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1
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Yip RKH, Hawkins ED, Bowden R, Rogers KL. Towards deciphering the bone marrow microenvironment with spatial multi-omics. Semin Cell Dev Biol 2025; 167:10-21. [PMID: 39889539 DOI: 10.1016/j.semcdb.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/23/2024] [Accepted: 01/18/2025] [Indexed: 02/03/2025]
Abstract
The tissue microenvironment refers to a localised tissue area where a complex combination of cells, structural components, and signalling molecules work together to support specific biological activities. A prime example is the bone marrow microenvironment, particularly the hematopoietic stem cell (HSC) niche, which is of immense interest due to its critical role in supporting lifelong blood cell production and the growth of malignant cells. In this review, we summarise the current understanding of HSC niche biology, highlighting insights gained from advanced imaging and genomic techniques. We also discuss the potential of emerging technologies such as spatial multi-omics to unravel bone marrow architecture in unprecedented detail.
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Affiliation(s)
- Raymond K H Yip
- Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Colonial Foundation Diagnostics Centre, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
| | - Edwin D Hawkins
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Colonial Foundation Diagnostics Centre, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
| | - Rory Bowden
- Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Kelly L Rogers
- Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
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2
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Ghanem W, Ezzeddine H, Saad R, Kiwan E, Dahdouh R, Fakih O, Sakhat G, Alam E, Najjar J, Assaf F, Chahine M, Dib N, Kortbawi R, Badra M, Moucharafieh R. State of the Nonunion: A review of the latest literature. Orthop Rev (Pavia) 2025; 17:129085. [PMID: 39925644 PMCID: PMC11807701 DOI: 10.52965/001c.129085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 12/06/2024] [Indexed: 02/11/2025] Open
Abstract
The distinction between prolonged bone healing and nonunion in long bone fracture remains a historical challenge in the field of orthopedics. Despite numerous proposed definitions and scoring systems, a consensus remains elusive, thereby complicating both diagnosis and treatment. An accurate diagnosis is necessary, facilitated by a range of imaging modalities. Bone nonunion management encompasses surgical and non-surgical options, including external or internal fixation, and bone grafting, tailored to the nonunion type. This review discusses the pathophysiology of nonunion, risk factors, diagnosis and treatment. It particularly addresses early detection and the impacts of nonunion on the patient. The aim of this review is to obtain a global and updated point of view regarding nonunion of the bone as well as to reflect on the potential use of untraditional methods in their treatment such as orthobiologics, along with emerging and non-invasive technologies including shockwave therapy, gene therapy, tissue engineering, regenerative medicine and 3D printing.
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Affiliation(s)
- Wendy Ghanem
- Department of Orthopedics and Traumatology, Faculty of Medicine University of Balamand
| | - Hady Ezzeddine
- Department of Orthopedics and Traumatology, Faculty of Medicine University of Balamand
| | - Rita Saad
- Department of Orthopedics and Traumatology, Faculty of Medicine University of Balamand
| | - Elyssa Kiwan
- Department of Orthopedics and Traumatology, Faculty of Medicine University of Balamand
| | - Raymonde Dahdouh
- Department of Orthopedics and Traumatology, Faculty of Medicine University of Balamand
| | - Omar Fakih
- Department of Orthopedics and Traumatology, Faculty of Medicine University of Balamand
| | - Georges Sakhat
- Department of Orthopedics and Traumatology, Faculty of Medicine University of Balamand
| | - Elie Alam
- Department of Orthopedics and Traumatology, Faculty of Medicine University of Balamand
| | - Joseph Najjar
- Department of Orthopedics and Traumatology, Faculty of Medicine University of Balamand
| | - Fouad Assaf
- Department of Orthopedics and Traumatology, Faculty of Medicine University of Balamand
| | - Moro Chahine
- Department of Orthopedics and Traumatology, Faculty of Medicine University of Balamand
| | - Nabil Dib
- Department of Orthopedics and Traumatology, Faculty of Medicine University of Balamand
| | - Rabih Kortbawi
- Department of Orthopedics and Traumatology, Faculty of Medicine University of Balamand
| | - Mohammad Badra
- Department of Orthopedics and Traumatology, Faculty of Medicine University of Balamand
- Department of Orthopedics and Traumatology, Clemenceau Medical, Beirut, Lebanon
| | - Ramzi Moucharafieh
- Department of Orthopedics and Traumatology, Faculty of Medicine University of Balamand
- Department of Orthopedics and Traumatology, Clemenceau Medical, Beirut, Lebanon
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Inson I, Chutoe C, Kanjanapipak J, Lertsuwan K. Cannabinoid Receptor Type 2 Agonist, GW405833, Reduced the Impacts of MDA-MB-231 Breast Cancer Cells on Bone Cells. Cancer Med 2025; 14:e70709. [PMID: 39980332 PMCID: PMC11842928 DOI: 10.1002/cam4.70709] [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: 11/16/2024] [Revised: 01/22/2025] [Accepted: 02/10/2025] [Indexed: 02/22/2025] Open
Abstract
AIM Breast cancer frequently metastasizes to bones. The interaction between breast cancer cells and bone cells results in osteolytic lesions by disrupting the balance between osteoblast-mediated bone production and osteoclast-mediated bone resorption. This study aims to investigate the effects of the cannabinoid receptor type 2 (CB2) agonist, GW405833, on interactions between breast cancer cells and osteoblasts as well as its impact on breast cancer-induced osteoclastogenesis. MATERIALS & METHODS MDA-MB-231, UMR-106, RAW 264.7 cells were used to represent breast cancer cells, osteoblast-like cells and macrophage-osteoclast precursor cells, respectively. Cell viability was evaluated by MTT assay, and breast cancer cell invasion was assessed by Transwell invasion assay. Tartrate-resistant acid phosphatase (TRAP) staining was utilized to evaluate osteoclastogenesis. RESULTS Our results demonstrated that GW405833 disrupted MDA-MB-231-induced UMR-106 cell death and promoted UMR-106 cell viability. The underlying mechanism of these effects was determined in this study. GW405833 reduced AKT phosphorylation in MDA-MB-231 cells without affecting mTOR protein expression or its phosphorylation. Conversely, in UMR-106 cells, GW405833 induced AKT and mTOR phosphorylated protein. Furthermore, the mTOR inhibitor reversed the GW405833-induced recovery of UMR-106 cell viability under MDA-MB-231-derived conditioned media (CM) exposure. These findings underscore the critical role of the AKT/mTOR pathway in mediating GW405833's inhibitory effects on cancer-bone interactions. Additionally, GW405833 suppressed osteoblast-enhanced breast cancer cell invasion and the expression of invasion-related proteins in both cell types, along with reducing osteoclastogenic factors induced by MDA-MB-231 CM in UMR-106 cells and suppressing MDA-MB-231 CM-enhanced osteoclastogenesis in RAW 264.7 cells. CONCLUSION This study highlights the therapeutic potential of cannabinoid receptor agonist for treating breast cancer bone metastasis and bone-related complications.
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Affiliation(s)
- Ingon Inson
- Department of Biochemistry, Faculty of ScienceMahidol UniversityBangkokThailand
| | - Chartinun Chutoe
- Department of Biochemistry, Faculty of ScienceMahidol UniversityBangkokThailand
| | | | - Kornkamon Lertsuwan
- Department of Biochemistry, Faculty of ScienceMahidol UniversityBangkokThailand
- Center of Calcium and Bone Research (COCAB), Faculty of ScienceMahidol UniversityBangkokThailand
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Cui X, Hou L, Yan B, Liu J, Zhang C, Sui P, Tong S, Luchsinger L, Mendelson A, Zhou D, Yang FC, Zhong H, Liang Y. Sexual dimorphism in the mouse bone marrow niche regulates hematopoietic engraftment via sex-specific Kdm5c/Cxcl12 signaling. J Clin Invest 2025; 135:e182125. [PMID: 39836478 PMCID: PMC11870739 DOI: 10.1172/jci182125] [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: 04/16/2024] [Accepted: 01/08/2025] [Indexed: 01/23/2025] Open
Abstract
The bone marrow (BM) niche is critical in regulating hematopoiesis, and sexual dimorphism and its underlying mechanism in the BM niche and its impact on hematopoiesis are not well understood. We show that male mice exhibited a higher abundance of leptin-receptor-expressing mesenchymal stromal cells (LepR-MSCs) compared with female mice. Sex-mismatched coculture and BM transplantation showed that the male BM niche provided superior support for in vitro colony formation and in vivo hematopoietic engraftment. The cotransplantation of male stromal cells significantly enhanced engraftment in female recipients. Single-cell RNA-seq revealed that the lower expression of the X-linked lysine H3K4 demethylase, Kdm5c, in male MSCs led to the increased expression of Cxcl12. In MSC-specific Kdm5c-KO mouse model, the reduction of KDM5C in female MSCs enhanced MSC quantity and function, ultimately improving engraftment to the male level. Kdm5c thus plays a role in driving sexual dimorphism in the BM niche and hematopoietic regeneration. Our study unveils a sex-dependent mechanism governing the BM niche regulation and its impact on hematopoietic engraftment. The finding offers potential implications for enhancing BM transplantation efficacy in clinical settings by harnessing the resource of male MSCs or targeting Kdm5c.
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Affiliation(s)
- Xiaojing Cui
- Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA
| | - Liming Hou
- Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA
| | - Bowen Yan
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida, USA
| | - Jinpeng Liu
- Department of Internal Medicine, University of Kentucky, Lexington, Kentucky, USA
| | - Cuiping Zhang
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA
| | - Pinpin Sui
- Department of Cell Systems & Anatomy, University of Texas Health at San Antonio, San Antonio, Texas, USA
| | - Sheng Tong
- Department of Bioengineering, University of Kentucky, Lexington, Kentucky, USA
| | - Larry Luchsinger
- Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA
| | - Avital Mendelson
- Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA
| | - Daohong Zhou
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida, USA
- Department of Biochemistry & Structural Biology, University of Texas Health at San Antonio, San Antonio, Texas, USA
| | - Feng-chun Yang
- Department of Cell Systems & Anatomy, University of Texas Health at San Antonio, San Antonio, Texas, USA
| | - Hui Zhong
- Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA
| | - Ying Liang
- Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA
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Fornari Laurindo L, Minniti G, Rodrigues VD, Fornari Laurindo L, Strozze Catharin VMC, Baisi Chagas EF, Dos Anjos VD, de Castro MVM, Baldi Júnior E, Ferraroni Sanches RC, Mendez-Sanchez N, Maria Barbalho S. Exploring the Logic and Conducting a Comprehensive Evaluation of the Adiponectin Receptor Agonists AdipoRon and AdipoAI's Impacts on Bone Metabolism and Repair-A Systematic Review. Curr Med Chem 2025; 32:1168-1194. [PMID: 39206478 DOI: 10.2174/0109298673308301240821052742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 05/17/2024] [Accepted: 07/05/2024] [Indexed: 09/04/2024]
Abstract
INTRODUCTION Adiponectin replacement therapy shows promising outcomes in various diseases, especially for bone-related disorders. Challenges in using the complete protein have led to alternative approaches, with AdipoRon and AdipoAI emerging as extensively researched drug candidates. Their influence on models of bone-related disorders has progressed considerably but there has been no review of their effectiveness in modulating bone metabolism and repair. METHODS This systematic review seeks to address this knowledge gap. Based on preclinical evidence from PubMed, EMBASE, and COCHRANE, ten studies were included following PRISMA guidelines. The JBI Checklist Critical Appraisal Tool assessed the quality of this systematic review. The studies encompassed various animal models, addressing bone defects, osseointegration, diabetes-associated periodontitis, fracture repair, growth retardation, and diabetes-associated peri-implantitis. RESULTS AdipoRon and AdipoAI demonstrated effectiveness in modulating bone metabolism and repair through diverse pathways, including the activation of AdipoR1/APPL1, inhibition of F-actin ring formation, suppression of IκB-α phosphorylation, p65 nuclear translocation and Wnt5a-Ror2 signaling pathway, reduction of CCL2 secretion and expression, regulation of autophagy via LC3A/B expression, modulation of SDF-1 production, activation of the ERK1/2 signaling pathway, modulation of bone integration-related markers and osteokines such as RANKL, BMP-2, OPG, OPN, and Runx2, inhibition of RANKL in osteoblasts, and inhibition of podosome formation via the activation of AMPK. CONCLUSION While preclinical studies show promise, human trials are crucial to confirm the clinical safety and effectiveness of AdipoRon and AdipoAI. Caution is necessary due to potential off-target effects, especially in bone therapy with multi-target approaches. Structural biology and computational methods can help predict and understand these effects.
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Affiliation(s)
- Lucas Fornari Laurindo
- Department of Biochemistry and Pharmacology, School of Medicine, Faculdade de Medicina de Marília (FAMEMA), Marília 17519-030, São Paulo, Brazil
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, São Paulo, Brazil
| | - Giulia Minniti
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, São Paulo, Brazil
| | - Victoria Dogani Rodrigues
- Department of Biochemistry and Pharmacology, School of Medicine, Faculdade de Medicina de Marília (FAMEMA), Marília 17519-030, São Paulo, Brazil
| | - Lívia Fornari Laurindo
- Medical Department, School of Medicine, Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto 15090-000, São Paulo, Brazil
| | - Virginia Maria Cavallari Strozze Catharin
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, São Paulo, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, São Paulo, Brazil
| | - Eduardo Federighi Baisi Chagas
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, São Paulo, Brazil
| | - Vinicius Dias Dos Anjos
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, São Paulo, Brazil
| | - Marcela Vialogo Marques de Castro
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, São Paulo, Brazil
| | - Edgar Baldi Júnior
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, São Paulo, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, São Paulo, Brazil
| | - Raquel Cristina Ferraroni Sanches
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, São Paulo, Brazil
| | - Nahum Mendez-Sanchez
- Liver Research Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
| | - Sandra Maria Barbalho
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, São Paulo, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, São Paulo, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), Marília 17500-000, São Paulo, Brazil
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6
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Rubino V, Hüppi M, Höpner S, Tortola L, Schnüriger N, Legenne H, Taylor L, Voggensperger S, Keller I, Bruggman R, Kronig MN, Bacher U, Kopf M, Ochsenbein AF, Riether C. IL-21/IL-21R signaling renders acute myeloid leukemia stem cells more susceptible to cytarabine treatment and CAR T cell therapy. Cell Rep Med 2024; 5:101826. [PMID: 39536753 PMCID: PMC11604404 DOI: 10.1016/j.xcrm.2024.101826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 07/31/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024]
Abstract
Self-renewal programs in leukemia stem cells (LSCs) predict poor prognosis in patients with acute myeloid leukemia (AML). We identify CD4+ T cell-derived interleukin (IL)-21 as an important negative regulator of self-renewal of LSCs. IL-21/IL-21R signaling favors asymmetric cell division and differentiation in LSCs through the activation of p38-MAPK signaling, resulting in reduced LSC numbers and significantly prolonged survival in murine AML models. In human AML, serum IL-21 at diagnosis is identified as an independent positive prognostic biomarker for outcome and correlates with improved survival and higher complete remission rates in patients that underwent high-dose chemotherapy. IL-21 treatment inhibits primary LSC function and enhances the effect of cytarabine and CD70 CAR T cell treatment on LSCs in vitro. Low-dose IL-21 treatment prolongs the survival of AML mice in syngeneic and xenograft experiments. Therefore, promoting IL-21/IL-21R signaling on LSCs may be an approach to reduce stemness and increase differentiation in AML.
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MESH Headings
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/therapy
- Leukemia, Myeloid, Acute/metabolism
- Animals
- Humans
- Cytarabine/pharmacology
- Cytarabine/therapeutic use
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/pathology
- Interleukins/metabolism
- Signal Transduction/drug effects
- Mice
- Immunotherapy, Adoptive/methods
- Female
- Mice, Inbred C57BL
- Male
- Receptors, Interleukin-21/metabolism
- Receptors, Interleukin-21/genetics
- Cell Differentiation/drug effects
- Xenograft Model Antitumor Assays
- Cell Line, Tumor
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- CD4-Positive T-Lymphocytes/drug effects
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Affiliation(s)
- Viviana Rubino
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland; Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Michelle Hüppi
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Sabine Höpner
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Luigi Tortola
- Institute for Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Noah Schnüriger
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland; Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Hugo Legenne
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland; Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Lea Taylor
- Interfaculty Bioinformatics Unit and SIB Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland
| | - Svenja Voggensperger
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Irene Keller
- Interfaculty Bioinformatics Unit and SIB Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland
| | - Remy Bruggman
- Interfaculty Bioinformatics Unit and SIB Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland
| | - Marie-Noëlle Kronig
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Ulrike Bacher
- Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Manfred Kopf
- Institute for Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Adrian F Ochsenbein
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Carsten Riether
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
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Chen L, Xu YX, Wang YS, Ren YY, Dong XM, Wu P, Xie T, Zhang Q, Zhou JL. Prostate cancer microenvironment: multidimensional regulation of immune cells, vascular system, stromal cells, and microbiota. Mol Cancer 2024; 23:229. [PMID: 39395984 PMCID: PMC11470719 DOI: 10.1186/s12943-024-02137-1] [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: 08/14/2024] [Accepted: 09/23/2024] [Indexed: 10/14/2024] Open
Abstract
BACKGROUND Prostate cancer (PCa) is one of the most prevalent malignancies in males worldwide. Increasing research attention has focused on the PCa microenvironment, which plays a crucial role in tumor progression and therapy resistance. This review aims to provide a comprehensive overview of the key components of the PCa microenvironment, including immune cells, vascular systems, stromal cells, and microbiota, and explore their implications for diagnosis and treatment. METHODS Keywords such as "prostate cancer", "tumor microenvironment", "immune cells", "vascular system", "stromal cells", and "microbiota" were used for literature retrieval through online databases including PubMed and Web of Science. Studies related to the PCa microenvironment were selected, with a particular focus on those discussing the roles of immune cells, vascular systems, stromal cells, and microbiota in the development, progression, and treatment of PCa. The selection criteria prioritized peer-reviewed articles published in the last five years, aiming to summarize and analyze the latest research advancements and clinical relevance regarding the PCa microenvironment. RESULTS The PCa microenvironment is highly complex and dynamic, with immune cells contributing to immunosuppressive conditions, stromal cells promoting tumor growth, and microbiota potentially affecting androgen metabolism. Vascular systems support angiogenesis, which fosters tumor expansion. Understanding these components offers insight into the mechanisms driving PCa progression and opens avenues for novel therapeutic strategies targeting the tumor microenvironment. CONCLUSIONS A deeper understanding of the PCa microenvironment is crucial for advancing diagnostic techniques and developing precision therapies. This review highlights the potential of targeting the microenvironment to improve patient outcomes, emphasizing its significance in the broader context of PCa research and treatment innovation.
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Affiliation(s)
- Lin Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Yu-Xin Xu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Yuan-Shuo Wang
- School of Pharmacy, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Ying-Ying Ren
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Xue-Man Dong
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Pu Wu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Tian Xie
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.
| | - Qi Zhang
- Department of Urology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, 310014, China.
| | - Jian-Liang Zhou
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.
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8
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Xin Z, Qin L, Tang Y, Guo S, Li F, Fang Y, Li G, Yao Y, Zheng B, Zhang B, Wu D, Xiao J, Ni C, Wei Q, Zhang T. Immune mediated support of metastasis: Implication for bone invasion. Cancer Commun (Lond) 2024; 44:967-991. [PMID: 39003618 PMCID: PMC11492328 DOI: 10.1002/cac2.12584] [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: 12/28/2023] [Revised: 06/05/2024] [Accepted: 06/18/2024] [Indexed: 07/15/2024] Open
Abstract
Bone is a common organ affected by metastasis in various advanced cancers, including lung, breast, prostate, colorectal, and melanoma. Once a patient is diagnosed with bone metastasis, the patient's quality of life and overall survival are significantly reduced owing to a wide range of morbidities and the increasing difficulty of treatment. Many studies have shown that bone metastasis is closely related to bone microenvironment, especially bone immune microenvironment. However, the effects of various immune cells in the bone microenvironment on bone metastasis remain unclear. Here, we described the changes in various immune cells during bone metastasis and discussed their related mechanisms. Osteoblasts, adipocytes, and other non-immune cells closely related to bone metastasis were also included. This review also summarized the existing treatment methods and potential therapeutic targets, and provided insights for future studies of cancer bone metastasis.
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Affiliation(s)
- Zengfeng Xin
- Department of Orthopedic SurgerySecond Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Luying Qin
- Cancer Institute (Key Laboratory of Cancer Prevention and InterventionNational Ministry of Education)Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Yang Tang
- Cancer Institute (Key Laboratory of Cancer Prevention and InterventionNational Ministry of Education)Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Siyu Guo
- Cancer Institute (Key Laboratory of Cancer Prevention and InterventionNational Ministry of Education)Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
- Department of Radiation OncologySecond Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Fangfang Li
- Cancer Institute (Key Laboratory of Cancer Prevention and InterventionNational Ministry of Education)Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Yuan Fang
- Cancer Institute (Key Laboratory of Cancer Prevention and InterventionNational Ministry of Education)Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Gege Li
- Cancer Institute (Key Laboratory of Cancer Prevention and InterventionNational Ministry of Education)Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Yihan Yao
- Cancer Institute (Key Laboratory of Cancer Prevention and InterventionNational Ministry of Education)Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Binbin Zheng
- Department of Respiratory MedicineNingbo Hangzhou Bay HospitalNingboZhejiangP. R. China
| | - Bicheng Zhang
- Cancer Institute (Key Laboratory of Cancer Prevention and InterventionNational Ministry of Education)Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
- Department of Radiation OncologySecond Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Dang Wu
- Cancer Institute (Key Laboratory of Cancer Prevention and InterventionNational Ministry of Education)Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
- Department of Radiation OncologySecond Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Jie Xiao
- Department of Orthopedic SurgerySecond Affiliated Hospital (Jiande Branch)Zhejiang University School of MedicineHangzhouZhejiangP. R. China
| | - Chao Ni
- Cancer Institute (Key Laboratory of Cancer Prevention and InterventionNational Ministry of Education)Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
- Department of Breast SurgerySecond Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Qichun Wei
- Cancer Institute (Key Laboratory of Cancer Prevention and InterventionNational Ministry of Education)Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
- Department of Radiation OncologySecond Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Ting Zhang
- Cancer Institute (Key Laboratory of Cancer Prevention and InterventionNational Ministry of Education)Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
- Department of Radiation OncologySecond Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
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9
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Joseph GJ, Johnson DB, Johnson RW. Immune checkpoint inhibitors in bone metastasis: Clinical challenges, toxicities, and mechanisms. J Bone Oncol 2023; 43:100505. [PMID: 37842554 PMCID: PMC10568292 DOI: 10.1016/j.jbo.2023.100505] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/19/2023] [Accepted: 09/19/2023] [Indexed: 10/17/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the field of anti-cancer therapy over the last decade; they provide durable clinical responses against tumors by inhibiting immune checkpoint proteins that canonically regulate the T cell-mediated immune response. Despite their success in many primary tumors and soft tissue metastases, ICIs function poorly in patients with bone metastases, and these patients do not have the same survival benefit as patients with the same primary tumor type (e.g., non-small cell lung cancer [NSCLC], urothelial, renal cell carcinoma [RCC], etc.) that has not metastasized to the bone. Additionally, immune-related adverse events including rheumatologic and musculoskeletal toxicities, bone loss, and increased fracture risk develop after treatment with ICIs. There are few preclinical studies that investigate the interplay of the immune system in bone metastases; however, the current literature suggests a role for CD8+ T cells and myeloid cell subsets in bone homeostasis. As such, this review focuses on findings from the clinical and pre-clinical studies that have investigated immune checkpoint blockade in the bone metastatic setting and highlights the need for more comprehensive investigations into the relationship between immune cell subsets, ICIs, and the bone-tumor microenvironment.
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Affiliation(s)
- Gwenyth J. Joseph
- Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Douglas B. Johnson
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Rachelle W. Johnson
- Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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10
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Krasnova O, Neganova I. Assembling the Puzzle Pieces. Insights for in Vitro Bone Remodeling. Stem Cell Rev Rep 2023; 19:1635-1658. [PMID: 37204634 DOI: 10.1007/s12015-023-10558-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/08/2023] [Indexed: 05/20/2023]
Abstract
As a highly dynamic organ, bone changes during throughout a person's life. This process is referred to as 'bone remodeling' and it involves two stages - a well-balanced osteoclastic bone resorption and an osteoblastic bone formation. Under normal physiological conditions bone remodeling is highly regulated that ensures tight coupling between bone formation and resorption, and its disruption results in a bone metabolic disorder, most commonly osteoporosis. Though osteoporosis is one of the most prevalent skeletal ailments that affect women and men aged over 40 of all races and ethnicities, currently there are few, if any safe and effective therapeutic interventions available. Developing state-of-the-art cellular systems for bone remodeling and osteoporosis can provide important insights into the cellular and molecular mechanisms involved in skeletal homeostasis and advise better therapies for patients. This review describes osteoblastogenesis and osteoclastogenesis as two vital processes for producing mature, active bone cells in the context of interactions between cells and the bone matrix. In addition, it considers current approaches in bone tissue engineering, pointing out cell sources, core factors and matrices used in scientific practice for modeling bone diseases and testing drugs. Finally, it focuses on the challenges that bone regenerative medicine is currently facing.
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Affiliation(s)
- O Krasnova
- Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, Russia
| | - I Neganova
- Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, Russia.
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11
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Aru B, Pehlivanoğlu C, Dal Z, Dereli-Çalışkan NN, Gürlü E, Yanıkkaya-Demirel G. A potential area of use for immune checkpoint inhibitors: Targeting bone marrow microenvironment in acute myeloid leukemia. Front Immunol 2023; 14:1108200. [PMID: 36742324 PMCID: PMC9895857 DOI: 10.3389/fimmu.2023.1108200] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 01/03/2023] [Indexed: 01/22/2023] Open
Abstract
Acute myeloid leukemia (AML) arises from the cells of myeloid lineage and is the most frequent leukemia type in adulthood accounting for about 80% of all cases. The most common treatment strategy for the treatment of AML includes chemotherapy, in rare cases radiotherapy and stem cell and bone marrow transplantation are considered. Immune checkpoint proteins involve in the negative regulation of immune cells, leading to an escape from immune surveillance, in turn, causing failure of tumor cell elimination. Immune checkpoint inhibitors (ICIs) target the negative regulation of the immune cells and support the immune system in terms of anti-tumor immunity. Bone marrow microenvironment (BMM) bears various blood cell lineages and the interactions between these lineages and the noncellular components of BMM are considered important for AML development and progression. Administration of ICIs for the AML treatment may be a promising option by regulating BMM. In this review, we summarize the current treatment options in AML treatment and discuss the possible application of ICIs in AML treatment from the perspective of the regulation of BMM.
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Affiliation(s)
- Başak Aru
- Immunology Department, Faculty of Medicine, Yeditepe University, Istanbul, Türkiye
| | - Cemil Pehlivanoğlu
- Immunology Department, Faculty of Medicine, Yeditepe University, Istanbul, Türkiye
| | - Zeynep Dal
- School of Medicine, Yeditepe University, Istanbul, Türkiye
| | | | - Ege Gürlü
- School of Medicine, Yeditepe University, Istanbul, Türkiye
| | - Gülderen Yanıkkaya-Demirel
- Immunology Department, Faculty of Medicine, Yeditepe University, Istanbul, Türkiye,*Correspondence: Gülderen Yanıkkaya-Demirel,
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12
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Esposito A, Klüppel M, Wilson BM, Meka SRK, Spagnoli A. CXCR4 mediates the effects of IGF-1R signaling in rodent bone homeostasis and fracture repair. Bone 2023; 166:116600. [PMID: 36368465 PMCID: PMC10057209 DOI: 10.1016/j.bone.2022.116600] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 10/26/2022] [Accepted: 10/28/2022] [Indexed: 11/10/2022]
Abstract
Non-union fractures have considerable clinical and economic burdens and yet the underlying pathogenesis remains largely undetermined. The fracture healing process involves cellular differentiation, callus formation and remodeling, and implies the recruitment and differentiation of mesenchymal stem cells that are not fully characterized. C-X-C chemokine receptor 4 (CXCR4) and Insulin-like growth factor 1 receptor (IGF-1R) are expressed in the fracture callus, but their interactions still remain elusive. We hypothesized that the regulation of CXCR4 by IGF-1R signaling is essential to maintain the bone homeostasis and to promote fracture repair. By using a combination of in vivo and in vitro approaches, we found that conditional ablation of IGF-1R in osteochondroprogenitors led to defects in bone formation and mineralization that associated with altered expression of CXCR4 by a discrete population of endosteal cells. These defects were corrected by AMD3100 (a CXCR4 antagonist). Furthermore, we found that the inducible ablation of IGF-1R in osteochondroprogenitors led to fracture healing failure, that associated with an altered expression of CXCR4. In vivo AMD3100 treatment improved fracture healing and normalized CXCR4 expression. Moreover, we determined that these effects were mediated through the IGF-1R/Insulin receptor substrate 1 (IRS-1) signaling pathway. Taken together, our studies identified a novel population of endosteal cells that is functionally regulated through the modulation of CXCR4 by IGF-1R signaling, and such control is essential in bone homeostasis and fracture healing. Knowledge gained from these studies has the potential to accelerate the development of novel therapeutic interventions by targeting CXCR4 signaling to treat non-unions.
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Affiliation(s)
- Alessandra Esposito
- Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, USA
| | - Michael Klüppel
- Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, USA
| | - Brittany M Wilson
- Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, USA
| | - Sai R K Meka
- Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, USA
| | - Anna Spagnoli
- Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, USA; Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA.
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13
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Sharma G, Pothuraju R, Kanchan RK, Batra SK, Siddiqui JA. Chemokines network in bone metastasis: Vital regulators of seeding and soiling. Semin Cancer Biol 2022; 86:457-472. [PMID: 35124194 PMCID: PMC9744380 DOI: 10.1016/j.semcancer.2022.02.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/20/2022] [Accepted: 02/01/2022] [Indexed: 02/07/2023]
Abstract
Chemokines are well equipped with chemo-attractive signals that can regulate cancer cell trafficking to specific organ sites. Currently, updated concepts have revealed the diverse role of chemokines in the biology of cancer initiation and progression. Genomic instabilities and alterations drive tumor heterogeneity, providing more options for the selection and metastatic progression to cancer cells. Tumor heterogeneity and acquired drug resistance are the main obstacles in managing cancer therapy and the primary root cause of metastasis. Studies emphasize that multiple chemokine/receptor axis are involved in cancer cell-mediated organ-specific distant metastasis. One of the persuasive mechanisms for heterogeneity and subsequent events is sturdily interlinked with the crosstalk between chemokines and their receptors on cancer cells and tissue-specific microenvironment. Among different metastatic niches, skeletal metastasis is frequently observed in the late stages of prostate, breast, and lung cancer and significantly reduces the survival of cancer patients. Therefore, it is crucial to elucidate the role of chemokines and their receptors in metastasis and bone remodeling. Here, we review the potential chemokine/receptor axis in tumorigenesis, tumor heterogeneity, metastasis, and vicious cycle in bone microenvironment.
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Affiliation(s)
- Gunjan Sharma
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ramesh Pothuraju
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ranjana Kumari Kanchan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Surinder Kumar Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Jawed Akhtar Siddiqui
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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14
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Fallati A, Di Marzo N, D’Amico G, Dander E. Mesenchymal Stromal Cells (MSCs): An Ally of B-Cell Acute Lymphoblastic Leukemia (B-ALL) Cells in Disease Maintenance and Progression within the Bone Marrow Hematopoietic Niche. Cancers (Basel) 2022; 14:cancers14143303. [PMID: 35884364 PMCID: PMC9323332 DOI: 10.3390/cancers14143303] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/17/2022] [Accepted: 07/04/2022] [Indexed: 12/04/2022] Open
Abstract
Simple Summary B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer. Even though the cure rate actually exceeds 85%, the prognosis of relapsed/refractory patients is dismal. Recent literature data indicate that the bone marrow (BM) microenvironment could play a crucial role in the onset, maintenance and progression of the disease. In particular, mesenchymal stromal cells (MSCs), which are key components of the BM niche, actively crosstalk with leukemic cells providing crucial signals for their survival and resistance to therapy. We hereby review the main mechanisms exploited by MSCs to nurture and protect B-ALL cells that could become appealing targets for innovative microenvironment remodeling therapies to be coupled with classical leukemia-directed strategies. Abstract Mesenchymal stromal cells (MSCs) are structural components of the bone marrow (BM) niche, where they functionally interact with hematopoietic stem cells and more differentiated progenitors, contributing to hematopoiesis regulation. A growing body of evidence is nowadays pointing to a further crucial contribution of MSCs to malignant hematopoiesis. In the context of B-cell acute lymphoblastic leukemia (B-ALL), MSCs can play a pivotal role in the definition of a leukemia-supportive microenvironment, impacting on disease pathogenesis at different steps including onset, maintenance and progression. B-ALL cells hijack the BM microenvironment, including MSCs residing in the BM niche, which in turn shelter leukemic cells and protect them from chemotherapeutic agents through different mechanisms. Evidence is now arising that altered MSCs can become precious allies to leukemic cells by providing nutrients, cytokines, pro-survivals signals and exchanging organelles, as hereafter reviewed. The study of the mechanisms exploited by MSCs to nurture and protect B-ALL blasts can be instrumental in finding new druggable candidates to target the leukemic BM microenvironment. Some of these microenvironment-targeting strategies are already in preclinical or clinical experimentation, and if coupled with leukemia-directed therapies, could represent a valuable option to improve the prognosis of relapsed/refractory patients, whose management represents an unmet medical need.
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15
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Effects of local vs systemic administration of CXCR4 inhibitor AMD3100 on orthodontic tooth movement in rats. Am J Orthod Dentofacial Orthop 2022; 162:182-192. [DOI: 10.1016/j.ajodo.2021.03.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 03/01/2021] [Accepted: 03/01/2021] [Indexed: 12/16/2022]
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16
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Breast Cancer Bone Metastasis: A Narrative Review of Emerging Targeted Drug Delivery Systems. Cells 2022; 11:cells11030388. [PMID: 35159207 PMCID: PMC8833898 DOI: 10.3390/cells11030388] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/10/2022] [Accepted: 01/16/2022] [Indexed: 01/06/2023] Open
Abstract
Bone is one of the most common metastatic sites among breast cancer (BC) patients. Once bone metastasis is developed, patients' survival and quality of life will be significantly declined. At present, there are limited therapeutic options for BC patients with bone metastasis. Different nanotechnology-based delivery systems have been developed aiming to specifically deliver the therapeutic agents to the bone. The conjugation of targeting agents to nanoparticles can enhance the selective delivery of various payloads to the metastatic bone lesion. The current review highlights promising and emerging advanced nanotechnologies designed for targeted delivery of anticancer therapeutics, contrast agents, photodynamic and photothermal materials to the bone to achieve the goal of treatment, diagnosis, and prevention of BC bone metastasis. A better understanding of various properties of these new therapeutic approaches may open up new landscapes in medicine towards improving the quality of life and overall survival of BC patients who experience bone metastasis.
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17
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Attaran S, Bissell MJ. The role of tumor microenvironment and exosomes in dormancy and relapse. Semin Cancer Biol 2022; 78:35-44. [PMID: 34757184 PMCID: PMC9605861 DOI: 10.1016/j.semcancer.2021.09.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 09/10/2021] [Accepted: 09/12/2021] [Indexed: 12/13/2022]
Abstract
Recent advancements in the field of cancer have established that the process of metastasis is organ-specific with tumor cell dissemination occurring in the very early stages of disease. Pre-metastatic niches are actively remodeled and transformed by both primary tumor specific factors and by influences from the extracellular matrix.Although improvements in cancer therapies have significantly improved outcomes in patients with early stage disease, the risk of recurrence and relapse leading to mortality remains high. Recent studies have emerged highlighting the influence of dormant tumor cells and exosomes as key players in cancer relapse. In this review we discuss the critical mediators of tumor progression and their link to cancer dormancy, while also exploring possible therapeutics for targeting relapse.
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Affiliation(s)
- Shireen Attaran
- Biological Systems & Engineering Division, Lawrence Berkeley National Laboratory, United States.
| | - Mina J Bissell
- Biological Systems & Engineering Division, Lawrence Berkeley National Laboratory, United States
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18
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Mitochondria and the Tumour Microenvironment in Blood Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1329:181-203. [PMID: 34664240 DOI: 10.1007/978-3-030-73119-9_10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
The bone marrow (BM) is a complex organ located within the cavities of bones. The main function of the BM is to produce all the blood cells required for a normal healthy blood system. As with any major organ, many diseases can arise from errors in bone marrow function, including non-malignant disorders such as anaemia and malignant disorders such as leukaemias. This article will explore the role of the bone marrow, in normal and diseased haematopoiesis, with an emphasis on the requirement for intercellular mitochondrial transfer in leukaemia.
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19
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Chai Y, Xu L, He R, Zhong L, Wang Y. Identification of hub genes specific to pulmonary metastasis in osteosarcoma through integrated bioinformatics analysis. Technol Health Care 2021; 30:735-745. [PMID: 34542049 DOI: 10.3233/thc-213163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Pulmonary metastasis is the most frequent cause of death in osteosarcoma (OS) patients. Recently, several bioinformatics studies specific to pulmonary metastatic osteosarcoma (PMOS) have been applied to identify genetic alterations. However, the interpretation and reliability of the results obtained were limited for the independent database analysis. OBJECTIVE The expression profiles and key pathways specific to PMOS remain to be comprehensively explored. Therefore, in our study, three original datasets of GEO database were selected. METHODS Initially, three microarray datasets (GSE14359, GSE14827, and GSE85537) were downloaded from the GEO database. Differentially expressed genes (DEGs) between PMOS and nonmetastatic osteosarcoma (NMOS) were identified and mined using DAVID. Subsequently, GO and KEGG pathway analyses were carried out for DEGs. Corresponding PPI network of DEGs was constructed based on the data collected from STRING datasets. The network was visualized with Cytoscape software, and ten hub genes were selected from the network. Finally, survival analysis of these hub genes also used the TARGET database. RESULTS In total, 569 upregulated and 1238 downregulated genes were filtered as DEGs between PMOS and NMOS. Based on the GO analysis result, these DEGs were significantly enriched in the anatomical structure development, extracellular matrix, biological adhesion, and cell adhesion terms. Based on the KEGG pathway analysis result, these DEGs were mainly enriched in the pathways in cancer, PI3K-Akt signaling, MAPK signaling, focal adhesion, cytokine-cytokine receptor interaction, and IL-17 signaling. Hub genes (ANXA1 and CXCL12) were significantly associated with overall survival time in OS patient. CONCLUSION Our results may provide new insight into pulmonary metastasis of OS. However, experimental studies remain necessary to elucidate the biological function and mechanism underlying PMOS.
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Affiliation(s)
- Yinan Chai
- Key Laboratory of Organ Development and Regeneration of Zhejiang Province, College of Life and Environmental Science, Hangzhou Normal University, Hangzhou, Zhejiang, China.,College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Lihan Xu
- Key Laboratory of Organ Development and Regeneration of Zhejiang Province, College of Life and Environmental Science, Hangzhou Normal University, Hangzhou, Zhejiang, China.,College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Rui He
- College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.,Department of stomatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Liangjun Zhong
- College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.,Department of stomatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yuying Wang
- Key Laboratory of Organ Development and Regeneration of Zhejiang Province, College of Life and Environmental Science, Hangzhou Normal University, Hangzhou, Zhejiang, China.,College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China
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20
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Zhang Z, Zheng Y, Zu J, Zhuang J, Xu G, Yan J, Liu X. Stromal cell-derived factor (SDF)-1α and platelet-rich plasma enhance bone regeneration and angiogenesis simultaneously in situ in rabbit calvaria. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2021; 32:125. [PMID: 34524548 PMCID: PMC8443516 DOI: 10.1007/s10856-021-06600-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 08/29/2021] [Indexed: 05/25/2023]
Abstract
The current study aimed to evaluate the effects of chemokine stromal cell-derived factor (SDF)-1α and platelet-rich plasma (PRP) on bone formation and angiogenesis, and to assess whether SDF-1α and PRP could function synergistically. Four evenly distributed defects (8 mm in diameter) were generated in the calvarial bones of New Zealand white rabbits. All rabbits received four treatment regimens containing autogenous bone particles (AB), SDF-1α, or PRP. AB group presented significantly less bone formation compared with the other three groups 2 and 4 weeks after surgery. The amount of newly formed bone in the AB+PRP+SDF-1α group was similar to that in the AB + SDF-1α group at the 4-week time-point (p = 0.65), and was much greater than that in the AB and AB+PRP group (p < 0.001). Meanwhile, more new blood vessels were formed in the AB+PRP, AB+SDF-1α, and AB+PRP+SDF-1α group versus the AB group. AB+PRP+SDF-1α group showed statistically increased angiogenesis compared with the AB+PRP and AB+SDF-1α groups (both p < 0.05) after treatment for 2 and 4 weeks. These findings indicated that SDF-1α and PRP might exhibit synergistic effects to promote angiogenesis in early bone regeneration.
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Affiliation(s)
- Zhengye Zhang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150001, PR China
| | - Yang Zheng
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150001, PR China
| | - Jianing Zu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150001, PR China
| | - Jinpeng Zhuang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150001, PR China
| | - Gongping Xu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150001, PR China
| | - Jinglong Yan
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150001, PR China.
| | - Xiaoqi Liu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150001, PR China.
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21
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Effects of Extracellular Osteoanabolic Agents on the Endogenous Response of Osteoblastic Cells. Cells 2021; 10:cells10092383. [PMID: 34572032 PMCID: PMC8471159 DOI: 10.3390/cells10092383] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/31/2021] [Accepted: 09/07/2021] [Indexed: 12/27/2022] Open
Abstract
The complex multidimensional skeletal organization can adapt its structure in accordance with external contexts, demonstrating excellent self-renewal capacity. Thus, optimal extracellular environmental properties are critical for bone regeneration and inextricably linked to the mechanical and biological states of bone. It is interesting to note that the microstructure of bone depends not only on genetic determinants (which control the bone remodeling loop through autocrine and paracrine signals) but also, more importantly, on the continuous response of cells to external mechanical cues. In particular, bone cells sense mechanical signals such as shear, tensile, loading and vibration, and once activated, they react by regulating bone anabolism. Although several specific surrounding conditions needed for osteoblast cells to specifically augment bone formation have been empirically discovered, most of the underlying biomechanical cellular processes underneath remain largely unknown. Nevertheless, exogenous stimuli of endogenous osteogenesis can be applied to promote the mineral apposition rate, bone formation, bone mass and bone strength, as well as expediting fracture repair and bone regeneration. The following review summarizes the latest studies related to the proliferation and differentiation of osteoblastic cells, enhanced by mechanical forces or supplemental signaling factors (such as trace metals, nutraceuticals, vitamins and exosomes), providing a thorough overview of the exogenous osteogenic agents which can be exploited to modulate and influence the mechanically induced anabolism of bone. Furthermore, this review aims to discuss the emerging role of extracellular stimuli in skeletal metabolism as well as their potential roles and provide new perspectives for the treatment of bone disorders.
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22
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Bone marrow/bone pre-metastatic niche for breast cancer cells colonization: The role of mesenchymal stromal cells. Crit Rev Oncol Hematol 2021; 164:103416. [PMID: 34237436 DOI: 10.1016/j.critrevonc.2021.103416] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 06/17/2021] [Accepted: 07/04/2021] [Indexed: 02/07/2023] Open
Abstract
Breast cancer is one of the most common oncological pathologies in women worldwide. While its early diagnosis has considerably improved, about 70 % of advanced patients develop bone metastases with a high mortality rate. Several authors demonstrated that primary breast cancer cells prepare their future metastatic niche -known as the pre-metastatic niche- to turn it into an "optimal soil" for colonization. The role of the different cellular components of the bone marrow/bone niche in bone metastasis has been well described. However, studying the changes that occur in this microenvironment before tumor cells arrival has become a novel research field. Therefore, the purpose of this review is to describe the current knowledge about the modulation of the normal bone marrow/bone niche by the primary breast tumor, in particular, highlighting the role of mesenchymal stem/stromal cells in transforming this soil into a pre-metastatic niche for breast cancer cells colonization.
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Wang C, Ying J, Nie X, Zhou T, Xiao D, Swarnkar G, Abu-Amer Y, Guan J, Shen J. Targeting angiogenesis for fracture nonunion treatment in inflammatory disease. Bone Res 2021; 9:29. [PMID: 34099632 PMCID: PMC8184936 DOI: 10.1038/s41413-021-00150-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 01/20/2021] [Accepted: 02/01/2021] [Indexed: 02/05/2023] Open
Abstract
Atrophic fracture nonunion poses a significant clinical problem with limited therapeutic interventions. In this study, we developed a unique nonunion model with high clinical relevance using serum transfer-induced rheumatoid arthritis (RA). Arthritic mice displayed fracture nonunion with the absence of fracture callus, diminished angiogenesis and fibrotic scar tissue formation leading to the failure of biomechanical properties, representing the major manifestations of atrophic nonunion in the clinic. Mechanistically, we demonstrated that the angiogenesis defect observed in RA mice was due to the downregulation of SPP1 and CXCL12 in chondrocytes, as evidenced by the restoration of angiogenesis upon SPP1 and CXCL12 treatment in vitro. In this regard, we developed a biodegradable scaffold loaded with SPP1 and CXCL12, which displayed a beneficial effect on angiogenesis and fracture repair in mice despite the presence of inflammation. Hence, these findings strongly suggest that the sustained release of SPP1 and CXCL12 represents an effective therapeutic approach to treat impaired angiogenesis and fracture nonunion under inflammatory conditions.
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Affiliation(s)
- Cuicui Wang
- grid.4367.60000 0001 2355 7002Department of Orthopaedic Surgery, School of Medicine, Washington University, St. Louis, MO USA
| | - Jun Ying
- grid.4367.60000 0001 2355 7002Department of Orthopaedic Surgery, School of Medicine, Washington University, St. Louis, MO USA ,grid.417400.60000 0004 1799 0055Department of Orthopaedic Surgery, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China ,grid.417400.60000 0004 1799 0055Institute of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiaolei Nie
- grid.4367.60000 0001 2355 7002Department of Mechanical Engineering & Materials Science, School of Engineering, Washington University, St. Louis, MO USA
| | - Tianhong Zhou
- grid.4367.60000 0001 2355 7002Department of Mechanical Engineering & Materials Science, School of Engineering, Washington University, St. Louis, MO USA
| | - Ding Xiao
- grid.4367.60000 0001 2355 7002Department of Orthopaedic Surgery, School of Medicine, Washington University, St. Louis, MO USA
| | - Gaurav Swarnkar
- grid.4367.60000 0001 2355 7002Department of Orthopaedic Surgery, School of Medicine, Washington University, St. Louis, MO USA
| | - Yousef Abu-Amer
- grid.4367.60000 0001 2355 7002Department of Orthopaedic Surgery, School of Medicine, Washington University, St. Louis, MO USA ,grid.415840.c0000 0004 0449 6533Shriners Hospital for Children, St. Louis, MO USA
| | - Jianjun Guan
- grid.4367.60000 0001 2355 7002Department of Mechanical Engineering & Materials Science, School of Engineering, Washington University, St. Louis, MO USA
| | - Jie Shen
- grid.4367.60000 0001 2355 7002Department of Orthopaedic Surgery, School of Medicine, Washington University, St. Louis, MO USA
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Tumor-Associated Macrophage Promotes the Survival of Cancer Cells upon Docetaxel Chemotherapy via the CSF1/CSF1R-CXCL12/CXCR4 Axis in Castration-Resistant Prostate Cancer. Genes (Basel) 2021; 12:genes12050773. [PMID: 34069563 PMCID: PMC8161256 DOI: 10.3390/genes12050773] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/04/2021] [Accepted: 05/18/2021] [Indexed: 01/16/2023] Open
Abstract
Castration-resistant prostate cancer (CRPC) is an advanced stage of prostate cancer that can progress rapidly even in patients treated with castration. Previously, we found that tumor-associated macrophages (TAM) can be recruited by CSF-1 secreted by docetaxel-treated prostate cancer cells and promote the survival of cancer cells in response to chemotherapy. The inhibition of CSF-1R can impede this effect and significantly prolong survival in xenograft mice. However, the actual mechanism of how TAM improves cancer cell survival still remains elusive and controversial. Here, for the first time, we found that the enhanced survival of cancer cells achieved by TAM was mainly mediated by CXCR4 activation from the increased secretion of CXCL12 from CSF-1 activated TAM. This finding helps to clarify the mechanism of chemoresistance for second-line chemotherapy using docetaxel, facilitating the development of novel drugs to overcome immune tolerance in castration-resistant prostate cancer.
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Hu C, He Y, Liu D, Zhao L, Fang S, Tan B, Dong S, Wang Y, He T, Bi Y. Hypoxia Preconditioning Promotes the Proliferation and Migration of Human Urine-Derived Stem Cells in Chronically Injured Liver of Mice by Upregulating CXCR4. Stem Cells Dev 2021; 30:526-536. [PMID: 33715421 DOI: 10.1089/scd.2021.0008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Our previous studies reported that urine-derived stem cells (USCs) possess a strong self-renewal ability and multidirectional differentiation potential and thus are an ideal candidate cell source for hepatocellular transplantation. USC transplantation may repair the pathological changes of chronic liver injury to a certain extent, and hypoxia pretreatment may improve the recovery efficiency of USCs. Therefore, the present study aimed to investigate the possible mechanism of the improved recovery efficiency of hypoxia-pretreated USCs. A chronic liver injury model was established by intraperitoneal injection of carbon tetrachloride into nude mice. USCs were transplanted via caudal vein injection. Hematoxylin and eosin staining and Masson's staining were performed to determine the pathology of the liver. Immunofluorescence and frozen section biopsy were performed to determine differentiation and cell fusion in vivo. Cell coculture was used to detect cell fusion in vitro. The proliferative ability of USCs was evaluated using cell viability and colony formation assays, and the migratory functions of USCs were evaluated using wound healing and transwell assays. The degeneration of hepatocytes and the level of fibrosis in the hypoxia transplantation group were improved compared with the normoxia transplantation group. It was found that exogenous USCs may be differentiated into functional hepatocytes or fused with hepatocytes in vivo. C-X-C motif chemokine (CXC) ligand 12 (CXCL12) expression levels in liver tissue of the chronic liver injury model were upregulated compared with those in the control group. The expression of CXC receptor 4 (CXCR4) in hypoxia-pretreated USCs was also significantly upregulated. The results suggested that USCs fused with different types of liver cells and that hypoxia treatment promoted the fusion rate in vitro by upregulating CXCR4 signaling. Furthermore, hypoxia pretreatment promoted cell proliferation, migration, and cell fusion by inducing CXCR4 signaling, leading to USC-elicited liver tissue recovery following injury in vivo.
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Affiliation(s)
- Chaoqun Hu
- Stem Cell Biology and Therapy Laboratory, Department of Pediatric Surgery Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, P.R. China
| | - Yun He
- Stem Cell Biology and Therapy Laboratory, Department of Pediatric Surgery Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, P.R. China
| | - Daijiang Liu
- Department of Gastroenterology, Chongqing University Central Hospital, Chongqing, P.R. China
| | - Li Zhao
- Stem Cell Biology and Therapy Laboratory, Department of Pediatric Surgery Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, P.R. China
| | - Shuyu Fang
- Stem Cell Biology and Therapy Laboratory, Department of Pediatric Surgery Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, P.R. China
| | - Bin Tan
- Stem Cell Biology and Therapy Laboratory, Department of Pediatric Surgery Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, P.R. China
| | - Shifang Dong
- Stem Cell Biology and Therapy Laboratory, Department of Pediatric Surgery Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, P.R. China
| | - Yi Wang
- Stem Cell Biology and Therapy Laboratory, Department of Pediatric Surgery Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, P.R. China
| | - Tongchuan He
- Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois, USA
| | - Yang Bi
- Stem Cell Biology and Therapy Laboratory, Department of Pediatric Surgery Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, P.R. China
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Sendker S, Waack K, Reinhardt D. Far from Health: The Bone Marrow Microenvironment in AML, A Leukemia Supportive Shelter. CHILDREN (BASEL, SWITZERLAND) 2021; 8:371. [PMID: 34066861 PMCID: PMC8150304 DOI: 10.3390/children8050371] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 04/30/2021] [Accepted: 05/03/2021] [Indexed: 12/28/2022]
Abstract
Acute myeloid leukemia (AML) is the second most common leukemia among children. Although significant progress in AML therapy has been achieved, treatment failure is still associated with poor prognosis, emphasizing the need for novel, innovative therapeutic approaches. To address this major obstacle, extensive knowledge about leukemogenesis and the complex interplay between leukemic cells and their microenvironment is required. The tremendous role of this bone marrow microenvironment in providing a supportive and protective shelter for leukemic cells, leading to disease development, progression, and relapse, has been emphasized by recent research. It has been revealed that the interplay between leukemic cells and surrounding cellular as well as non-cellular components is critical in the process of leukemogenesis. In this review, we provide a comprehensive overview of recently gained knowledge about the importance of the microenvironment in AML whilst focusing on promising future therapeutic targets. In this context, we describe ongoing clinical trials and future challenges for the development of targeted therapies for AML.
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Affiliation(s)
| | | | - Dirk Reinhardt
- Department of Pediatric Hematology and Oncology, Clinic of Pediatrics III, Essen University Hospital, 45147 Essen, Germany; (S.S.); (K.W.)
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Bahmad HF, Jalloul M, Azar J, Moubarak MM, Samad TA, Mukherji D, Al-Sayegh M, Abou-Kheir W. Tumor Microenvironment in Prostate Cancer: Toward Identification of Novel Molecular Biomarkers for Diagnosis, Prognosis, and Therapy Development. Front Genet 2021; 12:652747. [PMID: 33841508 PMCID: PMC8033163 DOI: 10.3389/fgene.2021.652747] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 03/08/2021] [Indexed: 12/12/2022] Open
Abstract
Prostate cancer (PCa) is by far the most commonly diagnosed cancer in men worldwide. Despite sensitivity to androgen deprivation, patients with advanced disease eventually develop resistance to therapy and may die of metastatic castration-resistant prostate cancer (mCRPC). A key challenge in the management of PCa is the clinical heterogeneity that is hard to predict using existing biomarkers. Defining molecular biomarkers for PCa that can reliably aid in diagnosis and distinguishing patients who require aggressive therapy from those who should avoid overtreatment is a significant unmet need. Mechanisms underlying the development of PCa are not confined to cancer epithelial cells, but also involve the tumor microenvironment. The crosstalk between epithelial cells and stroma in PCa has been shown to play an integral role in disease progression and metastasis. A number of key markers of reactive stroma has been identified including stem/progenitor cell markers, stromal-derived mediators of inflammation, regulators of angiogenesis, connective tissue growth factors, wingless homologs (Wnts), and integrins. Here, we provide a synopsis of the stromal-epithelial crosstalk in PCa focusing on the relevant molecular biomarkers pertaining to the tumor microenvironment and their role in diagnosis, prognosis, and therapy development.
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Affiliation(s)
- Hisham F. Bahmad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, United States
| | - Mohammad Jalloul
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Joseph Azar
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Maya M. Moubarak
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Tamara Abdul Samad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Deborah Mukherji
- Department of Internal Medicine, Division of Hematology-Oncology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Mohamed Al-Sayegh
- Biology Division, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Leguit RJ, Raymakers RAP, Hebeda KM, Goldschmeding R. CCN2 (Cellular Communication Network factor 2) in the bone marrow microenvironment, normal and malignant hematopoiesis. J Cell Commun Signal 2021; 15:25-56. [PMID: 33428075 PMCID: PMC7798015 DOI: 10.1007/s12079-020-00602-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 12/20/2020] [Indexed: 02/06/2023] Open
Abstract
CCN2, formerly termed Connective Tissue Growth Factor, is a protein belonging to the Cellular Communication Network (CCN)-family of secreted extracellular matrix-associated proteins. As a matricellular protein it is mainly considered to be active as a modifier of signaling activity of several different signaling pathways and as an orchestrator of their cross-talk. Furthermore, CCN2 and its fragments have been implicated in the regulation of a multitude of biological processes, including cell proliferation, differentiation, adhesion, migration, cell survival, apoptosis and the production of extracellular matrix products, as well as in more complex processes such as embryonic development, angiogenesis, chondrogenesis, osteogenesis, fibrosis, mechanotransduction and inflammation. Its function is complex and context dependent, depending on cell type, state of differentiation and microenvironmental context. CCN2 plays a role in many diseases, especially those associated with fibrosis, but has also been implicated in many different forms of cancer. In the bone marrow (BM), CCN2 is highly expressed in mesenchymal stem/stromal cells (MSCs). CCN2 is important for MSC function, supporting its proliferation, migration and differentiation. In addition, stromal CCN2 supports the maintenance and longtime survival of hematopoietic stem cells, and in the presence of interleukin 7, stimulates the differentiation of pro-B lymphocytes into pre-B lymphocytes. Overexpression of CCN2 is seen in the majority of B-acute lymphoblastic leukemias, especially in certain cytogenetic subgroups associated with poor outcome. In acute myeloid leukemia, CCN2 expression is increased in MSCs, which has been associated with leukemic engraftment in vivo. In this review, the complex function of CCN2 in the BM microenvironment and in normal as well as malignant hematopoiesis is discussed. In addition, an overview is given of data on the remaining CCN family members regarding normal and malignant hematopoiesis, having many similarities and some differences in their function.
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Affiliation(s)
- Roos J. Leguit
- Department of Pathology, University Medical Center Utrecht, H04-312, P.O. Box 85500, 3508 GA Utrecht, The Netherlands
| | - Reinier A. P. Raymakers
- Department of Hematology, UMCU Cancer Center, Heidelberglaan 100 B02.226, 3584 CX Utrecht, The Netherlands
| | - Konnie M. Hebeda
- Department of Pathology, Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Roel Goldschmeding
- Department of Pathology, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands
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Mollica V, Rizzo A, Rosellini M, Marchetti A, Ricci AD, Cimadamore A, Scarpelli M, Bonucci C, Andrini E, Errani C, Santoni M, Montironi R, Massari F. Bone Targeting Agents in Patients with Metastatic Prostate Cancer: State of the Art. Cancers (Basel) 2021; 13:cancers13030546. [PMID: 33535541 PMCID: PMC7867059 DOI: 10.3390/cancers13030546] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/26/2021] [Accepted: 01/27/2021] [Indexed: 02/03/2023] Open
Abstract
Simple Summary Over the disease course of metastatic prostate cancer, approximately the 90% of patients develops bone metastases, with bone involvement frequently leading to various skeletal complications including pathological fractures, spinal cord compression, and pain. Notably enough, the peculiar inclination of prostate cancer cells to seed the bone is considered an important cause of morbidity for prostate cancer patients. Recent years have witnessed the advent of several novel treatments for prostate cancer, and therapeutic paradigms are rapidly shifting. In this review, we aim at giving an overview of current knowledge on the relationship between prostate cancer and bone, especially focusing on the use of bone-targeted agents in this setting. Abstract Bone health represents a major issue in castration-resistant prostate cancer (CRPC) patients with bone metastases; in fact, the frequently prolonged use of hormonal agents causes important modifications in physiological bone turnover and most of these men will develop skeletal-related events (SREs), including spinal cord compression, pathologic fractures and need for surgery or radiation to bone, which are estimated to occur in almost half of this patient population. In the last decade, several novel therapeutic options have entered into clinical practice of bone metastatic CRPC, with recent approval of enzalutamide and abiraterone acetate, cabazitaxel chemotherapy and radium-223, on the basis of survival benefit suggested by landmark Phase III trials assessing these agents in this setting. Conversely, although bone-targeted agents (BTAs)—such as the bisphosphonate zoledronic acid and the receptor activator of nuclear factor kappa-B (RANK) ligand inhibitor denosumab—are approved for the prevention of SREs, these compounds have not shown benefit in terms of overall survival. However, emerging evidence has suggested that the combination of BTAs and abiraterone acetate, enzalutamide and the radiopharmaceutical radium-223 could result in improved clinical outcomes and prolonged survival in bone metastatic CRPC. In this review, we will provide an overview on bone tropism of prostate cancer and on the role of BTAs in metastatic hormone-sensitive and castration-resistant prostate cancer.
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Affiliation(s)
- Veronica Mollica
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy; (V.M.); (A.R.); (M.R.); (A.M.); (A.D.R.); (C.B.); (E.A.)
| | - Alessandro Rizzo
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy; (V.M.); (A.R.); (M.R.); (A.M.); (A.D.R.); (C.B.); (E.A.)
| | - Matteo Rosellini
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy; (V.M.); (A.R.); (M.R.); (A.M.); (A.D.R.); (C.B.); (E.A.)
| | - Andrea Marchetti
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy; (V.M.); (A.R.); (M.R.); (A.M.); (A.D.R.); (C.B.); (E.A.)
| | - Angela Dalia Ricci
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy; (V.M.); (A.R.); (M.R.); (A.M.); (A.D.R.); (C.B.); (E.A.)
| | - Alessia Cimadamore
- Section of Pathological Anatomy, School of Medicine, United Hospitals, Polytechnic University of the Marche Region, 60121 Ancona, Italy; (A.C.); (M.S.); (R.M.)
| | - Marina Scarpelli
- Section of Pathological Anatomy, School of Medicine, United Hospitals, Polytechnic University of the Marche Region, 60121 Ancona, Italy; (A.C.); (M.S.); (R.M.)
| | - Chiara Bonucci
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy; (V.M.); (A.R.); (M.R.); (A.M.); (A.D.R.); (C.B.); (E.A.)
| | - Elisa Andrini
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy; (V.M.); (A.R.); (M.R.); (A.M.); (A.D.R.); (C.B.); (E.A.)
| | - Costantino Errani
- Department of Musculo–Skeletal Oncology, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy;
| | - Matteo Santoni
- Oncology Unit, Macerata Hospital, 62100 Macerata, Italy;
| | - Rodolfo Montironi
- Section of Pathological Anatomy, School of Medicine, United Hospitals, Polytechnic University of the Marche Region, 60121 Ancona, Italy; (A.C.); (M.S.); (R.M.)
| | - Francesco Massari
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy; (V.M.); (A.R.); (M.R.); (A.M.); (A.D.R.); (C.B.); (E.A.)
- Correspondence: or
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Hochheuser C, Windt LJ, Kunze NY, de Vos DL, Tytgat GA, Voermans C, Timmerman I. Mesenchymal Stromal Cells in Neuroblastoma: Exploring Crosstalk and Therapeutic Implications. Stem Cells Dev 2021; 30:59-78. [PMID: 33287630 PMCID: PMC7826431 DOI: 10.1089/scd.2020.0142] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 12/07/2020] [Indexed: 02/07/2023] Open
Abstract
Neuroblastoma (NB) is the second most common solid cancer in childhood, accounting for 15% of cancer-related deaths in children. In high-risk NB patients, the majority suffers from metastasis. Despite intensive multimodal treatment, long-term survival remains <40%. The bone marrow (BM) is among the most common sites of distant metastasis in patients with high-risk NB. In this environment, small populations of tumor cells can persist after treatment (minimal residual disease) and induce relapse. Therapy resistance of these residual tumor cells in BM remains a major obstacle for the cure of NB. A detailed understanding of the microenvironment and its role in tumor progression is of utmost importance for improving the treatment efficiency of NB. In BM, mesenchymal stromal cells (MSCs) constitute an important part of the microenvironment, where they support hematopoiesis and modulate immune responses. Their role in tumor progression is not completely understood, especially for NB. Although MSCs have been found to promote epithelial-mesenchymal transition, tumor growth, and metastasis and to induce chemoresistance, some reports point toward a tumor-suppressive effect of MSCs. In this review, we aim to compile current knowledge about the role of MSCs in NB development and progression. We evaluate arguments that depict tumor-supportive versus -suppressive properties of MSCs in the context of NB and give an overview of factors involved in MSC-NB crosstalk. A focus lies on the BM as a metastatic niche, since that is the predominant site for NB metastasis and relapse. Finally, we will present opportunities and challenges for therapeutic targeting of MSCs in the BM microenvironment.
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Affiliation(s)
- Caroline Hochheuser
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Laurens J. Windt
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Nina Y. Kunze
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Dieuwke L. de Vos
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | | | - Carlijn Voermans
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Ilse Timmerman
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands
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Goto KT, Kajiya H, Tsutsumi T, Maeshiba M, Tsuzuki T, Ohgi K, Kawaguchi M, Ohno J, Okabe K. The Stromal Cell-derived Factor-1 Expression Protected in Periodontal Tissues Damage during Occlusal Traumatism. J HARD TISSUE BIOL 2021. [DOI: 10.2485/jhtb.30.63] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Kazuko T Goto
- Department of Dental Hygiene, Fukuoka College of Health Sciences, Fukuoka
| | - Hiroshi Kajiya
- Department of Physiological Science and Molecular Biology, Fukuoka Dental College
- Research Center for Oral Medicine, Fukuoka Dental College
| | | | | | | | - Kimiko Ohgi
- Department of Odontology, Fukuoka Dental College
| | | | - Jun Ohno
- Research Center for Oral Medicine, Fukuoka Dental College
| | - Koji Okabe
- Department of Physiological Science and Molecular Biology, Fukuoka Dental College
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Chen WC, Hu G, Hazlehurst LA. Contribution of the bone marrow stromal cells in mediating drug resistance in hematopoietic tumors. Curr Opin Pharmacol 2020; 54:36-43. [PMID: 32898723 PMCID: PMC7770000 DOI: 10.1016/j.coph.2020.08.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 07/31/2020] [Accepted: 08/06/2020] [Indexed: 12/21/2022]
Abstract
The bone marrow microenvironment (BMM) provides input via production of cytokines, chemokines, extracellular matrixes in the context of lower oxygen levels that influences self-renewal, survival, differentiation, progression, and therapeutic resistance of multiple myeloma and leukemic cells. Within the context of the BMM, tumor cells are supported by osteoblasts, bone marrow stromal cells (BMSCs), fibroblasts, myeloid cells, endothelial cells and blood vessels, as well as extracellular matrix (ECM) that contribute to tumor progression. Environmental mediated-drug resistance (EM-DR) contains cell adhesion-mediated drug resistance (CAM-DR) and soluble factor-mediated drug resistance (SM-DR) that contributes to de novo drug resistance. In this review, we focus on the crosstalk between the BMM and tumor cells as well as mechanisms underlying the BMM contributing to drug resistance in hematologic malignancies.
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Affiliation(s)
- Wei-Chih Chen
- Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26506 USA; Cancer Center, West Virginia University, Morgantown, WV 26506 USA
| | - Gangqing Hu
- Cancer Center, West Virginia University, Morgantown, WV 26506 USA; Department of Microbiology, Immunology and Cell Biology, School of Medicine, West Virginia University, Morgantown, WV 26506 USA
| | - Lori A Hazlehurst
- Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26506 USA; Cancer Center, West Virginia University, Morgantown, WV 26506 USA.
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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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Won JE, Lee YS, Park JH, Lee JH, Shin YS, Kim CH, Knowles JC, Kim HW. Hierarchical microchanneled scaffolds modulate multiple tissue-regenerative processes of immune-responses, angiogenesis, and stem cell homing. Biomaterials 2020; 227:119548. [DOI: 10.1016/j.biomaterials.2019.119548] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 10/05/2019] [Accepted: 10/14/2019] [Indexed: 12/27/2022]
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Mardani A, Gheytanchi E, Mousavie SH, Madjd Jabari Z, Shooshtarizadeh T. Clinical Significance of Cancer Stem Cell Markers CD133 and CXCR4 in Osteosarcomas. Asian Pac J Cancer Prev 2020; 21:67-73. [PMID: 31983166 PMCID: PMC7294029 DOI: 10.31557/apjcp.2020.21.1.67] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Indexed: 12/16/2022] Open
Abstract
Objective: Osteosarcomas (OS) is one the most common primary bone malignancy in humans with the lungs metastasis in most cases. Metastasis and recurrence of OS is attributed to cancer stem cells (CSCs). Our study aimed to evaluate the clinical significance of CD133 and C-X-C chemokine receptor type 4 (CXCR4) as the frequently applied markers for CSCs in OS patients. Methods: In this cross-sectional, a total of 50 tissue samples from the patients with primary OS were immunohistochemically examined to detect the expression of CD133 and CXCR4. The associations of the relative expression and clinical significance of each marker were also evaluated. Results: High level expression of CD133 was detected in 26% of OS patient tissues. Of the 12 patients who showed lung metastasis, 5 cases showed high expression of CD133 with marginal trend correlation (P=0.06). No significant correlation was observed between CD133 expression and clinicopathological factors. Only 36% of cases showed CXCR4 expression which was not significantly correlated with gender, age, tumor size, necrosis, stage and metastasis (P>0.05). Clinically, patients with concomitant CD133/CXCR4 expression had significant association with lung metastasis (P=0.05). Conclusion: Our findings showed that concomitant expression of CSC markers CD133/CXCR4 might had a synergistic effect on the OS poor prognosis. These markers could be considered as potential therapeutic candidates of OS targeted therapy.
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Affiliation(s)
- Azam Mardani
- Department of Pathology, Iran University of Medical Science, Tehran, Iran
| | - Elmira Gheytanchi
- Oncopathology Research Center, Iran University of Medical Science, Tehran, Iran
| | - Seyed Hamzeh Mousavie
- Department of Surgery, Rasool-Akram Hospital, Iran University of Medical Science, Tehran, Iran
| | - Zahra Madjd Jabari
- Oncopathology Research Center, Iran University of Medical Science, Tehran, Iran
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Abstract
Chemokines are a family of small proteins, subdivided by their conserved cysteine residues and common structural features. Chemokines interact with their cognate G-protein-coupled receptors to elicit downstream signals that result in cell migration, proliferation, and survival. This review presents evidence for how the various CXC and CC subfamily chemokines influence bone hemostasis by acting on osteoclasts, osteoblasts, and progenitor cells. Also discussed are the ways in which chemokines contribute to bone loss as a result of inflammatory diseases such as rheumatoid arthritis, HIV infection, and periodontal infection. Both positive and negative effects of chemokines on bone formation and bone loss are presented. In addition, the role of chemokines in altering the bone microenvironment through effects on angiogenesis and tumor invasion is discussed. Very few therapeutic agents that influence bone formation by targeting chemokines or chemokine receptors are available, although a few are currently being evaluated.
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Affiliation(s)
- Annette Gilchrist
- Department of Pharmaceutical Sciences, Midwestern University, Downers Grove, IL, USA.
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Daniel SK, Seo YD, Pillarisetty VG. The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies. Semin Cancer Biol 2019; 65:176-188. [PMID: 31874281 DOI: 10.1016/j.semcancer.2019.12.007] [Citation(s) in RCA: 137] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 12/03/2019] [Accepted: 12/11/2019] [Indexed: 02/07/2023]
Abstract
Single agent checkpoint inhibitor therapy has not been effective for most gastrointestinal solid tumors, but combination therapy with drugs targeting additional immunosuppressive pathways is being attempted. One such pathway, the CXCL12-CXCR4/CXCR7 chemokine axis, has attracted attention due to its effects on tumor cell survival and metastasis as well as immune cell migration. CXCL12 is a small protein that functions in normal hematopoietic stem cell homing in addition to repair of damaged tissue. Binding of CXCL12 to CXCR4 leads to activation of G protein signaling kinases such as P13K/mTOR and MEK/ERK while binding to CXCR7 leads to β-arrestin mediated signaling. While some gastric and colorectal carcinoma cells have been shown to make CXCL12, the primary source in pancreatic cancer and peritoneal metastases is cancer-associated fibroblasts. Binding of CXCL12 to CXCR4 and CXCR7 on tumor cells leads to anti-apoptotic signaling through Bcl-2 and survivin upregulation, as well as promotion of the epithelial-to-mesechymal transition through the Rho-ROCK pathway and alterations in cell adhesion molecules. High levels of CXCL12 seen in the bone marrow, liver, and spleen could partially explain why these are popular sites of metastases for many tumors. CXCL12 is a chemoattractant for lymphocytes at lower levels, but becomes chemorepellant at higher levels; it is unclear exactly what gradient exists in the tumor microenvironment and how this influences tumor-infiltrating lymphocytes. AMD3100 (Plerixafor or Mozobil) is a small molecule CXCR4 antagonist and is the most frequently used drug targeting the CXCL12-CXCR4/CXCR7 axis in clinical trials for gastrointestinal solid tumors currently. Other small molecules and monoclonal antibodies against CXCR4 are being trialed. Further understanding of the CXCL12- CXCR4/CXCR7 chemokine axis in the tumor microenvironment will allow more effective targeting of this pathway in combination immunotherapy.
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Affiliation(s)
- Sara K Daniel
- University of Washington, Dept. of Surgery, Seattle, WA, USA
| | - Y David Seo
- University of Washington, Dept. of Surgery, Seattle, WA, USA
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Jiang X, Xu C, Shi H, Cheng Q. PTH1-34 improves bone healing by promoting angiogenesis and facilitating MSCs migration and differentiation in a stabilized fracture mouse model. PLoS One 2019; 14:e0226163. [PMID: 31821371 PMCID: PMC6903750 DOI: 10.1371/journal.pone.0226163] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 11/20/2019] [Indexed: 11/18/2022] Open
Abstract
Objective PTH1-34 (parathyroid hormone 1–34) is the only clinical drug to promote osteogenesis. MSCs (mesenchymal stem cells) have multidirectional differentiation potential and are closely related to fracture healing. This study was to explore the effects of PTH1-34 on proliferation and differentiation of endothelial cells and MSCs in vitro, and on angiogenesis, and MSCs migration during fracture healing in vivo. Methods Mice with stabilized fracture were assigned to 4 groups: CON, PTH (PTH1-34 40 μg/kg/day), MSC (transplanted with 105 MSCs), PTH+MSCs. Mice were sacrificed 14 days after fracture, and callus tissues were harvested for microCT scan and immunohistochemistry analysis. The effects of PTH1-34 on angiogenesis, and MSCs differentiation and migration were assessed by wound healing, tube formation and immunofluorescence staining. Results Treatment with either PTH1-34, or MSCs promoted bone healing and vascular formation in fracture callus. The callus bone mass, bone volume, and bone mineral density were all greater in PTH and/or MSC groups than they were in CON (p<0.05). PTH1-34 increased small vessels formation (diameter ≤50μm), whereas MSCs increased the large ones (diameter >50μm). Expression of CD31 within calluses and trabecular bones were significantly higher in PTH1-34 treated group than that of not (p<0.05). Expression of CD31, VEGFR, VEGFR2, and vWF was upregulated, and wound healing and tube formation were increased in MSCs treated with PTH1-34 compared to that of control. Conclusions PTH1-34 improved the proliferation and differentiation of endothelial cells and MSCs, enhancing migration of MSCs to bone callus to promote angiogenesis and osteogenesis, and facilitating fracture healing.
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Affiliation(s)
- Xin Jiang
- Department of Osteoporosis and Bone Disease, Huadong Hospital Affiliated to Fudan University, Research Section of Geriatric Metabolic Bone Disease, Shanghai Geriatric Institute, Shanghai, China
| | - Cuidi Xu
- Department of Osteoporosis and Bone Disease, Huadong Hospital Affiliated to Fudan University, Research Section of Geriatric Metabolic Bone Disease, Shanghai Geriatric Institute, Shanghai, China
| | - Hongli Shi
- Department of Osteoporosis and Bone Disease, Huadong Hospital Affiliated to Fudan University, Research Section of Geriatric Metabolic Bone Disease, Shanghai Geriatric Institute, Shanghai, China
| | - Qun Cheng
- Department of Osteoporosis and Bone Disease, Huadong Hospital Affiliated to Fudan University, Research Section of Geriatric Metabolic Bone Disease, Shanghai Geriatric Institute, Shanghai, China
- * E-mail:
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Huang Z, Li G, Zhang Z, Gu R, Wang W, Lai X, Cui ZK, Zeng F, Xu S, Deng F. β2AR-HIF-1α-CXCL12 signaling of osteoblasts activated by isoproterenol promotes migration and invasion of prostate cancer cells. BMC Cancer 2019; 19:1142. [PMID: 31771535 PMCID: PMC6878637 DOI: 10.1186/s12885-019-6301-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 10/28/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Chronic stress is well known to promote tumor progression, however, little is known whether chronic stress-mediated regulation of osteoblasts contributes to the migration and invasion of metastatic cancer cells. METHODS The proliferation, migration and invasion of prostate cancer cells were assessed by CCK-8 and transwell assay. HIF-1α expression of osteoblasts and epithelial-mesenchymal transition (EMT) markers of prostate cancer cells were examined by Western blot. The mRNA level of cytokines associated with bone metastasis in osteoblasts and EMT markers in PC-3 and DU145 cells were performed by qRT-PCR. Functional rescue experiment of cells were performed by using siRNA, plasmid transfection and inhibitor treatment. RESULTS Isoproterenol (ISO), a pharmacological surrogate of sympathetic nerve activation induced by chronic stress, exhibited no direct effect on migration and invasion of PC-3 and DU145 prostate cancer cells. Whereas, osteoblasts pretreated with ISO promoted EMT, migration and invasion of PC-3 and DU145 cells, which could be inhibited by β2AR inhibitor. Mechanistically, ISO increased the secretion of CXCL12 via the β2AR-HIF-1α signaling in osteoblasts. Moreover, overexpression of HIF-1α osteoblasts promoted migration and invasion of PC-3 and DU145 cells, which was inhibited by addition of recombinant knockdown of CXCR4 in PC-3 and DU145 cells, and inhibiting CXCL12-CXCR4 signaling with LY2510924 blunted the effects of osteoblasts in response to ISO on EMT and migration as well as invasion of PC-3 and DU145 cells. CONCLUSIONS These findings demonstrated that β2AR-HIF-1α-CXCL12 signaling in osteoblasts facilitates migration and invasion as well as EMT of prostate cancer cells, and may play a potential role in affecting bone metastasis of prostate cancer.
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Affiliation(s)
- Zhibin Huang
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280 China
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515 China
- Department of Anesthesiology, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, 350001 China
| | - Guihuan Li
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515 China
| | - Zhishuai Zhang
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515 China
| | - Ruonan Gu
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280 China
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515 China
| | - Wenyang Wang
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515 China
| | - Xiaoju Lai
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515 China
| | - Zhong-Kai Cui
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515 China
| | - Fangyin Zeng
- Department of Clinical Laboratory, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, 510900 China
| | - Shiyuan Xu
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280 China
| | - Fan Deng
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515 China
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Lee E, Kim J, Kang Y, Shin JW. A Platform for Studying of the Three-Dimensional Migration of Hematopoietic Stem/Progenitor Cells. Tissue Eng Regen Med 2019; 17:25-31. [PMID: 32002840 DOI: 10.1007/s13770-019-00224-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 09/06/2019] [Accepted: 09/25/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Hematopoietic stem/progenitor cells (HSPCs) have the property to return to the bone marrow, which is believed to be critical in situations such as HSPC transplantation. This property plays an important role in the stemness, viability, and proliferation of HSPCs, also. However, most in vitro models so far have not sufficiently simulated the complicate environment. Here, we proposed a three-dimensional experimental platform for the quantitative study of the migration of HSPCs. METHODS After encapsulating osteoblasts (OBs) in alginate beads, we quantified the migration of HSPCs into the beads due to the physical environment using digital image processing. Intermittent hydrostatic pressure (IHP) was used to mimic the mechanical environment of human bone marrow without using any biochemical factors. The expression of stromal cell-derived factor 1 (SDF-1) under IHP was measured. RESULTS The results showed that the presence of OBs in the hydrogel scaffold initiate the movement of HSPCs. Furthermore, the IHP promotes the migration of HSPCs, even without the addition of any biochemical factors, and the results were confirmed by measuring SDF-1 levels. CONCLUSION We believe this suggested three-dimensional experimental platform consisting of a simulated in vivo physical environment and encapsulated OBs should contribute to in vitro migration studies used to investigate the effects of other external factors.
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Affiliation(s)
- Eunjin Lee
- Department of Biomedical Engineering, Inje University, 197 Inje-ro, Gimhae-si, Gyeongsangnam-do, 50834, Republic of Korea
| | - Jieun Kim
- Department of Biomedical Engineering, Inje University, 197 Inje-ro, Gimhae-si, Gyeongsangnam-do, 50834, Republic of Korea
| | - Yungyeong Kang
- Department of Biomedical Engineering, Inje University, 197 Inje-ro, Gimhae-si, Gyeongsangnam-do, 50834, Republic of Korea.
| | - Jung-Woog Shin
- Department of Biomedical Engineering, Inje University, 197 Inje-ro, Gimhae-si, Gyeongsangnam-do, 50834, Republic of Korea.
- Cardiovascular and Metabolic Disease Center, Institute of Aged Life Redesign, UHARC, Inje University, 197 Inje-ro, Gimhae-si, Gyeongsangnam-do, 50834, Republic of Korea.
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Abstract
PURPOSE OF REVIEW The goal of this review is to summarize recent experimental and clinical evidence for metastatic latency and the molecular mechanisms that regulate tumor dormancy in the bone. RECENT FINDINGS Tumor dormancy contributes to the progression of metastasis and thus has significant clinical implications for prognosis and treatment. Tumor-intrinsic signaling and specialized bone marrow niches play a pivotal role in determining the dormancy status of bone disseminated tumor cells. Experimental models have provided significant insight into the effects of the bone microenvironment on tumor cells; however, these models remain limited in their ability to study dormancy. Despite recent advances in the mechanistic understanding of how tumor cells remain dormant in the bone for prolonged periods of time, the signals that trigger spontaneous dormancy escape remain unclear. This review highlights the need for further investigation of mechanisms underlying tumor dormancy using clinically relevant models.
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Affiliation(s)
- Miranda E Clements
- Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Rachelle W Johnson
- Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
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Brylka LJ, Schinke T. Chemokines in Physiological and Pathological Bone Remodeling. Front Immunol 2019; 10:2182. [PMID: 31572390 PMCID: PMC6753917 DOI: 10.3389/fimmu.2019.02182] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 08/29/2019] [Indexed: 12/21/2022] Open
Abstract
The bone matrix is constantly remodeled by bone-resorbing osteoclasts and bone-forming osteoblasts. These two cell types are fundamentally different in terms of progenitor cells, mode of action and regulation by specific molecules, acting either systemically or locally. Importantly, there is increasing evidence for an impact of cell types or molecules of the adaptive and innate immune system on bone remodeling. Understanding these influences is the major goal of a novel research area termed osteoimmunology, which is of key relevance in the context of inflammation-induced bone loss, skeletal metastases, and diseases of impaired bone remodeling, such as osteoporosis. This review article aims at summarizing the current knowledge on one particular aspect of osteoimmunology, namely the impact of chemokines on skeletal cells in order to regulate bone remodeling under physiological and pathological conditions. Chemokines have key roles in the adaptive immune system by controlling migration, localization, and function of immune cells during inflammation. The vast majority of chemokines are divided into two subgroups based on the pattern of cysteine residues. More specifically, there are 27 known C-C-chemokines, binding to 10 different C-C receptors, and 17 known C-X-C-chemokines binding to seven different C-X-C receptors. Three additional chemokines do not fall into this category, and only one of them, i.e., CX3CL1, has been shown to influence bone remodeling cell types. There is a large amount of published studies demonstrating specific effects of certain chemokines on differentiation and function of osteoclasts and/or osteoblasts. Chemokine signaling by skeletal cells or by other cells of the bone marrow niche regulates bone formation and resorption through autocrine and paracrine mechanisms. In vivo evidence from mouse deficiency models strongly supports the role of certain chemokine signaling pathways in bone remodeling. We will summarize these data in the present review with a special focus on the most established subsets of chemokines. In combination with the other review articles of this issue, the knowledge presented here confirms that there is a physiologically relevant crosstalk between the innate immune system and bone remodeling cell types, whose molecular understanding is of high clinical relevance.
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Affiliation(s)
- Laura J Brylka
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thorsten Schinke
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Osagie-Clouard L, Sanghani-Kerai A, Coathup M, Meeson R, Briggs T, Blunn G. The influence of parathyroid hormone 1-34 on the osteogenic characteristics of adipose- and bone-marrow-derived mesenchymal stem cells from juvenile and ovarectomized rats. Bone Joint Res 2019; 8:397-404. [PMID: 31537997 PMCID: PMC6719529 DOI: 10.1302/2046-3758.88.bjr-2019-0018.r1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Objectives Mesenchymal stem cells (MSCs) are of growing interest in terms of bone regeneration. Most preclinical trials utilize bone-marrow-derived mesenchymal stem cells (bMSCs), although this is not without isolation and expansion difficulties. The aim of this study was: to compare the characteristics of bMSCs and adipose-derived mesenchymal stem cells (AdMSCs) from juvenile, adult, and ovarectomized (OVX) rats; and to assess the effect of human parathyroid hormone (hPTH) 1-34 on their osteogenic potential and migration to stromal cell-derived factor-1 (SDF-1). Methods Cells were isolated from the adipose and bone marrow of juvenile, adult, and previously OVX Wistar rats, and were characterized with flow cytometry, proliferation assays, osteogenic and adipogenic differentiation, and migration to SDF-1. Experiments were repeated with and without intermittent hPTH 1-34. Results Juvenile and adult MSCs demonstrated significantly increased osteogenic and adipogenic differentiation and superior migration towards SDF-1 compared with OVX groups; this was the case for AdMSCs and bMSCs equally. Parathyroid hormone (PTH) increased parameters of osteogenic differentiation and migration to SDF-1. This was significant for all cell types, although it had the most significant effect on cells derived from OVX animals. bMSCs from all groups showed increased mineralization and migration to SDF-1 compared with AdMSCs. Conclusion Juvenile MSCs showed significantly greater migration to SDF-1 and significantly greater osteogenic and adipogenic differentiation compared with cells from osteopenic rats; this was true for bMSCs and AdMSCs. The addition of PTH increased these characteristics, with the most significant effect on cells derived from OVX animals, further illustrating possible clinical application of both PTH and MSCs in bone regenerative therapies. Cite this article:L. Osagie-Clouard, A. Sanghani-Kerai, M. Coathup, R. Meeson, T. Briggs, G. Blunn. The influence of parathyroid hormone 1-34 on the osteogenic characteristics of adipose- and bone-marrow-derived mesenchymal stem cells from juvenile and ovarectomized rats. Bone Joint Res 2019;8:397–404. DOI: 10.1302/2046-3758.88.BJR-2019-0018.R1.
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Affiliation(s)
- Liza Osagie-Clouard
- Royal Free Hospital, London, UK; Honorary Lecturer, Institute of Orthopaedics and Musculoskeletal Sciences, Royal National Orthopaedic Hospital, Stanmore, UK
| | - Anita Sanghani-Kerai
- Institute of Orthopaedics and Musculoskeletal Sciences, Royal National Orthopaedic Hospital, Stanmore, UK
| | - Melanie Coathup
- University of Central Florida College of Medicine, Orlando, Florida, USA; Honorary Lecturer, Institute of Orthopaedics and Musculoskeletal Sciences, Royal National Orthopaedic Hospital, Stanmore, UK
| | - Richard Meeson
- Institute of Orthopaedics and Musculoskeletal Sciences, Royal National Orthopaedic Hospital, Stanmore, UK
| | - Timothy Briggs
- Institute of Orthopaedics and Musculoskeletal Sciences, Royal National Orthopaedic Hospital, Stanmore, UK
| | - Gordon Blunn
- Institute of Orthopaedics and Musculoskeletal Sciences, Royal National Orthopaedic Hospital, Stanmore, UK
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Abstract
PURPOSE OF REVIEW Osteocytes are the main mechanosensitive cells in bone. Integrin-based adhesions have been shown to facilitate mechanotransduction, and therefore play an important role in load-induced bone formation. This review outlines the role of integrins in osteocyte function (cell adhesion, signalling, and mechanotransduction) and possible role in disease. RECENT FINDINGS Both β1 and β3 integrins subunits have been shown to be required for osteocyte mechanotransduction. Antagonism of these integrin subunits in osteocytes resulted in impaired responses to fluid shear stress. Various disease states (osteoporosis, osteoarthritis, bone metastases) have been shown to result in altered integrin expression and function. Osteocyte integrins are required for normal cell function, with dysregulation of integrins seen in disease. Understanding the mechanism of faulty integrins in disease may aid in the creation of novel therapeutic approaches.
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Affiliation(s)
- Ivor P Geoghegan
- Department of Mechanical and Biomedical Engineering, Mechanobiology and Medical Device Research Group (MMDRG), Biomedical Engineering, National University of Ireland, Galway, Ireland
- Centre for Research in Medical Devices (CÚRAM), National University of Ireland, Galway, Ireland
| | - David A Hoey
- Centre for Research in Medical Devices (CÚRAM), National University of Ireland, Galway, Ireland
- Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
- Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin 2, Ireland
- Advanced Materials and Bioengineering Research Centre, Trinity College Dublin & RCSI, Dublin 2, Ireland
| | - Laoise M McNamara
- Department of Mechanical and Biomedical Engineering, Mechanobiology and Medical Device Research Group (MMDRG), Biomedical Engineering, National University of Ireland, Galway, Ireland.
- Centre for Research in Medical Devices (CÚRAM), National University of Ireland, Galway, Ireland.
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Popielarczyk TL, Huckle WR, Barrett JG. Human Bone Marrow-Derived Mesenchymal Stem Cells Home via the PI3K-Akt, MAPK, and Jak/Stat Signaling Pathways in Response to Platelet-Derived Growth Factor. Stem Cells Dev 2019; 28:1191-1202. [PMID: 31190615 DOI: 10.1089/scd.2019.0003] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have great potential to improve clinical outcomes for many inflammatory and degenerative diseases either through intravenously delivered MSCs or through mobilization and migration of endogenous MSCs to injury sites, termed "stem cell homing." Stem cell homing involves the processes of attachment to and transmigration through endothelial cells lining the vasculature and migration through the tissue stroma to a site of injury or inflammation. Although the process of leukocyte transendothelial migration (TEM) is well understood, far less is known about stem cell homing. In this study, a transwell-based model was developed to monitor adherence and TEM of human MSCs in response to chemokine exposure. Specifically, transwell membranes lined with human synovial microvascular endothelial cells were partitioned from the tissue injury-mimetic site containing chemokine stromal cell-derived factor-1 (SDF-1). Two population subsets of MSCs were studied: migratory cells that initiated transmigration on the endothelial lining and nonmigratory cells. We hypothesized that cells would adhere to and migrate through the endothelial lining in response to SDF-1 exposure and that gene and protein expression changes would be observed between migratory and nonmigratory cells. We validated a vasculature model for MSC transmigration that showed increased expression of several genes and activation of proteins of the PI3K-Akt, MAPK, and Jak/Stat signaling pathways. These findings showed that MSC homing may be driven by activation of PDGFRA/PI3K/Akt, PDGFRA/MAPK/Grb2, and PDGFRA/Jak2/Stat signaling, as a result of SDF-1-stimulated endothelial cell production of platelet-derived growth factor. This model can be used to further investigate these key regulatory molecules toward the development of targeted therapies.
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Affiliation(s)
- Tracee L Popielarczyk
- Department of Large Animal Clinical Sciences, Marion duPont Scott Equine Medical Center, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Leesburg, Virginia
| | - William R Huckle
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia
| | - Jennifer G Barrett
- Department of Large Animal Clinical Sciences, Marion duPont Scott Equine Medical Center, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Leesburg, Virginia
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Derakhshani M, Abbaszadeh H, Movassaghpour AA, Mehdizadeh A, Ebrahimi-Warkiani M, Yousefi M. Strategies for elevating hematopoietic stem cells expansion and engraftment capacity. Life Sci 2019; 232:116598. [PMID: 31247209 DOI: 10.1016/j.lfs.2019.116598] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 06/22/2019] [Accepted: 06/23/2019] [Indexed: 02/07/2023]
Abstract
Hematopoietic stem cells (HSCs) are a rare cell population in adult bone marrow, mobilized peripheral blood, and umbilical cord blood possessing self-renewal and differentiation capability into a full spectrum of blood cells. Bone marrow HSC transplantation has been considered as an ideal option for certain disorders treatment including hematologic diseases, leukemia, immunodeficiency, bone marrow failure syndrome, genetic defects such as thalassemia, sickle cell anemia, autoimmune disease, and certain solid cancers. Ex vivo proliferation of these cells prior to transplantation has been proposed as a potential solution against limited number of stem cells. In such culture process, MSCs have also been shown to exhibit high capacity for secretion of soluble mediators contributing to the principle biological and therapeutic activities of HSCs. In addition, endothelial cells have been introduced to bridge the blood and sub tissues in the bone marrow, as well as, HSCs regeneration induction and survival. Cell culture in the laboratory environment requires cell growth strict control to protect against contamination, symmetrical cell division and optimal conditions for maximum yield. In this regard, microfluidic systems provide culture and analysis capabilities in micro volume scales. Moreover, two-dimensional cultures cannot fully demonstrate extracellular matrix found in different tissues and organs as an abstract representation of three dimensional cell structure. Microfluidic systems can also strongly describe the effects of physical factors such as temperature and pressure on cell behavior.
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Affiliation(s)
- Mehdi Derakhshani
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Abbaszadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Akbar Movassaghpour
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Ebrahimi-Warkiani
- School of Biomedical Engineering, University Technology of Sydney, Sydney, New South Wales, 2007, Australia
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Wu J, Cao L, Liu Y, Zheng A, Jiao D, Zeng D, Wang X, Kaplan DL, Jiang X. Functionalization of Silk Fibroin Electrospun Scaffolds via BMSC Affinity Peptide Grafting through Oxidative Self-Polymerization of Dopamine for Bone Regeneration. ACS APPLIED MATERIALS & INTERFACES 2019; 11:8878-8895. [PMID: 30777748 DOI: 10.1021/acsami.8b22123] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Electrospun scaffolds have been broadly studied to enhance bone regeneration because of the ability to simulate the structure and biological functions of the extracellular matrix. Polydopamine (PDA) is used to coat various surfaces at a slightly basic pH (8-8.5) and spontaneously reacts with nucleophilic functional groups. It is suitable for surface modifications of scaffolds correlated with bone formation. E7 is a newly discovered peptide with specific affinity for bone marrow mesenchymal stem cells (BMSCs). It can be useful for recruiting stem cells. Here, electrospun silk fibroin (SF) scaffolds were fabricated, and PDA was used for surface modification followed by grafting E7 (SF-PDA-E7). These composite SF-PDA-E7 electrospun scaffolds improved hydrophilicity, facilitated cell proliferation and adhesion, and boosted the osteogenic differentiation of BMSCs by creating osteoinduction conditions under the synergistic effects of PDA and E7. Moreover, the scaffolds showed high efficiency for recruiting BMSCs induced by E7 both in vitro and in vivo, which was associated with the SDF-1α/CXCR4 axis and the p38, extracellular signal-related kinase, and Akt signal transduction pathways. These functionalized electrospun scaffolds promoted regeneration of bone in the rat calvarial bone defect model. In general, this study verified that PDA could be a simple and efficient method for surface modification, and E7-grafted PDA-modified SF electrospun scaffolds were suitable for bone tissue engineering.
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Affiliation(s)
| | | | - Yang Liu
- The State Key Laboratory of Bioreactor Engineering , East China University of Science and Technology , Shanghai 200237 , People's Republic of China
| | | | | | | | | | - David L Kaplan
- Department of Biomedical Engineering , 4 Colby Street, Tufts University , Medford , Massachusetts 02155 , United States
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Sowder ME, Johnson RW. Bone as a Preferential Site for Metastasis. JBMR Plus 2019; 3:e10126. [PMID: 30918918 PMCID: PMC6419612 DOI: 10.1002/jbm4.10126] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Accepted: 10/28/2018] [Indexed: 02/06/2023] Open
Abstract
Bone marrow provides a unique microenvironment favoring the colonization and outgrowth of metastatic tumor cells. Despite the high incidence of bone metastasis in breast and prostate cancer patients, many of the molecular mechanisms controlling metastatic progression remain unclear. Several gene signatures associated with bone metastasis have been reported, but no metastasis-specific gene alterations have been identified. Therefore, there has been considerable interest in understanding how the bone microenvironment impacts the behavior of disseminated tumor cells (DTCs) prior to and following colonization of the bone. Substantial evidence indicates that disruption of normal bone homeostasis by tumor-derived factors establishes a premetastatic niche within the bone that favors DTC colonization. Following dissemination, bone resident cells and the surrounding stroma provide critical signals that support tumor cell colonization, survival, and eventual outgrowth. Clinical data suggest that patients can harbor DTCs for years to decades prior to developing overt bone metastases, suggesting a period of tumor dormancy occurs in the bone marrow. Several dormancy-promoting factors have been recently identified; however, critical questions surrounding the molecular triggers and timing of tumor cell emergence from dormancy remain. Here, we review how metastatic tumor cells co-opt the bone marrow microenvironment for metastatic progression and discuss emerging insights into how to more effectively target DTCs and prevent metastasis. © 2018 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)
- Miranda E Sowder
- Program in Cancer BiologyVanderbilt UniversityNashvilleTNUSA
- Vanderbilt Center for Bone BiologyDepartment of MedicineDivision of Clinical PharmacologyVanderbilt University Medical CenterNashvilleTNUSA
| | - Rachelle W Johnson
- Program in Cancer BiologyVanderbilt UniversityNashvilleTNUSA
- Vanderbilt Center for Bone BiologyDepartment of MedicineDivision of Clinical PharmacologyVanderbilt University Medical CenterNashvilleTNUSA
- Department of MedicineDivision of Clinical PharmacologyVanderbilt University Medical CenterNashvilleTNUSA
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Kolb AD, Shupp AB, Mukhopadhyay D, Marini FC, Bussard KM. Osteoblasts are "educated" by crosstalk with metastatic breast cancer cells in the bone tumor microenvironment. Breast Cancer Res 2019; 21:31. [PMID: 30813947 PMCID: PMC6391840 DOI: 10.1186/s13058-019-1117-0] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 02/07/2019] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION In a cancer-free environment in the adult, the skeleton continuously undergoes remodeling. Bone-resorbing osteoclasts excavate erosion cavities, and bone-depositing osteoblasts synthesize osteoid matrix that forms new bone, with no net bone gain or loss. When metastatic breast cancer cells invade the bone, this balance is disrupted. Patients with bone metastatic breast cancer frequently suffer from osteolytic bone lesions that elicit severe bone pain and fractures. Bisphosphonate treatments are not curative. Under ideal circumstances, osteoblasts would synthesize new matrix to fill in erosion cavities caused by osteoclasts, but this is not what occurs. Our prior evidence demonstrated that osteoblasts are diverted from laying down bone matrix to producing cytokines that facilitate breast cancer cell maintenance in late-stage disease. Here, we have new evidence to suggest that there are subpopulations of osteoblasts in the tumor niche as evidenced by their protein marker expression that have distinct roles in tumor progression in the bone. METHODS Tumor-bearing tibia of mice was interrogated by immunofluorescent staining for the presence of osteoblasts and alterations in niche protein expression. De-identified tissue from patients with bone metastatic breast cancer was analyzed for osteoblast subpopulations via multi-plex immunofluorescent staining. Effects of breast cancer cells on osteoblasts were recapitulated in vitro by osteoblast exposure to breast cancer-conditioned medium. Triple-negative and estrogen receptor-positive breast cancer proliferation, cell cycle, and p21 expression were assessed upon contact with "educated" osteoblasts. RESULTS A subpopulation of osteoblasts was identified in the bone tumor microenvironment in vivo of both humans and mice with bone metastatic breast cancer that express RUNX2/OCN/OPN but is negative for IL-6 and alpha-smooth muscle actin. These tumor "educated" osteoblasts (EOs) have altered properties compared to "uneducated" osteoblasts and suppress both triple-negative and estrogen receptor-positive breast cancer cell proliferation and increase cancer cell p21 expression. EO effects on breast cancer proliferation were mediated by NOV and decorin. Importantly, the presence of EO cells in the tibia of mice bearing tumors led to increased amounts of alkaline phosphatase and suppressed the expression of inflammatory cytokines in vivo. CONCLUSIONS Our work reveals that there is a subpopulation of osteoblasts in the bone tumor microenvironment that demonstrate a functional role in retarding breast cancer cell growth.
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Affiliation(s)
- Alexus D. Kolb
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA USA
| | - Alison B. Shupp
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA USA
| | - Dimpi Mukhopadhyay
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA USA
| | - Frank C. Marini
- Comprehensive Cancer Center Wake Forest University and Wake Forest Institute of Regenerative Medicine, Winston-Salem, NC USA
| | - Karen M. Bussard
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA USA
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50
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Dash A, Das T, Knapp FFR. Targeted Radionuclide Therapy of Painful Bone Metastases: Past Developments, Current Status, Recent Advances and Future Directions. Curr Med Chem 2019; 27:3187-3249. [PMID: 30714520 DOI: 10.2174/0929867326666190201142814] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 10/29/2018] [Accepted: 12/06/2018] [Indexed: 12/13/2022]
Abstract
Bone pain arising from secondary skeletal malignancy constitutes one of the most common types of chronic pain among patients with cancer which can lead to rapid deterioration of the quality of life. Radionuclide therapy using bone-seeking radiopharmaceuticals based on the concept of localization of the agent at bone metastases sites to deliver focal cytotoxic levels of radiation emerged as an effective treatment modality for the palliation of symptomatic bone metastases. Bone-seeking radiopharmaceuticals not only provide palliative benefit but also improve clinical outcomes in terms of overall and progression-free survival. There is a steadily expanding list of therapeutic radionuclides which are used or can potentially be used in either ionic form or in combination with carrier molecules for the management of bone metastases. This article offers a narrative review of the armamentarium of bone-targeting radiopharmaceuticals based on currently approved investigational and potentially useful radionuclides and examines their efficacy for the treatment of painful skeletal metastases. In addition, the article also highlights the processes, opportunities, and challenges involved in the development of bone-seeking radiopharmaceuticals. Radium-223 is the first agent in this class to show an overall survival advantage in Castration-Resistant Prostate Cancer (CRPC) patients with bone metastases. This review summarizes recent advances, current clinical practice using radiopharmaceuticals for bone pain palliation, and the expected future prospects in this field.
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Affiliation(s)
- Ashutosh Dash
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India
| | - Tapas Das
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India
| | - Furn F Russ Knapp
- Medical Isotopes Program, Isotope Development Group, MS 6229, Bldg. 4501, Oak Ridge National Laboratory, PO Box 2008, 1 Bethel Valley Road, Oak Ridge, TN 37831, United States
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