL3-HMGB1 signaling axis regulating osteocyte RANKL expression in multiple myeloma. Haematologica 2025; 110:952-966. [PMID: 39605211 PMCID: PMC11959238 DOI: 10.3324/haematol.2024.286484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 11/15/2024] [Indexed: 11/29/2024] Open
Abstract
Multiple myeloma (MM) is a clonal plasma cell proliferative malignancy characterized by a debilitating bone disease. Osteolytic destruction, a hallmark of MM, is driven by increased osteoclast number and exacerbated bone resorption, primarily fueled by the excessive production of RANKL, the master regulator of osteoclast formation, within the tumor niche. We previously reported that osteocytes, the most abundant cells in the bone niche, promote tumor progression and support MM bone disease by overproducing RANKL. However, the molecular mechanisms underlying RANKL dysregulation in osteocytes in the context of MM bone disease are not entirely understood. Here, we present evidence that MM-derived CCL3 induces upregulation of RANKL expression in both human and murine osteocytes. Through a combination of in vitro, ex vivo, and in vivo models and clinical data, we demonstrate that genetic or pharmacologic inhibition of CCL3 prevents RANKL upregulation in osteocytes and attenuates the bone loss induced by MM cells. Mechanistic studies revealed that MM-derived CCL3 triggers the secretion of HMGB1 by osteocytes, a process required for osteocytic RANKL upregulation by MM cells. These findings identify a previously unknown CCL3-HMGB1 signaling axis in the MM tumor niche that drives bone resorption by promoting RANKL overproduction in osteocytes.
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Affiliation(s)
- Aric Anloague
- Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Hayley M Sabol
- Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Japneet Kaur
- Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, US; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock
| | - Sharmin Khan
- Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Cody Ashby
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, US; Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Carolina Schinke
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, US; Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR
| | - C Lowry Barnes
- Department of Orthopedic Surgery; University of Arkansas for Medical Sciences, Little Rock, AR
| | - Farah Alturkmani
- Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, US; Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences Little Rock, AR
| | - Elena Ambrogini
- Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, US; Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences Little Rock, AR, US; Central Arkansas Veterans Healthcare System, Little Rock, AR
| | - Michael Tveden Gundesen
- Department of Hematology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Thomas Lund
- Department of Hematology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Centre for Innovative Medical Technology, Odense University Hospital, Odense, Denmark
| | - Anne Kristine Amstrup
- Department of Endocrinology and Internal Medicine (MEA), THG, Aarhus University Hospital, Aarhus, Denmark
| | - Thomas Levin Andersen
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Department of Pathology, Odense University Hospital, Odense, Denmark; Department of Forensic Medicine, University of Aarhus, Aarhus, Denmark
| | | | - G David Roodman
- Division of Hematology and Oncology, Department of Medicine, Indiana University, Indianapolis, IN
| | - Teresita Bellido
- Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, US; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, US; Department of Orthopedic Surgery; University of Arkansas for Medical Sciences, Little Rock, AR, US; Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences Little Rock, AR, US; Central Arkansas Veterans Healthcare System, Little Rock, AR
| | - Jesus Delgado-Calle
- Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, US; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, US; Department of Orthopedic Surgery; University of Arkansas for Medical Sciences, Little Rock, AR, US; Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences Little Rock, AR.
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Jia Y, Li R, Li Y, Kachler K, Meng X, Gießl A, Qin Y, Zhang F, Liu N, Andreev D, Schett G, Bozec A. Melanoma bone metastasis-induced osteocyte ferroptosis via the HIF1α-HMOX1 axis. Bone Res 2025; 13:9. [PMID: 39814705 PMCID: PMC11735842 DOI: 10.1038/s41413-024-00384-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 09/11/2024] [Accepted: 10/15/2024] [Indexed: 01/30/2025] Open
Abstract
Osteocytes are the main cells in mineralized bone tissue. Elevated osteocyte apoptosis has been observed in lytic bone lesions of patients with multiple myeloma. However, their precise contribution to bone metastasis remains unclear. Here, we investigated the pathogenic mechanisms driving melanoma-induced osteocyte death. Both in vivo models and in vitro assays were combined with untargeted RNA sequencing approaches to explore the pathways governing melanoma-induced osteocyte death. We could show that ferroptosis is the primary mechanism behind osteocyte death in the context of melanoma bone metastasis. HMOX1 was identified as a crucial regulatory factor in this process, directly involved in inducing ferroptosis and affecting osteocyte viability. We uncover a non-canonical pathway that involves excessive autophagy-mediated ferritin degradation, highlighting the complex relationship between autophagy and ferroptosis in melanoma-induced osteocyte death. In addition, HIF1α pathway was shown as an upstream regulator, providing a potential target for modulating HMOX1 expression and influencing autophagy-dependent ferroptosis. In conclusion, our study provides insight into the pathogenic mechanisms of osteocyte death induced by melanoma bone metastasis, with a specific focus on ferroptosis and its regulation. This would enhance our comprehension of melanoma-induced osteocyte death.
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Affiliation(s)
- Yewei Jia
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Rui Li
- Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yixuan Li
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Katerina Kachler
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Xianyi Meng
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Andreas Gießl
- Department of Opthalmology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Yi Qin
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Fulin Zhang
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Ning Liu
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Darja Andreev
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Technische Universität Dresden (TUD), Center for Molecular and Cellular Bioengineering (CMCB), Center for Regenerative Therapies Dresden (CRTD), Dresden, Germany
| | - Georg Schett
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Aline Bozec
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
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Kaur J, Adhikari M, Sabol HM, Anloague A, Khan S, Kurihara N, Diaz-delCastillo M, Andreasen CM, Barnes CL, Stambough JB, Palmieri M, Reyes-Castro O, Zarrer J, Taipaleenmäki H, Ambrogini E, Almeida M, O’Brien CA, Nookaw I, Delgado-Calle J. Single-Cell Transcriptomic Analysis Identifies Senescent Osteocytes That Trigger Bone Destruction in Breast Cancer Metastasis. Cancer Res 2024; 84:3936-3952. [PMID: 39312185 PMCID: PMC11611663 DOI: 10.1158/0008-5472.can-24-0857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 07/22/2024] [Accepted: 09/19/2024] [Indexed: 09/25/2024]
Abstract
Breast cancer bone metastases increase fracture risk and are a major cause of morbidity and mortality among women. Upon colonization by tumor cells, the bone microenvironment undergoes profound reprogramming to support cancer progression, which disrupts the balance between osteoclasts and osteoblasts and leads to bone lesions. A deeper understanding of the processes mediating this reprogramming could help develop interventions for treating patients with bone metastases. Here, we demonstrated that osteocytes (Ot) in established breast cancer bone metastasis develop premature senescence and a distinctive senescence-associated secretory phenotype (SASP) that favors bone destruction. Single-cell RNA sequencing identified Ots from mice with breast cancer bone metastasis enriched in senescence, SASP markers, and pro-osteoclastogenic genes. Multiplex in situ hybridization and artificial intelligence-assisted analysis depicted Ots with senescence-associated satellite distension, telomere dysfunction, and p16Ink4a expression in mice and patients with breast cancer bone metastasis. Breast cancer cells promoted Ot senescence and enhanced their osteoclastogenic potential in in vitro and ex vivo organ cultures. Clearance of senescent cells with senolytics suppressed bone resorption and preserved bone mass in mice with breast cancer bone metastasis. These results demonstrate that Ots undergo pathological reprogramming by breast cancer cells and identify Ot senescence as an initiating event triggering lytic bone disease in breast cancer metastases. Significance: Breast cancer cells remodel the bone microenvironment by promoting premature cellular senescence and SASP in osteocytes, which can be targeted with senolytics to alleviate bone loss induced by metastatic breast cancer. See related commentary by Frieling and Lynch, p. 3917.
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Affiliation(s)
- Japneet Kaur
- Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, US
| | - Manish Adhikari
- Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, US
| | - Hayley M. Sabol
- Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, US
| | - Aric Anloague
- Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, US
| | - Sharmin Khan
- Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, US
| | - Noriyoshi Kurihara
- Division of Hematology and Oncology, Department of Medicine, Indiana University, Indianapolis, IN, US
| | | | - Christina Møller Andreasen
- Molecular Bone Histology lab, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
- Department of Clinical Pathology, Odense University Hospital, Odense University Hospital, Odense, Denmark
| | - C. Lowry Barnes
- Department of Orthopedic Surgery; University of Arkansas for Medical Sciences, Little Rock, AR, US
| | - Jeffrey B. Stambough
- Department of Orthopedic Surgery; University of Arkansas for Medical Sciences, Little Rock, AR, US
| | - Michela Palmieri
- Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, US
| | - Olivia Reyes-Castro
- Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, US
| | - Jennifer Zarrer
- Institute of Musculoskeletal Medicine, Musculoskeletal University Center Munich, University Hospital, LMU Munich, Germany
| | - Hanna Taipaleenmäki
- Institute of Musculoskeletal Medicine, Musculoskeletal University Center Munich, University Hospital, LMU Munich, Germany
| | - Elena Ambrogini
- Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, US
| | - Maria Almeida
- Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, US
| | - Charles A. O’Brien
- Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, US
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, US
| | - Intawat Nookaw
- Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR, US
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, US
| | - Jesus Delgado-Calle
- Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, US
- Department of Orthopedic Surgery; University of Arkansas for Medical Sciences, Little Rock, AR, US
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, US
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5
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Yu M, Cai Z, Zhang J, Zhang Y, Fu J, Cui X. Aberrant NSUN2-mediated m5C modification of exosomal LncRNA MALAT1 induced RANKL-mediated bone destruction in multiple myeloma. Commun Biol 2024; 7:1249. [PMID: 39358426 PMCID: PMC11446919 DOI: 10.1038/s42003-024-06918-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 09/18/2024] [Indexed: 10/04/2024] Open
Abstract
The impact of exosome-mediated crosstalk between multiple myeloma (MM) cells and osteoclasts (OCs) on bone lesions remains to be investigated. Here, we identified NSUN2 and YBX1-mediated m5C modifications upregulated LncRNA MALAT1 expression in MM cells, which could be transported to OCs via exosomes and promote bone lesions. Methodologically, RNA-seq was carried out to detect the cargoes of exosomes. TRAP staining and WB were used to evaluate osteoclastogenesis in vitro. Micro-CT and bone histomorphometric analyses were performed to identify bone destruction in vivo. RNA pull-down, RIP, MeRIP, and luciferase reporter assays were used to test the interactions between molecules. The clinical features of MALAT1, NSUN2 and YBX1 were verified through public datasets and clinicopathological data analyses. Mechanistically, MALAT1 was the highest expressed lncRNA in U266 exosomes and could be transported to RAW264.7 cells. MALAT1 could enhance the differentiation of RAW264.7 cells into OCs by stimulating RANKL expression and its downstream AKT and MAPKs signaling pathways via a ceRNA mechanism. Additionally, MALAT1 could be modified by NSUN2, an m5C methyltransferase, which in turn stabilized MALAT1 through the "reader" YBX1. Clinical studies indicated a notable positive correlation between MALAT1, NSUN2, YBX1 levels and bone destruction features, as well as with RANKL expression.
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Affiliation(s)
- Manya Yu
- The First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, No. 16369 Jingshi Road, Jinan, 250014, China
| | - Zhiguo Cai
- Department of Quality Control, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250014, China
| | - Jie Zhang
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250014, China
| | - Yanyu Zhang
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, 100091, Beijing, China
| | - Jiaqi Fu
- The First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, No. 16369 Jingshi Road, Jinan, 250014, China
| | - Xing Cui
- Department of Oncology and Hematology, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250001, China.
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Evans H, Andrews R, Abedi FA, Sprules A, Trend J, Lovric G, Green A, Chantry A, Clarkin C, Brown J, Lawson M. Evidence for peri-lacunar remodeling and altered osteocyte lacuno-canalicular network in mouse models of myeloma-induced bone disease. JBMR Plus 2024; 8:ziae093. [PMID: 39108360 PMCID: PMC11299509 DOI: 10.1093/jbmrpl/ziae093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 06/11/2024] [Accepted: 07/10/2024] [Indexed: 09/26/2024] Open
Abstract
Myeloma bone disease (MBD) affects ~90% of multiple myeloma patients, but current treatment options are suboptimal. Therefore, to successfully develop new therapies or optimize current ones, we must improve our fundamental knowledge of how myeloma affects bone microstructure and function. Here, we have investigated the osteocyte lacuno-canalicular network (LCN) in MBD, as bone porosity affects bone quality and resilience. We used the syngeneic 5TGM1-C57BL-Kalwrij and the xenograft U266-NSG models at end stage and compared them to healthy controls (naïve). Micro-computed tomography (μCT) and histomorphometry indicated the 5TGM1 and U266 models developed mild and extensive MBD, respectively, with the U266 model producing large osteolytic lesions. High-resolution synchrotron micro-CT (SR-μCT) revealed significant osteocyte lacunae changes in U266 bones but not 5TGM1, with a reduction in lacunae number and sphericity, and an increase in lacunae volume compared with naïve. Canalicular length, visualized using histological Ploton silver staining, appeared significantly shorter in 5TGM1 and U266 bones compared with naïve. Canalicular area as a proportion of the bone was also decreased by 24.2% in the U266 model. We observed significant upregulation of genes implicated in peri-lacunar remodeling (PLR), but immunohistochemistry confirmed that the osteocyte-specific protein sclerostin, a known driver of PLR, was unchanged between MBD and naïve bones. In summary, we have demonstrated evidence of PLR and altered organization of the osteocyte LCN in MBD mouse models. The next step would be to further understand the drivers and implications of PLR in MBD, and whether treatments to manipulate PLR and the LCN may improve patient outcomes.
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Affiliation(s)
- Holly Evans
- Division of Clinical Medicine and Mellanby Centre for Musculoskeletal Research, School of Medicine and Population Health, Faculty of Health, University of Sheffield, Sheffield S10 2RX, United Kingdom
| | - Rebecca Andrews
- Division of Clinical Medicine and Mellanby Centre for Musculoskeletal Research, School of Medicine and Population Health, Faculty of Health, University of Sheffield, Sheffield S10 2RX, United Kingdom
- Department of Haematology, Sheffield Teaching Hospitals, Royal Hallamshire Hospital NHS Foundation Trust, Sheffield S10 2JF, United Kingdom
| | - Fatma Ali Abedi
- Division of Clinical Medicine and Mellanby Centre for Musculoskeletal Research, School of Medicine and Population Health, Faculty of Health, University of Sheffield, Sheffield S10 2RX, United Kingdom
| | - Alexandria Sprules
- Division of Clinical Medicine and Mellanby Centre for Musculoskeletal Research, School of Medicine and Population Health, Faculty of Health, University of Sheffield, Sheffield S10 2RX, United Kingdom
| | - Jacob Trend
- School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom
| | - Goran Lovric
- TOMCAT beamline, Swiss Light Source, Paul Scherrer Institut, Forschungsstrasse 111, 5232 Villigen, Switzerland
| | - Alanna Green
- Division of Clinical Medicine and Mellanby Centre for Musculoskeletal Research, School of Medicine and Population Health, Faculty of Health, University of Sheffield, Sheffield S10 2RX, United Kingdom
| | - Andrew Chantry
- Division of Clinical Medicine and Mellanby Centre for Musculoskeletal Research, School of Medicine and Population Health, Faculty of Health, University of Sheffield, Sheffield S10 2RX, United Kingdom
- Department of Haematology, Sheffield Teaching Hospitals, Royal Hallamshire Hospital NHS Foundation Trust, Sheffield S10 2JF, United Kingdom
| | - Claire Clarkin
- School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom
| | - Janet Brown
- Division of Clinical Medicine and Mellanby Centre for Musculoskeletal Research, School of Medicine and Population Health, Faculty of Health, University of Sheffield, Sheffield S10 2RX, United Kingdom
- Department of Haematology, Sheffield Teaching Hospitals, Royal Hallamshire Hospital NHS Foundation Trust, Sheffield S10 2JF, United Kingdom
| | - Michelle Lawson
- Division of Clinical Medicine and Mellanby Centre for Musculoskeletal Research, School of Medicine and Population Health, Faculty of Health, University of Sheffield, Sheffield S10 2RX, United Kingdom
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7
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Grasedieck S, Panahi A, Jarvis MC, Borzooee F, Harris RS, Larijani M, Avet-Loiseau H, Samur M, Munshi N, Song K, Rouhi A, Kuchenbauer F. Redefining high risk multiple myeloma with an APOBEC/Inflammation-based classifier. Leukemia 2024; 38:1172-1177. [PMID: 38461190 PMCID: PMC11073955 DOI: 10.1038/s41375-024-02210-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 02/23/2024] [Accepted: 02/28/2024] [Indexed: 03/11/2024]
Affiliation(s)
- Sarah Grasedieck
- Department of Microbiology and Immunology, University of British Columbia, 2125 East Mall, Vancouver, BC, Canada
| | - Afsaneh Panahi
- Terry Fox Laboratory, BC Cancer Research Institute, Vancouver, BC, Canada
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Matthew C Jarvis
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, NC, USA
| | - Faezeh Borzooee
- Terry Fox Laboratory, BC Cancer Research Institute, Vancouver, BC, Canada
- Department of Molecular Biology and Biochemistry, Faculty of Science, Simon Fraser University, Burnaby, BC, Canada
| | - Reuben S Harris
- Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX, USA
- Howard Hughes Medical Institute, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Mani Larijani
- Department of Molecular Biology and Biochemistry, Faculty of Science, Simon Fraser University, Burnaby, BC, Canada
| | | | - Mehmet Samur
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Nikhil Munshi
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Kevin Song
- Leukemia/Bone Marrow Transplant Program of British Columbia, Vancouver General Hospital, BC Cancer, Vancouver, BC, Canada
| | - Arefeh Rouhi
- Terry Fox Laboratory, BC Cancer Research Institute, Vancouver, BC, Canada
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Florian Kuchenbauer
- Terry Fox Laboratory, BC Cancer Research Institute, Vancouver, BC, Canada.
- Leukemia/Bone Marrow Transplant Program of British Columbia, Vancouver General Hospital, BC Cancer, Vancouver, BC, Canada.
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8
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Verbruggen SW. Role of the osteocyte in bone metastasis - The importance of networking. J Bone Oncol 2024; 44:100526. [PMID: 38304485 PMCID: PMC10831278 DOI: 10.1016/j.jbo.2024.100526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 12/19/2023] [Accepted: 01/16/2024] [Indexed: 02/03/2024] Open
Abstract
Metastatic bone disease is a complex condition resulting from the migration and colonization of cancer cells from their primary site to the bone microenvironment, where they typically develop a metastatic niche. Osteocytes, the most abundant cells in bone tissue and the master regulators of bone remodelling, are increasingly thought to play a crucial role in this process through intricate interactions with cancer cells. This review covers the recent progress made in exploring the multifaceted interactions between osteocytes and cancer cells in the metastatic microenvironment, highlighting the importance of signalling networks in bone metastases. Though these interactions are particularly complex, the renewed focus of researchers on osteocytes within the last 5 years has uncovered multiple new potential molecular mechanisms underlying osteocyte-mediated regulation of cancer cell survival, proliferation, and invasion. A number of key papers will be discussed in detail, emphasizing the significance of signalling pathways and molecular crosstalk, and exploring potential therapeutic strategies targeting osteocyte-cancer cell interactions to improve patient treatment and outcomes.
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Affiliation(s)
- Stefaan W. Verbruggen
- Centre for Predictive in vitro Models and Centre for Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, United Kingdom
- Digital Environment Research Institute, Queen Mary University of London, United Kingdom
- INSIGNEO Institute for in silico Medicine and Department of Mechanical Engineering, University of Sheffield, United Kingdom
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9
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Zhang Y, Chen Q. Novel insights into osteocyte and inter-organ/tissue crosstalk. Front Endocrinol (Lausanne) 2024; 14:1308408. [PMID: 38685911 PMCID: PMC11057460 DOI: 10.3389/fendo.2023.1308408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 12/14/2023] [Indexed: 05/02/2024] Open
Abstract
Osteocyte, a cell type living within the mineralized bone matrix and connected to each other by means of numerous dendrites, appears to play a major role in body homeostasis. Benefiting from the maturation of osteocyte extraction and culture technique, many cross-sectional studies have been conducted as a subject of intense research in recent years, illustrating the osteocyte-organ/tissue communication not only mechanically but also biochemically. The present review comprehensively evaluates the new research work on the possible crosstalk between osteocyte and closely situated or remote vital organs/tissues. We aim to bring together recent key advances and discuss the mutual effect of osteocyte and brain, kidney, vascular calcification, muscle, liver, adipose tissue, and tumor metastasis and elucidate the therapeutic potential of osteocyte.
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Affiliation(s)
- Yan Zhang
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qingchang Chen
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Research Center for Medical Imaging in Hubei Province, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
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10
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Yang M, Chen Y, Zhu L, You L, Tong H, Meng H, Sheng J, Jin J. Harnessing Nanotechnology: Emerging Strategies for Multiple Myeloma Therapy. Biomolecules 2024; 14:83. [PMID: 38254683 PMCID: PMC10813273 DOI: 10.3390/biom14010083] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/02/2024] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
Advances in nanotechnology have provided novel avenues for the diagnosis and treatment of multiple myeloma (MM), a hematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow. This review elucidates the potential of nanotechnology to revolutionize myeloma therapy, focusing on nanoparticle-based drug delivery systems, nanoscale imaging techniques, and nano-immunotherapy. Nanoparticle-based drug delivery systems offer enhanced drug targeting, reduced systemic toxicity, and improved therapeutic efficacy. We discuss the latest developments in nanocarriers, such as liposomes, polymeric nanoparticles, and inorganic nanoparticles, used for the delivery of chemotherapeutic agents, siRNA, and miRNA in MM treatment. We delve into nanoscale imaging techniques which provide spatial multi-omic data, offering a holistic view of the tumor microenvironment. This spatial resolution can help decipher the complex interplay between cancer cells and their surrounding environment, facilitating the development of highly targeted therapies. Lastly, we explore the burgeoning field of nano-immunotherapy, which employs nanoparticles to modulate the immune system for myeloma treatment. Specifically, we consider how nanoparticles can be used to deliver tumor antigens to antigen-presenting cells, thus enhancing the body's immune response against myeloma cells. In conclusion, nanotechnology holds great promise for improving the prognosis and quality of life of MM patients. However, several challenges remain, including the need for further preclinical and clinical trials to assess the safety and efficacy of these emerging strategies. Future research should also focus on developing personalized nanomedicine approaches, which could tailor treatments to individual patients based on their genetic and molecular profiles.
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Affiliation(s)
- Min Yang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (M.Y.); (Y.C.); (L.Z.); (L.Y.); (H.T.); (H.M.)
- Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou 310027, China
- Zhejiang Provincial Clinical Research Center for Hematological Disorders, Hangzhou 310003, China
- Zhejiang University Cancer Center, Hangzhou 310029, China;
| | - Yu Chen
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (M.Y.); (Y.C.); (L.Z.); (L.Y.); (H.T.); (H.M.)
- Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou 310027, China
- Zhejiang Provincial Clinical Research Center for Hematological Disorders, Hangzhou 310003, China
- Zhejiang University Cancer Center, Hangzhou 310029, China;
| | - Li Zhu
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (M.Y.); (Y.C.); (L.Z.); (L.Y.); (H.T.); (H.M.)
- Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou 310027, China
- Zhejiang Provincial Clinical Research Center for Hematological Disorders, Hangzhou 310003, China
- Zhejiang University Cancer Center, Hangzhou 310029, China;
| | - Liangshun You
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (M.Y.); (Y.C.); (L.Z.); (L.Y.); (H.T.); (H.M.)
- Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou 310027, China
- Zhejiang Provincial Clinical Research Center for Hematological Disorders, Hangzhou 310003, China
- Zhejiang University Cancer Center, Hangzhou 310029, China;
| | - Hongyan Tong
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (M.Y.); (Y.C.); (L.Z.); (L.Y.); (H.T.); (H.M.)
- Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou 310027, China
- Zhejiang Provincial Clinical Research Center for Hematological Disorders, Hangzhou 310003, China
- Zhejiang University Cancer Center, Hangzhou 310029, China;
| | - Haitao Meng
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (M.Y.); (Y.C.); (L.Z.); (L.Y.); (H.T.); (H.M.)
- Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou 310027, China
- Zhejiang Provincial Clinical Research Center for Hematological Disorders, Hangzhou 310003, China
- Zhejiang University Cancer Center, Hangzhou 310029, China;
| | - Jianpeng Sheng
- Zhejiang University Cancer Center, Hangzhou 310029, China;
| | - Jie Jin
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (M.Y.); (Y.C.); (L.Z.); (L.Y.); (H.T.); (H.M.)
- Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou 310027, China
- Zhejiang Provincial Clinical Research Center for Hematological Disorders, Hangzhou 310003, China
- Zhejiang University Cancer Center, Hangzhou 310029, China;
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11
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Sarazin BA, Liu B, Goldman E, Whitefield AN, Lynch ME. Bone-homing metastatic breast cancer cells impair osteocytes' mechanoresponse in a 3D loading model. Heliyon 2023; 9:e20248. [PMID: 37767467 PMCID: PMC10520780 DOI: 10.1016/j.heliyon.2023.e20248] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 06/23/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Breast cancer predominantly metastasizes to the skeleton. Mechanical loading is reliably anabolic in bone, and also inhibits bone metastatic tumor formation and bone loss in vivo. To study the underlying mechanisms, we developed a 3D culture model for osteocytes, the primary bone mechanosensor. We verified that MLO-Y4s responded to perfusion by reducing their rankl and rankl:opg gene expression. We next cultured MLO-Y4s with tumor-conditioned media (TCM) collected from human breast cancer cells (MDA-MB-231s) and a corresponding bone-homing subclone to test the impacts on osteocytes' mechanosensation. We found that TCM from the bone-homing subclone was more detrimental to MLO-Y4 growth and viability, and it abrogated loading-induced changes to rankl:opg. Our studies demonstrate that MLO-Y4s, including their mechanoresponse to perfusion, were more negatively impacted by soluble factors from bone-homing breast cancer cells compared to those from parental cells.
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Affiliation(s)
- Blayne A. Sarazin
- Department of Mechanical Engineering, University of Colorado, Boulder, CO, 80309, USA
| | - Boyuan Liu
- Department of Mechanical Engineering, University of Colorado, Boulder, CO, 80309, USA
| | - Elaine Goldman
- Department of Mechanical Engineering, University of Colorado, Boulder, CO, 80309, USA
| | - Ashlyn N. Whitefield
- Department of Mechanical Engineering, University of Colorado, Boulder, CO, 80309, USA
| | - Maureen E. Lynch
- Department of Mechanical Engineering, University of Colorado, Boulder, CO, 80309, USA
- BioFrontiers Institute, University of Colorado, Boulder, CO, 80309, USA
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12
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Kitase Y, Prideaux M. Regulation of the Osteocyte Secretome with Aging and Disease. Calcif Tissue Int 2023; 113:48-67. [PMID: 37148298 DOI: 10.1007/s00223-023-01089-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 04/21/2023] [Indexed: 05/08/2023]
Abstract
As the most numerous and long-lived of all bone cells, osteocytes have essential functions in regulating skeletal health. Through the lacunar-canalicular system, secreted proteins from osteocytes can reach cells throughout the bone. Furthermore, the intimate connectivity between the lacunar-canalicular system and the bone vasculature allows for the transport of osteocyte-secreted factors into the circulation to reach the entire body. Local and endocrine osteocyte signaling regulates physiological processes such as bone remodeling, bone mechanoadaptation, and mineral homeostasis. However, these processes are disrupted by impaired osteocyte function induced by aging and disease. Dysfunctional osteocyte signaling is now associated with the pathogenesis of many disorders, including chronic kidney disease, cancer, diabetes mellitus, and periodontitis. In this review, we focus on the targeting of bone and extraskeletal tissues by the osteocyte secretome. In particular, we highlight the secreted osteocyte proteins, which are known to be dysregulated during aging and disease, and their roles during disease progression. We also discuss how therapeutic or genetic targeting of osteocyte-secreted proteins can improve both skeletal and systemic health.
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Affiliation(s)
- Yukiko Kitase
- Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN, 46202, USA
- Department of Anatomy, Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN, 46202, USA
| | - Matthew Prideaux
- Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN, 46202, USA.
- Department of Anatomy, Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN, 46202, USA.
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13
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Anloague A, Delgado-Calle J. Osteocytes: New Kids on the Block for Cancer in Bone Therapy. Cancers (Basel) 2023; 15:2645. [PMID: 37174109 PMCID: PMC10177382 DOI: 10.3390/cancers15092645] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 05/02/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023] Open
Abstract
The tumor microenvironment plays a central role in the onset and progression of cancer in the bone. Cancer cells, either from tumors originating in the bone or from metastatic cancer cells from other body systems, are located in specialized niches where they interact with different cells of the bone marrow. These interactions transform the bone into an ideal niche for cancer cell migration, proliferation, and survival and cause an imbalance in bone homeostasis that severely affects the integrity of the skeleton. During the last decade, preclinical studies have identified new cellular mechanisms responsible for the dependency between cancer cells and bone cells. In this review, we focus on osteocytes, long-lived cells residing in the mineral matrix that have recently been identified as key players in the spread of cancer in bone. We highlight the most recent discoveries on how osteocytes support tumor growth and promote bone disease. Additionally, we discuss how the reciprocal crosstalk between osteocytes and cancer cells provides the opportunity to develop new therapeutic strategies to treat cancer in the bone.
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Affiliation(s)
- Aric Anloague
- Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Jesus Delgado-Calle
- Department of Physiology and Cell Biology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
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14
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Zheng L, Zhou D, Ju F, Liu Z, Yan C, Dong Z, Chen S, Deng L, Chan S, Deng J, Zhang X. Oscillating Fluid Flow Activated Osteocyte Lysate-Based Hydrogel for Regulating Osteoblast/Osteoclast Homeostasis to Enhance Bone Repair. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2204592. [PMID: 37017573 PMCID: PMC10214251 DOI: 10.1002/advs.202204592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 02/23/2023] [Indexed: 05/27/2023]
Abstract
As major regulators on bone formation/resorption in response to mechanical stimuli, osteocytes have shown great promise for restoring bone injury. However, due to the unmanageable and unabiding cell functions in unloading or diseased environments, the efficacy of osteogenic induction by osteocytes has been enormously limited. Herein, a facile method of oscillating fluid flow (OFF) loading for cell culture is reported, which enables osteocytes to initiate only osteogenesis and not the osteolysis process. After OFF loading, multiple and sufficient soluble mediators are produced in osteocytes, and the collected osteocyte lysates invariably induce robust osteoblastic differentiation and proliferation while restraining osteoclast generation and activity under unloading or pathological conditions. Mechanistic studies confirm that elevated glycolysis and activation of the ERK1/2 and Wnt/β-catenin pathways are the major contributors to the initiation of osteoinduction functions induced by osteocytes. Moreover, an osteocyte lysate-based hydrogel is designed to establish a stockpile of "active osteocytes" to sustainably deliver bioactive proteins, resulting in accelerated healing through regulation of endogenous osteoblast/osteoclast homeostasis.
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Affiliation(s)
- Liyuan Zheng
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory DiseasesSchool of Medicine, Shenzhen Campus of Sun Yat‐Sen UniversitySun Yat‐sen UniversityShenzhen518106P. R. China
| | - Disheng Zhou
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory DiseasesSchool of Medicine, Shenzhen Campus of Sun Yat‐Sen UniversitySun Yat‐sen UniversityShenzhen518106P. R. China
| | - Feier Ju
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory DiseasesSchool of Medicine, Shenzhen Campus of Sun Yat‐Sen UniversitySun Yat‐sen UniversityShenzhen518106P. R. China
| | - Zixuan Liu
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory DiseasesSchool of Medicine, Shenzhen Campus of Sun Yat‐Sen UniversitySun Yat‐sen UniversityShenzhen518106P. R. China
| | - Chenzhi Yan
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory DiseasesSchool of Medicine, Shenzhen Campus of Sun Yat‐Sen UniversitySun Yat‐sen UniversityShenzhen518106P. R. China
| | - Zhaoxia Dong
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory DiseasesSchool of Medicine, Shenzhen Campus of Sun Yat‐Sen UniversitySun Yat‐sen UniversityShenzhen518106P. R. China
| | - Shuna Chen
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory DiseasesSchool of Medicine, Shenzhen Campus of Sun Yat‐Sen UniversitySun Yat‐sen UniversityShenzhen518106P. R. China
| | - Lizhi Deng
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory DiseasesSchool of Medicine, Shenzhen Campus of Sun Yat‐Sen UniversitySun Yat‐sen UniversityShenzhen518106P. R. China
| | - Szehoi Chan
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory DiseasesSchool of Medicine, Shenzhen Campus of Sun Yat‐Sen UniversitySun Yat‐sen UniversityShenzhen518106P. R. China
| | - Junjie Deng
- Joint Centre of Translational MedicineThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang325000P. R. China
- Joint Centre of Translational MedicineWenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000P. R. China
- Zhejiang Engineering Research Center for Tissue Repair MaterialsWenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000P. R. China
| | - Xingding Zhang
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory DiseasesSchool of Medicine, Shenzhen Campus of Sun Yat‐Sen UniversitySun Yat‐sen UniversityShenzhen518106P. R. China
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15
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Teramachi J, Miki H, Nakamura S, Hiasa M, Harada T, Abe M. Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents. J Bone Miner Metab 2023; 41:388-403. [PMID: 36856824 PMCID: PMC9975874 DOI: 10.1007/s00774-023-01403-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 01/20/2023] [Indexed: 03/02/2023]
Abstract
INTRODUCTION Multiple myeloma (MM) is a malignancy of plasma cells with characteristic bone disease. Despite recent great strides achieved in MM treatment owing to the implementation of new anti-MM agents, MM is still incurable and bone destruction remains a serious unmet issue in patients with MM. APPROACH In this review, we will summarize and discuss the mechanisms of the formation of bone disease in MM and the available preclinical and clinical evidence on the treatment for MM bone disease. CONCLUSIONS MM cells produce a variety of cytokines to stimulate receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. MM cells alter the microenvironment through bone destruction where they colonize, which in turn favors tumor growth and survival, thereby forming a vicious cycle between tumor progression and bone destruction. Denosumab or zoledronic acid is currently recommended to be administered at the start of treatment in newly diagnosed patients with MM with bone disease. Proteasome inhibitors and the anti-CD38 monoclonal antibody daratumumab have been demonstrated to exert bone-modifying activity in responders. Besides their anti-tumor activity, the effects of new anti-MM agents on bone metabolism should be more precisely analyzed in patients with MM. Because prognosis in patients with MM has been significantly improved owing to the implementation of new agents, the therapeutic impact of bone-modifying agents should be re-estimated in the era of these new agents.
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Affiliation(s)
- Jumpei Teramachi
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
- Department of Oral Function and Anatomy, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Graduate School, 2-5-1 Shikata, Okayama, 700-8525, Japan.
| | - Hirokazu Miki
- Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital, Tokushima, Japan
| | - Shingen Nakamura
- Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Masahiro Hiasa
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
- Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Takeshi Harada
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
| | - Masahiro Abe
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
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16
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Intermediate-dose cyclophosphamide and bortezomib for PBSC mobilization in multiple myeloma. Transfus Apher Sci 2023:103649. [PMID: 36739175 DOI: 10.1016/j.transci.2023.103649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 01/28/2023] [Accepted: 01/30/2023] [Indexed: 02/04/2023]
Abstract
Although the incorporation of bortezomib into induction regimens has improved, response rates in patients with multiple myeloma (MM), the role of bortezomib in the, peripheral blood stem cell (PBSC) mobilization remains unclear. We assessed the, PBSC mobilization efficacy, safety, and disease response of intermediate-dose, cyclophosphamide and bortezomib in the PBSC mobilization. Twenty-one patients with, newly diagnosed MM were enrolled in a phase II, non-randomized study that used, bortezomib (1.3 mg/m2/day on days 1, 4, 8, and 11) and intermediate-dose, cyclophosphamide (2 g/m2/day on days 2, 3) (Bor-ID-CY). The data from 15 patients, who received intermediate-dose cyclophosphamide (ID-CY) were used as a historical, control group. The total CD34 + cell yield of Bor-ID-CY and ID-CY groups were not, significantly different (median 6.3 ×106/kg vs. 6.5 ×106/kg, p = 0.19). All three patients, with mobilization failure of two groups had t(11;14). Six patients in Bor-ID-CY group, were upgraded from a status that was less than a very good partial response (VGPR), at the time of PBSC mobilization to a VGPR or better after PBSC mobilization, (p = 0.014). Four patients in Bor-ID-CY group developed sepsis. The time to, engraftment was similar in the two groups. The addition of bortezomib to ID-CY did not, impact the stem cell yield or quality.
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17
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Zhang F, Zhuang J. Pathophysiology and therapeutic advances in myeloma bone disease. Chronic Dis Transl Med 2022; 8:264-270. [PMID: 36420171 PMCID: PMC9676126 DOI: 10.1002/cdt3.35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/19/2022] [Accepted: 05/26/2022] [Indexed: 11/11/2022] Open
Abstract
Bone disease is the most common complication in patients with multiple myeloma (MM), and it may lead to skeletal-related events (SREs) such as bone pain, pathological fractures, and spinal cord compression, which impair a patients' quality of life and survival. The pathogenesis of myeloma bone disease (MBD) involves disruption of bone reconstitution balance including excessive activation of osteoclasts, inhibition of osteoblasts, and participation of osteocytes and bone marrow stromal cells. Various factors, such as the receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG), dickkopf-1 (DKK-1), sclerostin, and activin-A, are involved in the development of MBD. Bisphosphonates and the anti-RANKL antibody denosumab are currently the main treatment options for MBD, delaying the onset of SREs. Denosumab is preferred in patients with MM and renal dysfunction. Although effective drugs have been approved, antimyeloma therapy is the most important method for controlling bone disease.
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Affiliation(s)
- Fujing Zhang
- Department of HematologyPeking Union Medical College HospitalBeijingChina
- Chinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Junling Zhuang
- Department of HematologyPeking Union Medical College HospitalBeijingChina
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18
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Melaccio A, Reale A, Saltarella I, Desantis V, Lamanuzzi A, Cicco S, Frassanito MA, Vacca A, Ria R. Pathways of Angiogenic and Inflammatory Cytokines in Multiple Myeloma: Role in Plasma Cell Clonal Expansion and Drug Resistance. J Clin Med 2022; 11:jcm11216491. [PMID: 36362718 PMCID: PMC9658666 DOI: 10.3390/jcm11216491] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 10/23/2022] [Accepted: 10/25/2022] [Indexed: 11/06/2022] Open
Abstract
Multiple myeloma (MM) is the second most common hematological malignancy, and despite the introduction of innovative therapies, remains an incurable disease. Identifying early and minimally or non-invasive biomarkers for predicting clinical outcomes and therapeutic responses is an active field of investigation. Malignant plasma cells (PCs) reside in the bone marrow (BM) microenvironment (BMME) which comprises cells (e.g., tumour, immune, stromal cells), components of the extracellular matrix (ECM) and vesicular and non-vesicular (soluble) molecules, all factors that support PCs’ survival and proliferation. The interaction between PCs and BM stromal cells (BMSCs), a hallmark of MM progression, is based not only on intercellular interactions but also on autocrine and paracrine circuits mediated by soluble or vesicular components. In fact, PCs and BMSCs secrete various cytokines, including angiogenic cytokines, essential for the formation of specialized niches called “osteoblastic and vascular niches”, thus supporting neovascularization and bone disease, vital processes that modulate the pathophysiological PCs–BMME interactions, and ultimately promoting disease progression. Here, we aim to discuss the roles of cytokines and growth factors in pathogenetic pathways in MM and as prognostic and predictive biomarkers. We also discuss the potential of targeted drugs that simultaneously block PCs’ proliferation and survival, PCs–BMSCs interactions and BMSCs activity, which may represent the future goal of MM therapy.
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Affiliation(s)
- Assunta Melaccio
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine “G. Baccelli”, University of Bari Medical School, 70124 Bari, Italy
- Correspondence: (A.M.); (R.R.); Tel.: +39-320-55-17-232 (A.M.)
| | - Antonia Reale
- Myeloma Research Group, Australian Centre for Blood Diseases, Central Clinical School, Monash University—Alfred Health, Melbourne 3004, Australia
| | - Ilaria Saltarella
- Department of Biomedical Sciences and Human Oncology, Pharmacology Section, University of Bari Aldo Moro Medical School, 70124 Bari, Italy
| | - Vanessa Desantis
- Department of Biomedical Sciences and Human Oncology, Pharmacology Section, University of Bari Aldo Moro Medical School, 70124 Bari, Italy
| | - Aurelia Lamanuzzi
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine “G. Baccelli”, University of Bari Medical School, 70124 Bari, Italy
| | - Sebastiano Cicco
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine “G. Baccelli”, University of Bari Medical School, 70124 Bari, Italy
| | - Maria Antonia Frassanito
- General Pathology Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy
| | - Angelo Vacca
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine “G. Baccelli”, University of Bari Medical School, 70124 Bari, Italy
| | - Roberto Ria
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine “G. Baccelli”, University of Bari Medical School, 70124 Bari, Italy
- Correspondence: (A.M.); (R.R.); Tel.: +39-320-55-17-232 (A.M.)
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19
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Lourenço D, Lopes R, Pestana C, Queirós AC, João C, Carneiro EA. Patient-Derived Multiple Myeloma 3D Models for Personalized Medicine-Are We There Yet? Int J Mol Sci 2022; 23:12888. [PMID: 36361677 PMCID: PMC9657251 DOI: 10.3390/ijms232112888] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/19/2022] [Accepted: 10/22/2022] [Indexed: 12/03/2023] Open
Abstract
Despite the wide variety of existing therapies, multiple myeloma (MM) remains a disease with dismal prognosis. Choosing the right treatment for each patient remains one of the major challenges. A new approach being explored is the use of ex vivo models for personalized medicine. Two-dimensional culture or animal models often fail to predict clinical outcomes. Three-dimensional ex vivo models using patients' bone marrow (BM) cells may better reproduce the complexity and heterogeneity of the BM microenvironment. Here, we review the strengths and limitations of currently existing patient-derived ex vivo three-dimensional MM models. We analyze their biochemical and biophysical properties, molecular and cellular characteristics, as well as their potential for drug testing and identification of disease biomarkers. Furthermore, we discuss the remaining challenges and give some insight on how to achieve a more biomimetic and accurate MM BM model. Overall, there is still a need for standardized culture methods and refined readout techniques. Including both myeloma and other cells of the BM microenvironment in a simple and reproducible three-dimensional scaffold is the key to faithfully mapping and examining the relationship between these players in MM. This will allow a patient-personalized profile, providing a powerful tool for clinical and research applications.
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Affiliation(s)
- Diana Lourenço
- Myeloma Lymphoma Research Group—Champalimaud Experimental Clinical Research Programme of Champalimaud Foundation, 1400-038 Lisbon, Portugal
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Raquel Lopes
- Myeloma Lymphoma Research Group—Champalimaud Experimental Clinical Research Programme of Champalimaud Foundation, 1400-038 Lisbon, Portugal
- Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal
| | - Carolina Pestana
- Myeloma Lymphoma Research Group—Champalimaud Experimental Clinical Research Programme of Champalimaud Foundation, 1400-038 Lisbon, Portugal
- Centre of Statistics and Its Applications, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal
| | - Ana C. Queirós
- Myeloma Lymphoma Research Group—Champalimaud Experimental Clinical Research Programme of Champalimaud Foundation, 1400-038 Lisbon, Portugal
| | - Cristina João
- Myeloma Lymphoma Research Group—Champalimaud Experimental Clinical Research Programme of Champalimaud Foundation, 1400-038 Lisbon, Portugal
- Faculty of Medical Sciences, NOVA Medical School, 1169-056 Lisbon, Portugal
- Hemato-Oncology Department of Champalimaud Foundation, 1400-038 Lisbon, Portugal
| | - Emilie Arnault Carneiro
- Myeloma Lymphoma Research Group—Champalimaud Experimental Clinical Research Programme of Champalimaud Foundation, 1400-038 Lisbon, Portugal
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20
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Liu H, He J, Bagheri-Yarmand R, Li Z, Liu R, Wang Z, Bach DH, Huang YH, Lin P, Guise TA, Gagel RF, Yang J. Osteocyte CIITA aggravates osteolytic bone lesions in myeloma. Nat Commun 2022; 13:3684. [PMID: 35760800 PMCID: PMC9237076 DOI: 10.1038/s41467-022-31356-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 06/15/2022] [Indexed: 11/09/2022] Open
Abstract
Osteolytic destruction is a hallmark of multiple myeloma, resulting from activation of osteoclast-mediated bone resorption and reduction of osteoblast-mediated bone formation. However, the molecular mechanisms underlying the differentiation and activity of osteoclasts and osteoblasts within a myelomatous microenvironment remain unclear. Here, we demonstrate that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions. CIITA upregulates the secretion of osteolytic cytokines from osteocytes through acetylation at histone 3 lysine 14 in the promoter of TNFSF11 (encoding RANKL) and SOST (encoding sclerostin), leading to enhanced osteoclastogenesis and decreased osteoblastogenesis. In turn, myeloma cell-secreted 2-deoxy-D-ribose, the product of thymidine catalyzed by the function of thymidine phosphorylase, upregulates CIITA expression in osteocytes through the STAT1/IRF1 signaling pathway. Our work thus broadens the understanding of myeloma-induced osteolysis and indicates a potential strategy for disrupting tumor-osteocyte interaction to prevent or treat patients with myeloma bone disease.
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Affiliation(s)
- Huan Liu
- Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA.,Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Jin He
- Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA.,Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rozita Bagheri-Yarmand
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Zongwei Li
- Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA.,Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rui Liu
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Zhiming Wang
- Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA.,Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Duc-Hiep Bach
- Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA
| | - Yung-Hsing Huang
- Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA
| | - Pei Lin
- Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Theresa A Guise
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Robert F Gagel
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Jing Yang
- Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA. .,Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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21
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Sabol HM, Amorim T, Ashby C, Halladay D, Anderson J, Cregor M, Sweet M, Nookaew I, Kurihara N, Roodman GD, Bellido T, Delgado-Calle J. Notch3 signaling between myeloma cells and osteocytes in the tumor niche promotes tumor growth and bone destruction. Neoplasia 2022; 28:100785. [PMID: 35390742 PMCID: PMC8990177 DOI: 10.1016/j.neo.2022.100785] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 03/10/2022] [Indexed: 12/03/2022]
Abstract
In multiple myeloma (MM), communication via Notch signaling in the tumor niche stimulates tumor progression and bone destruction. We previously showed that osteocytes activate Notch, increase Notch3 expression, and stimulate proliferation in MM cells. We show here that Notch3 inhibition in MM cells reduced MM proliferation, decreased Rankl expression, and abrogated the ability of MM cells to promote osteoclastogenesis. Further, Notch3 inhibition in MM cells partially prevented the Notch activation and increased proliferation induced by osteocytes, demonstrating that Notch3 mediates MM-osteocyte communication. Consistently, pro-proliferative and pro-osteoclastogenic pathways were upregulated in CD138+ cells from newly diagnosed MM patients with high vs. low NOTCH3 expression. These results show that NOTCH3 signaling in MM cells stimulates proliferation and increases their osteoclastogenic potential. In contrast, Notch2 inhibition did not alter MM cell proliferation or communication with osteocytes. Lastly, mice injected with Notch3 knock-down MM cells had a 50% decrease in tumor burden and a 50% reduction in osteolytic lesions than mice bearing control MM cells. Together, these findings identify Notch3 as a mediator of cell communication among MM cells and between MM cells and osteocytes in the MM tumor niche and warrant future studies to exploit Notch3 as a therapeutic target to treat MM.
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Affiliation(s)
- Hayley M Sabol
- Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Tânia Amorim
- Medicine, Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Cody Ashby
- Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR, United States; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, United States
| | - David Halladay
- Medicine, Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Judith Anderson
- Medicine, Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Meloney Cregor
- Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Megan Sweet
- Medicine, Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Intawat Nookaew
- Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR, United States; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, United States
| | - Noriyoshi Kurihara
- Medicine, Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - G David Roodman
- Medicine, Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Teresita Bellido
- Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, United States; Central Arkansas Veterans Healthcare System, Little Rock, AR, United States; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, United States
| | - Jesus Delgado-Calle
- Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, United States; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, United States.
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22
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Lin JM, Yuan XJ, Zhang L, Li G, Gan XR, Xu WH. Does Waldenstrom's macroglobulinemia also cause bone destruction? A rare case report. J Int Med Res 2022; 50:3000605221096161. [PMID: 35485877 PMCID: PMC9067037 DOI: 10.1177/03000605221096161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 04/05/2022] [Indexed: 12/03/2022] Open
Abstract
Waldenstrom's macroglobulinemia (WM) is a rare type of malignant B-cell lymphoma. The main feature of WM is elevated serum monoclonal immunoglobulin M, similar to multiple myeloma (MM). Unlike in MM, the rarity of destructive bone lesions in WM has been repeatedly emphasized. We report a unique case of WM with a vertebral compression fracture as the first symptom. This case highlights that the presence or absence of bone destruction may not clearly distinguish between WM and MM. The possibility of WM should be considered in patients with vertebral fracture and destruction as the first presentation. Performing vertebral bone marrow aspiration biopsy during percutaneous vertebroplasty is a convenient and effective method to assist in the diagnosis of WM.
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Affiliation(s)
- Jun-Ming Lin
- Department of Orthopaedic Surgery, People’s Hospital of Yichun City, Jiangxi Province, P.R. China
| | - Xiao-Jun Yuan
- Department of Orthopaedic Surgery, People’s Hospital of Yichun City, Jiangxi Province, P.R. China
| | - Lu Zhang
- Department of Assisted Reproduction, Yichun Maternal and Child Health Hospital, Jiangxi Province, P.R. China
| | - Guang Li
- Department of Orthopaedic Surgery, People’s Hospital of Yichun City, Jiangxi Province, P.R. China
| | - Xin-rong Gan
- Department of Orthopaedic Surgery, People’s Hospital of Yichun City, Jiangxi Province, P.R. China
| | - Wen-Hua Xu
- Department of Orthopaedic Surgery, People’s Hospital of Yichun City, Jiangxi Province, P.R. China
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23
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Gau YC, Yeh TJ, Hsu CM, Hsiao SY, Hsiao HH. Pathogenesis and Treatment of Myeloma-Related Bone Disease. Int J Mol Sci 2022; 23:ijms23063112. [PMID: 35328533 PMCID: PMC8951013 DOI: 10.3390/ijms23063112] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/04/2022] [Accepted: 03/09/2022] [Indexed: 02/06/2023] Open
Abstract
Multiple myeloma is a hematologic malignancy of plasma cells that causes bone-destructive lesions and associated skeletal-related events (SREs). The pathogenesis of myeloma-related bone disease (MBD) is the imbalance of the bone-remodeling process, which results from osteoclast activation, osteoblast suppression, and the immunosuppressed bone marrow microenvironment. Many important signaling cascades, including the RANKL/RANK/OPG axis, Notch signaling, the Wnt/β-Catenin signaling pathways, and signaling molecules, such as DKK-1, sclerostin, osteopontin, activin A, chemokines, and interleukins are involved and play critical roles in MBD. Currently, bisphosphonate and denosumab are the gold standard for MBD prevention and treatment. As the molecular mechanisms of MBD become increasingly well understood, novel agents are being thoroughly explored in both preclinical and clinical settings. Herein, we will provide an updated overview of the pathogenesis of MBD, summarize the clinical management and guidelines, and discuss novel bone-modifying therapies for further management of MBD.
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Affiliation(s)
- Yuh-Ching Gau
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (Y.-C.G.); (T.-J.Y.); (C.-M.H.)
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Tsung-Jang Yeh
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (Y.-C.G.); (T.-J.Y.); (C.-M.H.)
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chin-Mu Hsu
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (Y.-C.G.); (T.-J.Y.); (C.-M.H.)
| | - Samuel Yien Hsiao
- Department of Biology, University of Rutgers-Camden, Camden, NJ 08102, USA;
| | - Hui-Hua Hsiao
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (Y.-C.G.); (T.-J.Y.); (C.-M.H.)
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Faculty of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Correspondence: ; Tel.: +816-7-3162429
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24
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Sethakorn N, Heninger E, Sánchez-de-Diego C, Ding AB, Yada RC, Kerr SC, Kosoff D, Beebe DJ, Lang JM. Advancing Treatment of Bone Metastases through Novel Translational Approaches Targeting the Bone Microenvironment. Cancers (Basel) 2022; 14:757. [PMID: 35159026 PMCID: PMC8833657 DOI: 10.3390/cancers14030757] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/21/2022] [Accepted: 01/29/2022] [Indexed: 02/04/2023] Open
Abstract
Bone metastases represent a lethal condition that frequently occurs in solid tumors such as prostate, breast, lung, and renal cell carcinomas, and increase the risk of skeletal-related events (SREs) including pain, pathologic fractures, and spinal cord compression. This unique metastatic niche consists of a multicellular complex that cancer cells co-opt to engender bone remodeling, immune suppression, and stromal-mediated therapeutic resistance. This review comprehensively discusses clinical challenges of bone metastases, novel preclinical models of the bone and bone marrow microenviroment, and crucial signaling pathways active in bone homeostasis and metastatic niche. These studies establish the context to summarize the current state of investigational agents targeting BM, and approaches to improve BM-targeting therapies. Finally, we discuss opportunities to advance research in bone and bone marrow microenvironments by increasing complexity of humanized preclinical models and fostering interdisciplinary collaborations to translational research in this challenging metastatic niche.
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Affiliation(s)
- Nan Sethakorn
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA; (N.S.); (E.H.); (C.S.-d.-D.); (A.B.D.); (S.C.K.); (D.K.); (D.J.B.)
- Division of Hematology/Oncology, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, USA
- Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Erika Heninger
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA; (N.S.); (E.H.); (C.S.-d.-D.); (A.B.D.); (S.C.K.); (D.K.); (D.J.B.)
| | - Cristina Sánchez-de-Diego
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA; (N.S.); (E.H.); (C.S.-d.-D.); (A.B.D.); (S.C.K.); (D.K.); (D.J.B.)
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA;
| | - Adeline B. Ding
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA; (N.S.); (E.H.); (C.S.-d.-D.); (A.B.D.); (S.C.K.); (D.K.); (D.J.B.)
| | - Ravi Chandra Yada
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA;
| | - Sheena C. Kerr
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA; (N.S.); (E.H.); (C.S.-d.-D.); (A.B.D.); (S.C.K.); (D.K.); (D.J.B.)
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA;
| | - David Kosoff
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA; (N.S.); (E.H.); (C.S.-d.-D.); (A.B.D.); (S.C.K.); (D.K.); (D.J.B.)
- Division of Hematology/Oncology, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, USA
- Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - David J. Beebe
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA; (N.S.); (E.H.); (C.S.-d.-D.); (A.B.D.); (S.C.K.); (D.K.); (D.J.B.)
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA;
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Joshua M. Lang
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA; (N.S.); (E.H.); (C.S.-d.-D.); (A.B.D.); (S.C.K.); (D.K.); (D.J.B.)
- Division of Hematology/Oncology, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, USA
- Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
- Wisconsin Institutes for Medical Research, 1111 Highland Ave., Madison, WI 53705, USA
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25
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Satcher RL, Zhang XHF. Evolving cancer-niche interactions and therapeutic targets during bone metastasis. Nat Rev Cancer 2022; 22:85-101. [PMID: 34611349 DOI: 10.1038/s41568-021-00406-5] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/02/2021] [Indexed: 12/14/2022]
Abstract
Many cancer types metastasize to bone. This propensity may be a product of genetic traits of the primary tumour in some cancers. Upon arrival, cancer cells establish interactions with various bone-resident cells during the process of colonization. These interactions, to a large degree, dictate cancer cell fates at multiple steps of the metastatic cascade, from single cells to overt metastases. The bone microenvironment may even influence cancer cells to subsequently spread to multiple other organs. Therefore, it is imperative to spatiotemporally delineate the evolving cancer-bone crosstalk during bone colonization. In this Review, we provide a summary of the bone microenvironment and its impact on bone metastasis. On the basis of the microscopic anatomy, we tentatively define a roadmap of the journey of cancer cells through bone relative to various microenvironment components, including the potential of bone to function as a launch pad for secondary metastasis. Finally, we examine common and distinct features of bone metastasis from various cancer types. Our goal is to stimulate future studies leading to the development of a broader scope of potent therapies.
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Affiliation(s)
- Robert L Satcher
- Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiang H-F Zhang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
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26
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Abstract
Osteocytes, former osteoblasts encapsulated by mineralized bone matrix, are far from being passive and metabolically inactive bone cells. Instead, osteocytes are multifunctional and dynamic cells capable of integrating hormonal and mechanical signals and transmitting them to effector cells in bone and in distant tissues. Osteocytes are a major source of molecules that regulate bone homeostasis by integrating both mechanical cues and hormonal signals that coordinate the differentiation and function of osteoclasts and osteoblasts. Osteocyte function is altered in both rare and common bone diseases, suggesting that osteocyte dysfunction is directly involved in the pathophysiology of several disorders affecting the skeleton. Advances in osteocyte biology initiated the development of novel therapeutics interfering with osteocyte-secreted molecules. Moreover, osteocytes are targets and key distributors of biological signals mediating the beneficial effects of several bone therapeutics used in the clinic. Here we review the most recent discoveries in osteocyte biology demonstrating that osteocytes regulate bone homeostasis and bone marrow fat via paracrine signaling, influence body composition and energy metabolism via endocrine signaling, and contribute to the damaging effects of diabetes mellitus and hematologic and metastatic cancers in the skeleton.
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Affiliation(s)
- Jesus Delgado-Calle
- 1Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas,2Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Teresita Bellido
- 1Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas,2Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas,3Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
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27
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Abstract
PURPOSE OF REVIEW While the function of osteocytes under physiologic conditions is well defined, their role and involvement in cancer disease remains relatively unexplored, especially in a context of non-bone metastatic cancer. This review will focus on describing the more advanced knowledge regarding the interactions between osteocytes and cancer. RECENT FINDINGS We will discuss the involvement of osteocytes in the onset and progression of osteosarcoma, with the common bone cancers, as well as the interaction that is established between osteocytes and multiple myeloma. Mechanisms responsible for cancer dissemination to bone, as frequently occur with advanced breast and prostate cancers, will be reviewed. While a role for osteocytes in the stimulation and proliferation of cancer cells has been reported, protective effects of osteocytes against bone colonization have been described as well, thus increasing ambiguity regarding the role of osteocytes in cancer progression and dissemination. Lastly, supporting the idea that skeletal defects can occur also in the absence of direct cancer dissemination or osteolytic lesions directly adjacent to the bone, our recent findings will be presented showing that in the absence of bone metastases, the bone microenvironment and, particularly, osteocytes, can manifest a clear and dramatic response to the distant, non-metastatic tumor. Our observations support new studies to clarify whether treatments designed to preserve the osteocytes can be combined with traditional anticancer therapies, even when bone is not directly affected by tumor growth.
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Affiliation(s)
- Fabrizio Pin
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Matt Prideaux
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Lynda F Bonewald
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
- Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Andrea Bonetto
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
- Department of Otolaryngology-Head & Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
- Department of Surgery, Indiana University School of Medicine, 980 W Walnut Street, R3-C522, Indianapolis, IN, 46202, USA.
- Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA.
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28
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Abstract
PURPOSE OF REVIEW In this review, we provide an overview of what is currently known about the impacts of mechanical stimuli on metastatic tumor-induced bone disease (TIBD). Further, we focus on the role of the osteocyte, the skeleton's primary mechanosensory cell, which is central to the skeleton's mechanoresponse, sensing and integrating local mechanical stimuli, and then controlling the downstream remodeling balance as appropriate. RECENT FINDINGS Exercise and controlled mechanical loading have anabolic effects on bone tissue in models of bone metastasis. They also have anti-tumorigenic properties, in part due to offsetting the vicious cycle of osteolytic bone loss as well as regulating inflammatory signals. The impacts of metastatic cancer on the mechanosensory function of osteocytes remains unclear. Increased mechanical stimuli are a potential method for mitigating TIBD.
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Affiliation(s)
- Blayne A Sarazin
- Department of Mechanical Engineering, University of Colorado, 427 UCB, Boulder, CO, 80309, USA
| | - Claire L Ihle
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Philip Owens
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Department of Veterans Affairs, Research Service, Eastern Colorado Health Care System, Aurora, CO, 80045, USA
| | - Maureen E Lynch
- Department of Mechanical Engineering, University of Colorado, 427 UCB, Boulder, CO, 80309, USA.
- Biofrontiers Institute, University of Colorado, Boulder, CO, 80309, USA.
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29
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Li Y, Zhang L, Xu T, Zhao X, Jiang X, Xiao F, Sun H, Wang L. Aberrant ENPP2 expression promotes tumor progression in multiple myeloma. Leuk Lymphoma 2021; 63:963-974. [PMID: 34847837 DOI: 10.1080/10428194.2021.2010055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) has been recently linked to tumor development. However, its role in modulating multiple myeloma (MM) disease progression remains unclear. Here, we demonstrated that CD138+ cells isolated from MM patients presented with higher expression of ENPP2 compared with CD138- cells. Treatment of MM cells with IL-6 resulted in ENPP2 upregulation. ENPP2 overexpression promoted proliferation, inhibited apoptosis, increased lysophosphatidic acid (LPA) generation, and upregulated osteoclastogenesis mediator expression in MM cells. In contrast, ENPP2 inhibition induced apoptosis, suppressed proliferation and survival, decreased LPA generation and downregulated osteoclastogenesis mediator expression. In an MM xenograft mouse model, ENPP2 knockdown significantly reduced MM tumor burden by inhibiting cell proliferation and inducing apoptosis. Furthermore, ENPP2 knockdown decreased the levels of LPA, osteoclastogenesis mediators in sera of mice with MM. Our findings revealed the tumor-promoting role of ENPP2 in MM, thus providing new molecular evidence for targeting the ENPP2-LPA axis in MM therapy.
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Affiliation(s)
- Yuxiang Li
- Laboratory of Molecular Diagnosis and Regenerative Medicine, the Affiliate Hospital of Qingdao University, Qingdao, P. R. China.,Department of Neuroimmune and Antibody Engineering, Beijing Institute of Basic Medical Sciences, Beijing, P.R. China
| | - Lin Zhang
- Laboratory of Molecular Diagnosis and Regenerative Medicine, the Affiliate Hospital of Qingdao University, Qingdao, P. R. China
| | - Tianxin Xu
- School of Nursing, Jilin University, Changchun, P. R. China
| | - Xia Zhao
- Laboratory of Molecular Diagnosis and Regenerative Medicine, the Affiliate Hospital of Qingdao University, Qingdao, P. R. China
| | - Xiaona Jiang
- Laboratory of Molecular Diagnosis and Regenerative Medicine, the Affiliate Hospital of Qingdao University, Qingdao, P. R. China
| | - Fengjun Xiao
- Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing, P.R. China
| | - Huiyan Sun
- Central Laboratory, Hebei Yanda Medical Research Institute, Sanhe, P. R. China
| | - Lisheng Wang
- Laboratory of Molecular Diagnosis and Regenerative Medicine, the Affiliate Hospital of Qingdao University, Qingdao, P. R. China.,Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing, P.R. China
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Myeloma-Bone Interaction: A Vicious Cycle via TAK1-PIM2 Signaling. Cancers (Basel) 2021; 13:cancers13174441. [PMID: 34503251 PMCID: PMC8431187 DOI: 10.3390/cancers13174441] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Myeloma cells interact with their ambient cells in the bone, such as bone marrow stromal cells, osteoclasts, and osteocytes, resulting in enhancement of osteoclastogenesis and inhibition of osteoblastogenesis while enhancing their growth and drug resistance. The activation of the TAK1–PIM2 signaling axis appears to be vital for this mutual interaction, posing it as an important therapeutic target to suppress tumor expansion and ameliorate bone destruction in multiple myeloma. Abstract Multiple myeloma (MM) has a propensity to develop preferentially in bone and form bone-destructive lesions. MM cells enhance osteoclastogenesis and bone resorption through activation of the RANKL–NF-κB signaling pathway while suppressing bone formation by inhibiting osteoblastogenesis from bone marrow stromal cells (BMSCs) by factors elaborated in the bone marrow and bone in MM, including the soluble Wnt inhibitors DKK-1 and sclerostin, activin A, and TGF-β, resulting in systemic bone destruction with loss of bone. Osteocytes have been drawn attention as multifunctional regulators in bone metabolism. MM cells induce apoptosis in osteocytes to trigger the production of factors, including RANKL, sclerostin, and DKK-1, to further exacerbate bone destruction. Bone lesions developed in MM, in turn, provide microenvironments suited for MM cell growth/survival, including niches to foster MM cells and their precursors. Thus, MM cells alter the microenvironments through bone destruction in the bone where they reside, which in turn potentiates tumor growth and survival, thereby generating a vicious loop between tumor progression and bone destruction. The serine/threonine kinases PIM2 and TAK1, an upstream mediator of PIM2, are overexpressed in bone marrow stromal cells and osteoclasts as well in MM cells in bone lesions. Upregulation of the TAK1–PIM2 pathway plays a critical role in tumor expansion and bone destruction, posing the TAK1–PIM2 pathway as a pivotal therapeutic target in MM.
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Xiao S, Li L, Yao J, Wang L, Li K, Yang C, Wang C, Fan Y. Microcracks on the Rat Root Surface Induced by Orthodontic Force, Crack Extension Simulation, and Proteomics Study. Ann Biomed Eng 2021; 49:2228-2242. [PMID: 33686616 DOI: 10.1007/s10439-021-02733-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 01/13/2021] [Indexed: 12/12/2022]
Abstract
Root resorption is a common complication during orthodontic treatment. Microcracks occur on the root surface after an orthodontic force is applied and may be related to the root resorption caused by the orthodontic process. However, the mechanisms underlying root resorption induced by microcracks remain unclear. In this study, a rat orthodontic model was used to investigate the biological mechanisms of root resorption caused by microcracks. First, the first molar was loaded with 0.5-N orthodontic force for 7 days, and microcracks were observed on the root apex surface using a scanning electron microscope. Second, to describe the mechanical principle resulting in microcracks, a finite element model of rat orthodontics was established, which showed that a maximum stress on the root apex can cause microcrack extension. Third, after 7 days of loading in vivo, histological observation revealed that root resorption occurred in the stress concentration area and cementoclasts appeared in the resorption cavity. Finally, proteomics analysis of the root apex area, excluding the periodontal ligament, revealed that the NOX2, Aifm1, and MAPK signaling pathways were involved in the root resorption process. Microcrack extension on the root surface increases calcium ion concentrations, alters the proteins related to root resorption, and promotes cementoclast formation.
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Affiliation(s)
- Shengzhao Xiao
- Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Chinese Education Ministry, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China
| | - Linhao Li
- Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Chinese Education Ministry, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China.
| | - Jie Yao
- Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Chinese Education Ministry, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China
| | - Lizhen Wang
- Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Chinese Education Ministry, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China
| | - Kaimin Li
- Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Chinese Education Ministry, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China
| | - Chongshi Yang
- College of Stomatology, Chongqing Medical University, Chongqing, 401147, China
| | - Chao Wang
- Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Chinese Education Ministry, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China
- College of Stomatology, Chongqing Medical University, Chongqing, 401147, China
| | - Yubo Fan
- Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Chinese Education Ministry, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China.
- School of Engineering Medicine, Beihang University, Beijing, 100083, China.
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32
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Non-bone metastatic cancers promote osteocyte-induced bone destruction. Cancer Lett 2021; 520:80-90. [PMID: 34233150 DOI: 10.1016/j.canlet.2021.06.030] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 06/24/2021] [Accepted: 06/29/2021] [Indexed: 02/07/2023]
Abstract
The effects of bone metastatic cancer on the skeleton are well described, whereas less is known regarding the effects of non-metastatic bone cancer on bone. Here we investigated the effects of three non-bone metastatic cancer cachexia models, namely Colon-26 adenocarcinoma (C26), ES-2 ovarian cancer (ES-2), and Lewis lung carcinoma (LLC). Even though C26, ES-2 and LLC tumor growth resulted in comparable weight and muscle loss, the ES-2 and LLC hosts exhibited severe bone loss, whereas only modest bone loss was observed in the C26 bearers, correlating with increased TRAP+ osteoclasts in the femurs of ES-2 and LLC but not C26 hosts. Surprisingly, all three showed increased osteocyte lacunar area indicating osteocytic osteolysis and displayed dramatically increased osteocyte death, as well as empty lacunae. To test whether tumor-secreted factors were responsible for the observed effect, IDG-SW3 osteocyte cells were co-cultured with cancer cells in permeable trans-wells. Apoptosis was observed in the osteocyte cells exposed to all three cancer cell lines suggesting that all tumors were cytotoxic for osteocytes. In addition, the expression of the osteoclastic markers, Acp5, CtsK, Atp6v0d2 and Mmp13, was elevated in IDG-SW3 osteocytes exposed to tumor factors, supporting the in vivo observations of increased lacunar size due to osteocytic osteolysis. For the first time, we describe osteocytic bone destruction and extensive osteocyte cell death in non-bone metastatic cancer. These bone alterations, in conjunction with muscle wasting, may create a musculoskeletal system that is incapable of full recovery upon eradication of tumor. Co-treatment with bone preserving therapies should be considered.
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Mukkamalla SKR, Malipeddi D. Myeloma Bone Disease: A Comprehensive Review. Int J Mol Sci 2021; 22:6208. [PMID: 34201396 PMCID: PMC8227693 DOI: 10.3390/ijms22126208] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 05/17/2021] [Accepted: 06/03/2021] [Indexed: 12/11/2022] Open
Abstract
Multiple myeloma (MM) is a neoplastic clonal proliferation of plasma cells in the bone marrow microenvironment, characterized by overproduction of heavy- and light-chain monoclonal proteins (M-protein). These proteins are mainly found in the serum and/or urine. Reduction in normal gammaglobulins (immunoparesis) leads to an increased risk of infection. The primary site of origin is the bone marrow for nearly all patients affected by MM with disseminated marrow involvement in most cases. MM is known to involve bones and result in myeloma bone disease. Osteolytic lesions are seen in 80% of patients with MM which are complicated frequently by skeletal-related events (SRE) such as hypercalcemia, bone pain, pathological fractures, vertebral collapse, and spinal cord compression. These deteriorate the patient's quality of life and affect the overall survival of the patient. The underlying pathogenesis of myeloma bone disease involves uncoupling of the bone remodeling processes. Interaction of myeloma cells with the bone marrow microenvironment promotes the release of many biochemical markers including osteoclast activating factors and osteoblast inhibitory factors. Elevated levels of osteoclast activating factors such as RANK/RANKL/OPG, MIP-1-α., TNF-α, IL-3, IL-6, and IL-11 increase bone resorption by osteoclast stimulation, differentiation, and maturation, whereas osteoblast inhibitory factors such as the Wnt/DKK1 pathway, secreted frizzle related protein-2, and runt-related transcription factor 2 inhibit osteoblast differentiation and formation leading to decreased bone formation. These biochemical factors also help in development and utilization of appropriate anti-myeloma treatments in myeloma patients. This review article summarizes the pathophysiology and the recent developments of abnormal bone remodeling in MM, while reviewing various approved and potential treatments for myeloma bone disease.
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Affiliation(s)
| | - Dhatri Malipeddi
- Internal Medicine, Canton Medical Education Foundation/NEOMED, Canton, OH 44710, USA;
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34
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Adhikari M, Delgado-Calle J. Role of Osteocytes in Cancer Progression in the Bone and the Associated Skeletal Disease. Curr Osteoporos Rep 2021; 19:247-255. [PMID: 33818732 PMCID: PMC8486016 DOI: 10.1007/s11914-021-00679-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2021] [Indexed: 11/29/2022]
Abstract
PURPOSE OF REVIEW The goal of this manuscript is to review the current knowledge on the role of osteocytes in cancer in the bone, discuss the potential of osteocytes as a therapeutic target, and propose future research needed to understand the crosstalk between cancer cells and osteocytes in the tumor niche. RECENT FINDINGS Numerous studies have established that cancer cells manipulate osteocytes to facilitate invasion and tumor progression in bone. Moreover, cancer cells dysregulate osteocyte function to disrupt physiological bone remodeling, leading to the development of bone disease. Targeting osteocytes and their derived factors has proven to effectively interfere with the progression of cancer in the bone and the associated bone disease. Osteocytes communicate with cancer cells and are also part of the vicious cycle of cancer in the bone. Additional studies investigating the role of osteocytes on metastases to the bone and the development of drug resistance are needed.
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Affiliation(s)
- Manish Adhikari
- Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
| | - Jesús Delgado-Calle
- Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
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35
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Giannakoulas N, Ntanasis-Stathopoulos I, Terpos E. The Role of Marrow Microenvironment in the Growth and Development of Malignant Plasma Cells in Multiple Myeloma. Int J Mol Sci 2021; 22:ijms22094462. [PMID: 33923357 PMCID: PMC8123209 DOI: 10.3390/ijms22094462] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 04/20/2021] [Accepted: 04/22/2021] [Indexed: 12/16/2022] Open
Abstract
The development and effectiveness of novel therapies in multiple myeloma have been established in large clinical trials. However, multiple myeloma remains an incurable malignancy despite significant therapeutic advances. Accumulating data have elucidated our understanding of the genetic background of the malignant plasma cells along with the role of the bone marrow microenvironment. Currently, the interaction among myeloma cells and the components of the microenvironment are considered crucial in multiple myeloma pathogenesis. Adhesion molecules, cytokines and the extracellular matrix play a critical role in the interplay among genetically transformed clonal plasma cells and stromal cells, leading to the proliferation, progression and survival of myeloma cells. In this review, we provide an overview of the multifaceted role of the bone marrow microenvironment in the growth and development of malignant plasma cells in multiple myeloma.
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Affiliation(s)
- Nikolaos Giannakoulas
- Department of Hematology of University Hospital of Larisa, Faculty of Medicine, University of Thessaly, 41110 Larisa, Greece;
| | - Ioannis Ntanasis-Stathopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece;
| | - Evangelos Terpos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece;
- Correspondence:
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Moloudizargari M, Hekmatirad S, Mofarahe ZS, Asghari MH. Exosomal microRNA panels as biomarkers for hematological malignancies. Curr Probl Cancer 2021; 45:100726. [PMID: 33752898 DOI: 10.1016/j.currproblcancer.2021.100726] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 02/11/2021] [Indexed: 02/07/2023]
Abstract
Hematological malignancies are classified as a heterogeneous category of cancers with various degrees of incidence and prognosis and different etiologies. Due to their aggressive essence they should be diagnosed as early as possible to improve prognosis, treatment outcome and survival. Bases on the limitations of previously identified biomarkers in terms of sensitivity, specificity and predictability, it is necessary to develop new diagnostic tools and biomarkers for the early diagnosis of hematological malignancies. Exosomes are nanovesicles secreted by almost all cell types in both physiological and pathological conditions. They play major roles in intercellular communication and are recently being considered as disease biomarkers. These nanovesicles carry proteins, lipids and nucleic acids like microRNAs (miRNAs). miRNAs are small noncoding RNAs, which act as translational suppressors via regulating protein-coding genes. The aberrant expression of miRNAs has been shown in various conditions including hematological malignancies. Moreover, it is now known that tumor cells secrete higher amounts of exosomes compared to normal cells. The idea of using exosomal miRNAs in serum as biomarkers is based on their surprisingly high stability and specificity. In the present paper, we reviewed and recommended exosomal miRNA panels including (miR-150, miR-155 and miR-1246), (miR-17-5p, miR-20a-5p, miR-16-5p and miR-5a-5p), (miR-18a, Let-7b) and (miR192-5p, miR21-5p, miR320b and Let-7d), for their potential to be used as non-invasive biomarkers in different hematological malignancies such as multiple myeloma, leukemia, and lymphoma.
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Affiliation(s)
- Milad Moloudizargari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shirin Hekmatirad
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Zahra Shams Mofarahe
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Asghari
- Department of Pharmacology and Toxicology, School of Medicine, Babol University of Medical Sciences, Babol, Iran.
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Osteocyte Vegf-a contributes to myeloma-associated angiogenesis and is regulated by Fgf23. Sci Rep 2020; 10:17319. [PMID: 33057033 PMCID: PMC7560700 DOI: 10.1038/s41598-020-74352-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 09/16/2020] [Indexed: 12/12/2022] Open
Abstract
Multiple Myeloma (MM) induces bone destruction, decreases bone formation, and increases marrow angiogenesis in patients. We reported that osteocytes (Ocys) directly interact with MM cells to increase tumor growth and expression of Ocy-derived factors that promote bone resorption and suppress bone formation. However, the contribution of Ocys to enhanced marrow vascularization in MM is unclear. Since the MM microenvironment is hypoxic, we assessed if hypoxia and/or interactions with MM cells increases pro-angiogenic signaling in Ocys. Hypoxia and/or co-culture with MM cells significantly increased Vegf-a expression in MLOA5-Ocys, and conditioned media (CM) from MLOA5s or MM-MLOA5 co-cultured in hypoxia, significantly increased endothelial tube length compared to normoxic CM. Further, Vegf-a knockdown in MLOA5s or primary Ocys co-cultured with MM cells or neutralizing Vegf-a in MM-Ocy co-culture CM completely blocked the increased endothelial activity. Importantly, Vegf-a-expressing Ocy numbers were significantly increased in MM-injected mouse bones, positively correlating with tumor vessel area. Finally, we demonstrate that direct contact with MM cells increases Ocy Fgf23, which enhanced Vegf-a expression in Ocys. Fgf23 deletion in Ocys blocked these changes. These results suggest hypoxia and MM cells induce a pro-angiogenic phenotype in Ocys via Fgf23 and Vegf-a signaling, which can promote MM-induced marrow vascularization.
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38
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Pathogenic Mechanisms of Myeloma Bone Disease and Possible Roles for NRF2. Int J Mol Sci 2020; 21:ijms21186723. [PMID: 32937821 PMCID: PMC7555756 DOI: 10.3390/ijms21186723] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/07/2020] [Accepted: 09/12/2020] [Indexed: 12/14/2022] Open
Abstract
Osteolytic bone lesions are one of the central features of multiple myeloma (MM) and lead to bone pain, fractures, decreased quality of life, and decreased survival. Dysfunction of the osteoclast (OC)/osteoblast (OB) axis plays a key role in the development of myeloma-associated osteolytic lesions. Many signaling pathways and factors are associated with myeloma bone diseases (MBDs), including the RANKL/OPG and NF-κB pathways. NRF2, a master regulator of inflammatory signaling, might play a role in the regulation of bone metabolism via anti-inflammatory signaling and decreased reactive oxygen species (ROS) levels. The loss of NRF2 expression in OCs reduced bone mass via the RANK/RANKL pathway and other downstream signaling pathways that affect osteoclastogenesis. The NRF2 level in OBs could interfere with interleukin (IL)-6 expression, which is associated with bone metabolism and myeloma cells. In addition to direct impact on OCs and OBs, the activity of NRF2 on myeloma cells and mesenchymal stromal cells influences the inflammatory stress/ROS level in these cells, which has an impact on OCs, OBs, and osteocytes. The interaction between these cells and OCs affects the osteoclastogenesis of myeloma bone lesions associated with NRF2. Therefore, we have reviewed the effects of NRF2 on OCs and OBs in MBDs.
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Bone, a Secondary Growth Site of Breast and Prostate Carcinomas: Role of Osteocytes. Cancers (Basel) 2020; 12:cancers12071812. [PMID: 32640686 PMCID: PMC7408809 DOI: 10.3390/cancers12071812] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/30/2020] [Accepted: 07/01/2020] [Indexed: 02/06/2023] Open
Abstract
Bone is the primarily preferred site for breast and prostate cancer to metastasize. Bone metastases are responsible for most deaths related to breast and prostate cancer. The bone's particular microenvironment makes it conducive for the growth of cancer cells. Studies on bone metastasis have focused on the interaction between cancer cells and the bone microenvironment. Osteocytes, the most common cell type of bone tissue, have received little attention in bone metastasis, although they are master signal sensors, integrators, and skeleton transducers. They play an important role in regulating bone mass by acting on both osteoblasts and osteoclasts, through the release of proteins such as sclerostin, Dickkopf-1 (DKK-1), and fibroblast growth factor 23 (FGF23). Osteocytes have been extensively re-evaluated, in light of their multiple functions: with different experimental approaches, it has been shown that, indeed, osteocytes are actively involved in the colonization of bone tissue by cancer cells. The present review focuses on recent research on the role that osteocytes play in bone metastasis of breast and prostate cancers. Moreover, the studies here summarized open up perspectives for new therapeutic approaches focused on modulating the activity of osteocytes to improve the condition of the bone metastatic patients. A better understanding of the complex interactions between cancer cells and bone-resident cells is indispensable for identifying potential therapeutic targets to stop tumor progression and prevent bone metastases.
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40
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Børset M, Sundan A, Waage A, Standal T. Why do myeloma patients have bone disease? A historical perspective. Blood Rev 2020; 41:100646. [DOI: 10.1016/j.blre.2019.100646] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 11/19/2019] [Accepted: 11/25/2019] [Indexed: 12/18/2022]
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41
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Zarrer J, Haider MT, Smit DJ, Taipaleenmäki H. Pathological Crosstalk between Metastatic Breast Cancer Cells and the Bone Microenvironment. Biomolecules 2020; 10:biom10020337. [PMID: 32092997 PMCID: PMC7072692 DOI: 10.3390/biom10020337] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 02/15/2020] [Accepted: 02/17/2020] [Indexed: 12/12/2022] Open
Abstract
Bone is the most common metastatic site in breast cancer. Upon arrival to the bone, disseminated tumor cells can undergo a period of dormancy but often eventually grow and hijack the bone microenvironment. The bone marrow microenvironment consists of multiple cell types including the bone cells, adipocytes, endothelial cells, and nerve cells that all have crucial functions in the maintenance of bone homeostasis. Tumor cells severely disturb the tightly controlled cellular and molecular interactions in the bone marrow fueling their own survival and growth. While the role of bone resorbing osteoclasts in breast cancer bone metastases is well established, the function of other bone cells, as well as adipocytes, endothelial cells, and nerve cells is less understood. In this review, we discuss the composition of the physiological bone microenvironment and how the presence of tumor cells influences the microenvironment, creating a pathological crosstalk between the cells. A better understanding of the cellular and molecular events that occur in the metastatic bone microenvironment could facilitate the identification of novel cellular targets to treat this devastating disease.
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Affiliation(s)
- Jennifer Zarrer
- Molecular Skeletal Biology Laboratory, Department of Trauma, Hand and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Marie-Therese Haider
- Molecular Skeletal Biology Laboratory, Department of Trauma, Hand and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Daniel J. Smit
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Hanna Taipaleenmäki
- Molecular Skeletal Biology Laboratory, Department of Trauma, Hand and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Correspondence:
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Marino S, Petrusca DN, Roodman GD. Therapeutic targets in myeloma bone disease. Br J Pharmacol 2020; 178:1907-1922. [PMID: 31647573 DOI: 10.1111/bph.14889] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 09/09/2019] [Accepted: 09/17/2019] [Indexed: 12/13/2022] Open
Abstract
Multiple myeloma (MM) is the second most common haematological malignancy and is characterized by a clonal proliferation of neoplastic plasma cells within the bone marrow. MM is the most frequent cancer involving the skeleton, causing osteolytic lesions, bone pain and pathological fractures that dramatically decrease MM patients' quality of life and survival. MM bone disease (MBD) results from uncoupling of bone remodelling in which excessive bone resorption is not compensated by new bone formation, due to a persistent suppression of osteoblast activity. Current management of MBD includes antiresorptive agents, bisphosphonates and denosumab, that are only partially effective due to their inability to repair the existing lesions. Thus, research into agents that prevent bone destruction and more importantly repair existing lesions by inducing new bone formation is essential. This review discusses the mechanisms regulating the uncoupled bone remodelling in MM and summarizes current advances in the treatment of MBD. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.
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Affiliation(s)
- Silvia Marino
- Department of Medicine, Division Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Daniela N Petrusca
- Department of Medicine, Division Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - G David Roodman
- Department of Medicine, Division Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Roudebush VA Medical Center, Indianapolis, Indiana, USA
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43
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Shiozawa Y. The Roles of Bone Marrow-Resident Cells as a Microenvironment for Bone Metastasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1226:57-72. [PMID: 32030676 DOI: 10.1007/978-3-030-36214-0_5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
It has been appreciated that the cross talk between bone metastatic cancer cells and bone marrow microenvironment influence one another to worsen bone metastatic disease progression. Bone marrow contains various cell types, including (1) cells of mesenchymal origin (e.g., osteoblasts, osteocytes, and adipocytes), (2) cells of hematopoietic origin (e.g., osteoclast and immune cells), and (3) others (e.g., endothelial cells and nerves). The recent studies have enabled us to discover many important cancer-derived factors responsible for the development of bone metastasis. However, many critical questions regarding the roles of bone microenvironment in bone metastatic progression remain elusive. To answer these questions, a deeper understanding of the cross talk between bone metastatic cancer and bone marrow microenvironment is clearly warranted.
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Affiliation(s)
- Yusuke Shiozawa
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, NC, USA.
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44
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Abstract
Bone is the most frequent site of breast cancer and prostate cancer metastasis, and one of the most common sites of metastasis for many solid tumors. Once cancer cells colonize in the bone, it imposes a major clinical challenge for the treatment of the disease, and fatality rates increase drastically. Bone, the largest organ in the body, provides a fertile microenvironment enriched with nutrients, growth factors and hormones, a generous reward for cancer cells. Dependent on cancer type, cancer cells can cause osteoblastic (bone forming) or osteolytic lesions to promote the net resorption and/or release of growth factors from the bone extracellular matrix. These processes activate a "vicious cycle", leading to disruption of bone integrity and promoting cancer cell growth and migration. Cancer cells influence the bone microenvironment favoring their colonization and growth. In order to metastasize to the bone, cancer cells must first migrate from the site of origin, and once established within the bone, they must overcome the dormant inducing effects of resident cells. If successful, cancer cells can then colonize and continually disrupt bone homeostasis that is primarily maintained by osteocytes, the most abundant bone cell type. For example, it has been shown that exercise induces osteocytes to release anabolic factors that inhibit osteoclast resorptive activity, promote dormancy and the release of anti-cancer factors that inhibit breast cancer cell metastasis. In this review, we will summarize recent research findings and provide mechanistic insights related to the role of osteocytes in osteolytic metastasis.
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Kyriazoglou A, Ntanasis-Stathopoulos I, Terpos E, Fotiou D, Kastritis E, Dimopoulos MA, Gavriatopoulou M. Emerging Insights Into the Role of the Hippo Pathway in Multiple Myeloma and Associated Bone Disease. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2019; 20:57-62. [PMID: 31734019 DOI: 10.1016/j.clml.2019.09.620] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Revised: 08/11/2019] [Accepted: 09/29/2019] [Indexed: 02/06/2023]
Abstract
Multiple myeloma (MM) is an incurable plasma-cell dyscrasia with numerous treatment options currently available; however, drug resistance is usually inevitable, so there is a constant need for novel treatment approaches. The Hippo pathway has emerged as an important mediator of oncogenesis in solid tumors. More recently, its key role in regulating apoptosis and mediating resistance in MM and other hematologic malignancies has been demonstrated in preclinical studies, which provides a strong basis for further clinical investigation. The Hippo pathway is also implicated in the pathogenesis of MM-induced bone disease, as it regulates both osteoblast and osteoclast function. We provide an overview of the available data regarding the role of the Hippo signaling components in the pathophysiology of MM. A better understanding of the underlying interactions at the molecular and cellular levels will lead to novel and promising treatment approaches.
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Affiliation(s)
- Anastasios Kyriazoglou
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, Athens, Greece
| | - Ioannis Ntanasis-Stathopoulos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, Athens, Greece
| | - Evangelos Terpos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, Athens, Greece
| | - Despina Fotiou
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, Athens, Greece
| | - Efstathios Kastritis
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, Athens, Greece
| | - Meletios A Dimopoulos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, Athens, Greece
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, Athens, Greece.
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He ZC, Li XY, Guo YL, Ma D, Fang Q, Ren LL, Zhang ZY, Wang W, Yu ZY, Zhao P, Wang JS. Heme oxygenase-1 attenuates the inhibitory effect of bortezomib against the APRIL-NF-κB-CCL3 signaling pathways in multiple myeloma cells: Corelated with bortezomib tolerance in multiple myeloma. J Cell Biochem 2019; 120:6972-6987. [PMID: 30368867 DOI: 10.1002/jcb.27879] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 09/21/2018] [Indexed: 01/24/2023]
Abstract
Osteoclasts (OCs) play an essential role in bone destruction in patients with multiple myeloma (MM). Bortezomib can ameliorate bone destruction in patients with MM, but advanced MM often resists bortezomib. We studied the molecular mechanisms of bortezomib tolerance in MM. The expression of the MM-related genes in newly diagnosed patients with MM and normal donors were studied. C-C motif chemokine ligand 3 (CCL3) is a cytokine involved in the differentiation of OCs, and its expression is closely related to APRIL (a proliferation-inducing ligand). We found that bortezomib treatment inhibited APRIL and CCL3. But the heme oxygenase-1 (HO-1) activator hemin attenuated the inhibitory effects of bortezomib on APRIL and CCL3. We induced mononuclear cells to differentiate into OCs, and the enzyme-linked immunosorbent assay showed that the more OCs differentiated, the higher the levels CCL3 secretions detected. Animal experiments showed that hemin promoted MM cell infiltration in mice. The weight and survival rate of tumor mice were associated with HO-1 expression. Immunohistochemical staining showed that HO-1, APRIL, and CCL3 staining were positively stained in the tumor infiltrating sites. Then, MM cells were transfected with L-HO-1/si-HO-1 expression vectors and cultured with an nuclear factor (NF)-kappa B (κB) pathway inhibitor, QNZ. The results showed that HO-1 was the upstream gene of APRIL, NF-κB, and CCL3. We showed that HO-1 could attenuate the inhibitory effect of bortezomib against the APRIL-NF-κB-CCL3 signaling pathways in MM cells, and the tolerance of MM cells to bortezomib and the promotion of bone destruction are related to HO-1.
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Affiliation(s)
- Zheng C He
- Department of Hematology, Affiliated Hospital of Medical University, Guiyang, China.,Hematological Institute of Guizhou Province, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.,Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Centre, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Xin Y Li
- Department of Hematology, Affiliated Hospital of Medical University, Guiyang, China.,Hematological Institute of Guizhou Province, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.,Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Centre, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Yong L Guo
- Department of Hematology, Affiliated Hospital of Medical University, Guiyang, China.,Hematological Institute of Guizhou Province, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.,Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Centre, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Dan Ma
- Department of Hematology, Affiliated Hospital of Medical University, Guiyang, China.,Hematological Institute of Guizhou Province, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.,Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Centre, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Qin Fang
- Department of Pharmacy, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Ling L Ren
- Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Zhao Y Zhang
- Department of Hematology, Affiliated Hospital of Medical University, Guiyang, China.,Hematological Institute of Guizhou Province, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.,Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Centre, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Weili Wang
- Department of Hematology, Affiliated Hospital of Medical University, Guiyang, China.,Hematological Institute of Guizhou Province, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.,Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Centre, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Zheng Y Yu
- Department of Hematology, Affiliated Hospital of Medical University, Guiyang, China.,Hematological Institute of Guizhou Province, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.,Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Centre, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Peng Zhao
- Department of Hematology, Affiliated Hospital of Medical University, Guiyang, China.,Hematological Institute of Guizhou Province, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.,Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Centre, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Ji S Wang
- Department of Hematology, Affiliated Hospital of Medical University, Guiyang, China.,Hematological Institute of Guizhou Province, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.,Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Centre, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
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47
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Atkinson EG, Delgado‐Calle J. The Emerging Role of Osteocytes in Cancer in Bone. JBMR Plus 2019; 3:e10186. [PMID: 30918922 PMCID: PMC6419608 DOI: 10.1002/jbm4.10186] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 01/29/2019] [Accepted: 02/06/2019] [Indexed: 12/13/2022] Open
Abstract
Advances in the last decade have established the osteocyte, the most abundant cell in bone, as a dynamic and multifunctional cell capable of controlling bone homeostasis by regulating the function of both osteoblasts and osteoclasts. In addition, accumulating evidence demonstrates that osteocyte function is altered in several skeletal disorders, and targeting osteocytes and their derived factors improves skeletal health. Despite the remarkable progress in our understanding of osteocyte biology, there has been a paucity of information regarding the role of osteocytes in the progression of cancer in bone. Exciting, recent discoveries suggest that tumor cells communicate with osteocytes to generate a microenvironment that supports the growth and survival of cancer cells and stimulates bone destruction. This review features these novel findings and discussions regarding the impact of chemotherapy on osteocyte function and the potential of targeting osteocytes for the treatment of cancer in bone. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Emily G Atkinson
- Department of Anatomy and Cell BiologyIndiana University School of MedicineIndianapolisINUSA
| | - Jesús Delgado‐Calle
- Department of Anatomy and Cell BiologyIndiana University School of MedicineIndianapolisINUSA
- Department of MedicineDivision of Hematology/OncologyIndiana University School of MedicineIndianapolisINUSA
- Indiana Center for Musculoskeletal HealthIndiana University School of MedicineIndianapolisINUSA
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48
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Myeloma bone disease: from biology findings to treatment approaches. Blood 2019; 133:1534-1539. [PMID: 30760454 DOI: 10.1182/blood-2018-11-852459] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 02/10/2019] [Indexed: 12/16/2022] Open
Abstract
Bone disease is a cardinal complication of multiple myeloma that affects quality of life and survival. Osteocytes have emerged as key players in the development of myeloma-related bone disease. Along with other factors, they participate in increased osteoclast activity, decreased osteoblast function, and immunosuppressed marrow microenvironment, which deregulate bone turnover and result in bone loss and skeletal-related events. Denosumab is a novel alternative to bisphosphonates against myeloma bone disease. Special considerations in this constantly evolving field are thoroughly discussed.
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49
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Fornetti J, Welm AL, Stewart SA. Understanding the Bone in Cancer Metastasis. J Bone Miner Res 2018; 33:2099-2113. [PMID: 30476357 DOI: 10.1002/jbmr.3618] [Citation(s) in RCA: 303] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 10/17/2018] [Accepted: 10/18/2018] [Indexed: 12/11/2022]
Abstract
The bone is the third most common site of metastasis for a wide range of solid tumors including lung, breast, prostate, colorectal, thyroid, gynecologic, and melanoma, with 70% of metastatic prostate and breast cancer patients harboring bone metastasis.1 Unfortunately, once cancer spreads to the bone, it is rarely cured and is associated with a wide range of morbidities including pain, increased risk of fracture, and hypercalcemia. This fact has driven experts in the fields of bone and cancer biology to study the bone, and has revealed that there is a great deal that each can teach the other. The complexity of the bone was first described in 1889 when Stephen Paget proposed that tumor cells have a proclivity for certain organs, where they "seed" into a friendly "soil" and eventually grow into metastatic lesions. Dr. Paget went on to argue that although many study the "seed" it would be paramount to understand the "soil." Since this original work, significant advances have been made not only in understanding the cell-autonomous mechanisms that drive metastasis, but also alterations which drive changes to the "soil" that allow a tumor cell to thrive. Indeed, it is now clear that the "soil" in different metastatic sites is unique, and thus the mechanisms that allow tumor cells to remain in a dormant or growing state are specific to the organ in question. In the bone, our knowledge of the components that contribute to this fertile "soil" continues to expand, but our understanding of how they impact tumor growth in the bone remains in its infancy. Indeed, we now appreciate that the endosteal niche likely contributes to tumor cell dormancy, and that osteoclasts, osteocytes, and adipocytes can impact tumor cell growth. Here, we discuss the bone microenvironment and how it impacts cancer cell seeding, dormancy, and growth. © 2018 American Society for Bone and Mineral Research.
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Affiliation(s)
- Jaime Fornetti
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Alana L Welm
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Sheila A Stewart
- Departments of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.,Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.,Integrating Communication within the Cancer Environment (ICCE) Institute, Washington University School of Medicine, St. Louis, MO, USA
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50
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Mehdi SJ, Johnson SK, Epstein J, Zangari M, Qu P, Hoering A, van Rhee F, Schinke C, Thanendrarajan S, Barlogie B, Davies FE, Morgan GJ, Yaccoby S. Mesenchymal stem cells gene signature in high-risk myeloma bone marrow linked to suppression of distinct IGFBP2-expressing small adipocytes. Br J Haematol 2018; 184:578-593. [PMID: 30408155 DOI: 10.1111/bjh.15669] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 09/25/2018] [Indexed: 02/06/2023]
Abstract
Recent studies suggest that multiple myeloma (MM) induces proliferation and expansion of bone marrow (BM) mesenchymal stem cells (MSCs), but others showed that MM cells induce MSC senescence. To clarify the interaction between MM and MSCs, we exploited our established MSC gene signature to identify gene expression changes in myeloma MSCs and associated functional differences. Single MSCs from patients with MM had changes in expression of genes associated with cellular proliferation and senescence and a higher proportion of senescent cells and lower proliferative potential than those from age-matched healthy donors. Single MSCs from both sources heterogeneously express MSC genes associated with adipogenesis and osteoblastogenesis. We identified the gene encoding insulin-like growth factor-binding protein 2 (IGFBP2), an MSC gene commonly altered in high risk MM, as under-expressed. Morphologically, IGFBP2+ cells are underrepresented in MM BM compared to smouldering MM. Strong IGFBP2 and adiponectin co-expression was detected in a subset of small adipocytes. Co-culturing normal MSCs with myeloma cells suppressed MSC differentiation to adipocytes and osteoblasts, and reduced expression of IGFBP2 and adiponectin. Recombinant IGFBP2 blocked IGF1-mediated myeloma cell growth. Our data demonstrate that myeloma MSCs are less proliferative and that IGFBP2+ small adipocytes are a distinct mesenchymal cell population suppressed by myeloma.
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Affiliation(s)
- Syed J Mehdi
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Sarah K Johnson
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Joshua Epstein
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Maurizio Zangari
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Pingping Qu
- Cancer Research and Biostatistics, Seattle, WA, USA
| | | | - Frits van Rhee
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Carolina Schinke
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | | | - Bart Barlogie
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Faith E Davies
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Gareth J Morgan
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Shmuel Yaccoby
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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