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Yang Q, Wang W, Cheng D, Wang Y, Han Y, Huang J, Peng X. Non-coding RNA in exosomes: Regulating bone metastasis of lung cancer and its clinical application prospect. Transl Oncol 2024; 46:102002. [PMID: 38797017 PMCID: PMC11153237 DOI: 10.1016/j.tranon.2024.102002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/20/2024] [Accepted: 05/19/2024] [Indexed: 05/29/2024] Open
Abstract
Lung cancer is a highly prevalent malignancy with poor prognosis and rapid progression. It most frequently metastasizes to the bone, where it can pose a severe threat to the patient's survival. Once metastasized, the disease is often incurable and can result in severe complications such as hypercalcemia, bone pain, fractures, spinal cord compression, and subsequent paralysis. Exosomes are bilayer vesicle nanoparticles secreted by most of the extracellular vesicles, which can be found in almost all organisms and play an essential role in intercellular communication. Through their ability to regulate related bone cells, exosomes carry bioactive molecules, including proteins, lipids, and non-coding RNAs (ncRNAs), that can be extremely important in bone remodeling. Studies have been conducted on the role play by proteins, lncRNA, and microRNA-all ncRNAs-carried by exosomes in the bone metastases of lung cancer. In this review, the latest progress of the regulatory mechanism of ncRNAs carried by exosomes in lung cancer bone metastasis has been reviewed. The clinical use of exosomes as a promising biomarker, drug transporter, and therapeutic target was highlighted to offer a novel diagnostic and treatment approach for patients with lung cancer bone metastases.
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Affiliation(s)
- Qing Yang
- Nuclear Medicine Department, The First Affiliated Hospital of Yangtze University, Jingzhou 434000, Hubei, China; Health Science Center of Yangtze University, Jingzhou 434023, Hubei, China
| | - Wei Wang
- Department of Rehabilitation Radiology, Beijing Rehabilitation Hospital, Capital Medical University, Beijing 100144, China
| | - Dezhou Cheng
- Health Science Center of Yangtze University, Jingzhou 434023, Hubei, China
| | - Yiling Wang
- Health Science Center of Yangtze University, Jingzhou 434023, Hubei, China
| | - Yukun Han
- Health Science Center of Yangtze University, Jingzhou 434023, Hubei, China
| | - Jinbai Huang
- Nuclear Medicine Department, The First Affiliated Hospital of Yangtze University, Jingzhou 434000, Hubei, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, Hubei, China.
| | - Xiaochun Peng
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei, China.
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2
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Maji S, Pradhan AK, Kumar A, Bhoopathi P, Mannangatti P, Guo C, Windle JJ, Subler MA, Wang XY, Semmes OJ, Nyalwidhe JO, Mukhopadhyay N, Paul AK, Hatfield B, Levit MM, Madan E, Sarkar D, Emdad L, Cohen DJ, Gogna R, Cavenee WK, Das SK, Fisher PB. MDA-9/Syntenin in the tumor and microenvironment defines prostate cancer bone metastasis. Proc Natl Acad Sci U S A 2023; 120:e2307094120. [PMID: 37922327 PMCID: PMC10636346 DOI: 10.1073/pnas.2307094120] [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: 04/29/2023] [Accepted: 09/25/2023] [Indexed: 11/05/2023] Open
Abstract
Bone metastasis is a frequent and incurable consequence of advanced prostate cancer (PC). An interplay between disseminated tumor cells and heterogeneous bone resident cells in the metastatic niche initiates this process. Melanoma differentiation associated gene-9 (mda-9/Syntenin/syndecan binding protein) is a prometastatic gene expressed in multiple organs, including bone marrow-derived mesenchymal stromal cells (BM-MSCs), under both physiological and pathological conditions. We demonstrate that PDGF-AA secreted by tumor cells induces CXCL5 expression in BM-MSCs by suppressing MDA-9-dependent YAP/MST signaling. CXCL5-derived tumor cell proliferation and immune suppression are consequences of the MDA-9/CXCL5 signaling axis, promoting PC disease progression. mda-9 knockout tumor cells express less PDGF-AA and do not develop bone metastases. Our data document a previously undefined role of MDA-9/Syntenin in the tumor and microenvironment in regulating PC bone metastasis. This study provides a framework for translational strategies to ameliorate health complications and morbidity associated with advanced PC.
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Affiliation(s)
- Santanu Maji
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
| | - Anjan K. Pradhan
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
| | - Amit Kumar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
| | - Praveen Bhoopathi
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
| | - Padmanabhan Mannangatti
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
| | - Chunqing Guo
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
| | - Jolene J. Windle
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
| | - Mark A. Subler
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
| | - Xiang-Yang Wang
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
| | - Oliver J. Semmes
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA23507
| | - Julius O. Nyalwidhe
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA23507
| | - Nitai Mukhopadhyay
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- Department of Biostatistics, Virginia Commonwealth University, School of Medicine, Richmond, VA23238
| | - Asit Kr. Paul
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- Department of Internal Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA23238
| | - Bryce Hatfield
- Department of Pathology, Virginia Commonwealth University, School of Medicine, Richmond, VA23238
| | - Michael M. Levit
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, VA23238
| | - Esha Madan
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- Department of Surgery, Virginia Commonwealth University, School of Medicine, Richmond, VA23238
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
| | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
| | - David J. Cohen
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, VA23238
| | - Rajan Gogna
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
| | - Webster K. Cavenee
- Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA92093
| | - Swadesh K. Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
| | - Paul B. Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA23298
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3
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Zhang Y, Hu J, Li T, Hao S, Wu X. Construction of a Diagnostic Model for Distinguishing Benign or Malignant Bone Cancer by Mining miRNA Expression Data. Biochem Genet 2023; 61:299-315. [PMID: 35861903 DOI: 10.1007/s10528-022-10259-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 04/18/2022] [Indexed: 01/24/2023]
Abstract
Bone tumor is a kind of rare cancer, the location of which is mainly in bone tissue as well as cartilage tissue. Bone tumor is mainly classified into benign and malignant types. The survival rate of patients with bone tumors can be considerably improved by early detection, and the danger of amputation caused by bone tumors can be greatly reduced. In this study, we first screened the top 25% serum miRNAs with the greatest variance in patients with malignant and benign bone tumor and healthy individuals. The expression of serum miRNAs in patients with bone tumor was then examined using unsupervised clustering and PCA, and the results revealed that the overall expression of serum miRNAs was ineffective in distinguishing patients with benign/malignant bone tumors. Subsequently, we screened 19 miRNA biomarkers that could be used to determine the benign/malignant bone tumor of patients by LASSO logistic regression. These genes were validated using ROC curves. Results showed that there were 11 miRNAs that could accurately distinguish benign/malignant bone tumor alone. These 11 miRNAs were, namely, hsa-miR-192-5p, hsa-miR-137, hsa-miR-142-3p, hsa-miR-155-3p, hsa-miR-1205, hsa-miR-1273a, hsa-miR-3187-3p, hsa-miR-1255b-2-3p, hsa-miR-1288-5p, hsa-miR-6836-5p, and hsa-miR-6862-5p. Next, we established a diagnostic model using logistic regression and validated the diagnostic model using ROC curves; the result of which showed that the model had good diagnostic efficacy. Then, we also verified that the diagnostic model established by these 11 miRNAs could distinguish patients with benign/malignant bone tumor using unsupervised clustering as well as PCA. Finally, by using qPCR, we validated the expression of 11 miRNAs in the serum of patients with malignant and benign bone tumors, as well as healthy volunteers. The results were consistent with the trend of miRNAs expression in public databases. In summary, we examined the differential expression of serum miRNAs in individuals with benign and malignant bone tumors and discovered 11 miRNA biomarkers that could be utilized to discriminate between the two.
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Affiliation(s)
- Yueming Zhang
- Department of Orthopedics, Area 3, Tangshan Gongren Hospital, No. 27 Wenhua Road, Lubei District, Tangshan, 063003, Hebei, China.
| | - Jianwei Hu
- Department of Orthopedics, Area 3, Tangshan Gongren Hospital, No. 27 Wenhua Road, Lubei District, Tangshan, 063003, Hebei, China
| | - Tao Li
- Department of Surgery, Tangshan Ninth Hospital, Tangshan, 063099, Hebei, China
| | - Shizhu Hao
- Department of Surgical Oncology, Area 1, Tangshan Gongren Hospital, Tangshan, 063003, Hebei, China
| | - Xiaotang Wu
- Shanghai Engineering Research Center of Pharmaceutical Translation, Shanghai, 200231, China
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4
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Olivan M, Garcia M, Suárez L, Guiu M, Gros L, Méndez O, Rigau M, Reventós J, Segura MF, de Torres I, Planas J, de la Cruz X, Gomis RR, Morote J, Rodríguez-Barrueco R, Santamaria A. Loss of microRNA-135b Enhances Bone Metastasis in Prostate Cancer and Predicts Aggressiveness in Human Prostate Samples. Cancers (Basel) 2021; 13:6202. [PMID: 34944822 PMCID: PMC8699528 DOI: 10.3390/cancers13246202] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 11/29/2021] [Accepted: 12/03/2021] [Indexed: 12/22/2022] Open
Abstract
About 70% of advanced-stage prostate cancer (PCa) patients will experience bone metastasis, which severely affects patients' quality of life and progresses to lethal PCa in most cases. Hence, understanding the molecular heterogeneity of PCa cell populations and the signaling pathways associated with bone tropism is crucial. For this purpose, we generated an animal model with high penetrance to metastasize to bone using an intracardiac percutaneous injection of PC3 cells to identify PCa metastasis-promoting factors. Using genomic high-throughput analysis we identified a miRNA signature involved in bone metastasis that also presents potential as a biomarker of PCa progression in human samples. In particular, the downregulation of miR-135b favored the incidence of bone metastases by significantly increasing PCa cells' migratory capacity. Moreover, the PLAG1, JAKMIP2, PDGFA, and VTI1b target genes were identified as potential mediators of miR-135b's role in the dissemination to bone. In this study, we provide a genomic signature involved in PCa bone growth, contributing to a better understanding of the mechanisms responsible for this process. In the future, our results could ultimately translate into promising new therapeutic targets for the treatment of lethal PCa.
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Affiliation(s)
- Mireia Olivan
- Translational Oncology Laboratory, Anatomy Unit, Department of Pathology and Experimental Therapy, School of Medicine, Universitat de Barcelona (UB), 08907 L’Hospitalet de Llobregat, Spain;
- Molecular Mechanisms and Experimental Therapy in Oncology-Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L’Hospitalet de Llobregat, Spain
- Cell Cycle and Cancer Laboratory, Biomedical Research Group in Urology, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain; (M.G.); (L.S.); (L.G.); (O.M.); (I.d.T.); (J.P.); (J.M.)
| | - Marta Garcia
- Cell Cycle and Cancer Laboratory, Biomedical Research Group in Urology, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain; (M.G.); (L.S.); (L.G.); (O.M.); (I.d.T.); (J.P.); (J.M.)
- Developmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
| | - Leticia Suárez
- Cell Cycle and Cancer Laboratory, Biomedical Research Group in Urology, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain; (M.G.); (L.S.); (L.G.); (O.M.); (I.d.T.); (J.P.); (J.M.)
| | - Marc Guiu
- Cancer Science Programme, Institute for Research in Biomedicine (IRB-Barcelona), 08028 Barcelona, Spain; (M.G.); (R.R.G.)
| | - Laura Gros
- Cell Cycle and Cancer Laboratory, Biomedical Research Group in Urology, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain; (M.G.); (L.S.); (L.G.); (O.M.); (I.d.T.); (J.P.); (J.M.)
| | - Olga Méndez
- Cell Cycle and Cancer Laboratory, Biomedical Research Group in Urology, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain; (M.G.); (L.S.); (L.G.); (O.M.); (I.d.T.); (J.P.); (J.M.)
| | - Marina Rigau
- Bellvitge Biomedical Research Institute (IDIBELL), 08908 L’Hospitalet de Llobregat, Spain; (M.R.); (J.R.)
| | - Jaume Reventós
- Bellvitge Biomedical Research Institute (IDIBELL), 08908 L’Hospitalet de Llobregat, Spain; (M.R.); (J.R.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
- Departament de Ciències Bàsiques, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
| | - Miguel F. Segura
- Group of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain;
| | - Inés de Torres
- Cell Cycle and Cancer Laboratory, Biomedical Research Group in Urology, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain; (M.G.); (L.S.); (L.G.); (O.M.); (I.d.T.); (J.P.); (J.M.)
- Department of Pathology, University Hospital Vall d’Hebron, Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Jacques Planas
- Cell Cycle and Cancer Laboratory, Biomedical Research Group in Urology, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain; (M.G.); (L.S.); (L.G.); (O.M.); (I.d.T.); (J.P.); (J.M.)
- Department of Urology, University Hospital Vall d’Hebron, Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Xavier de la Cruz
- Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain;
- Group of Clinical and Translational Bioinformatics, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Roger R. Gomis
- Cancer Science Programme, Institute for Research in Biomedicine (IRB-Barcelona), 08028 Barcelona, Spain; (M.G.); (R.R.G.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain;
| | - Juan Morote
- Cell Cycle and Cancer Laboratory, Biomedical Research Group in Urology, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain; (M.G.); (L.S.); (L.G.); (O.M.); (I.d.T.); (J.P.); (J.M.)
- Department of Urology, University Hospital Vall d’Hebron, Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Ruth Rodríguez-Barrueco
- Translational Oncology Laboratory, Anatomy Unit, Department of Pathology and Experimental Therapy, School of Medicine, Universitat de Barcelona (UB), 08907 L’Hospitalet de Llobregat, Spain;
- Molecular Mechanisms and Experimental Therapy in Oncology-Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L’Hospitalet de Llobregat, Spain
| | - Anna Santamaria
- Cell Cycle and Cancer Laboratory, Biomedical Research Group in Urology, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain; (M.G.); (L.S.); (L.G.); (O.M.); (I.d.T.); (J.P.); (J.M.)
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Xu SB, Fan RH, Qin X, Han RM. microRNA Prognostic Signature for Postoperative Success of Metastatic Orthopedic Cancers: Implications for Precision Microsurgery. Front Cell Dev Biol 2021; 9:704505. [PMID: 34277644 PMCID: PMC8285058 DOI: 10.3389/fcell.2021.704505] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 05/14/2021] [Indexed: 12/26/2022] Open
Abstract
The importance of miRNA prognostic signature in cancer, particular cancer metastasis is increasingly being realized. Bone metastasis from several primary human cancers can be managed in clinics by surgical intervention but the prognostic impact of miRNA signature on post-surgery outcome of patients is unknown. This study evaluated a miRNA signature for post-operative outcome of patients with bone metastatic disease. First, the miRNAs, miR-135, miR-203, miR-10b, miR-194, miR-886, and miR-124 were evaluated in bone metastatic tissues, relative to adjacent control tissue. The cohorts of samples (n = 44) consisted of bone metastatic cancer patients with primary lung (n = 18) or breast cancer (n = 26). miR-203 was significantly down-regulated while miR-10b was significantly up-regulated in bone metastasis. Additionally, miR-135 was significantly differentially expressed in the primary lung cancer patients while miR-194 in primary breast cancer patients. The low miR-203- high miR-10b expression was designated high risk group and, compared to the low risk group (high miR-203-low miR-10b expression). Patients with the signature high risk fared significantly better with surgical intervention, in terms of survival at 12 months time point (40% survival with surgery vs. 10% survival without surgery), as revealed by retrospective analysis of patient data. This work reveals potential utilization of miRNA expression levels in not only the general prognosis of cancer metastasis but also the prognosis of surgical intervention with implication for better stratification of patients.
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Affiliation(s)
- Shi-Bao Xu
- Department of Orthopedics, JiaoZuo People's Hospital, Jiaozuo, China
| | - Rong-Hao Fan
- Department of Orthopedics, JiaoZuo People's Hospital, Jiaozuo, China
| | - Xiao Qin
- Department of Orthopedics, JiaoZuo People's Hospital, Jiaozuo, China
| | - Rui-Ming Han
- Department of Orthopedics, JiaoZuo People's Hospital, Jiaozuo, China
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6
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Kinget L, Roussel E, Lambrechts D, Boeckx B, Vanginderhuysen L, Albersen M, Rodríguez-Antona C, Graña-Castro O, Inglada-Pérez L, Verbiest A, Zucman-Rossi J, Couchy G, Caruso S, Laenen A, Baldewijns M, Beuselinck B. MicroRNAs Possibly Involved in the Development of Bone Metastasis in Clear-Cell Renal Cell Carcinoma. Cancers (Basel) 2021; 13:cancers13071554. [PMID: 33800656 PMCID: PMC8036650 DOI: 10.3390/cancers13071554] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/23/2021] [Accepted: 03/24/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Bone metastases cause substantial morbidity and implicate worse clinical outcomes for clear-cell renal cell carcinoma patients. MicroRNAs are small RNA molecules that modulate gene translation and are involved in the development of cancer and metastasis. We identified six microRNAs that are potentially specifically involved in metastasis to bone, of which two seem protective and four implicate a higher risk. This aids further understanding of the process of metastasizing to bone. Furthermore, these microRNA hold potential for biomarkers or therapeutic targets. Abstract Bone metastasis in clear-cell renal cell carcinoma (ccRCC) leads to substantial morbidity through skeletal related adverse events and implicates worse clinical outcomes. MicroRNAs (miRNA) are small non-protein coding RNA molecules with important regulatory functions in cancer development and metastasis. In this retrospective analysis we present dysregulated miRNA in ccRCC, which are associated with bone metastasis. In particular, miR-23a-3p, miR-27a-3p, miR-20a-5p, and miR-335-3p specifically correlated with the earlier appearance of bone metastasis, compared to metastasis in other organs. In contrast, miR-30b-3p and miR-139-3p were correlated with less occurrence of bone metastasis. These miRNAs are potential biomarkers and attractive targets for miRNA inhibitors or mimics, which could lead to novel therapeutic possibilities for bone targeted treatment in metastatic ccRCC.
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Affiliation(s)
- Lisa Kinget
- Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, 3000 Leuven, Belgium; (L.K.); (L.V.); (A.V.)
| | - Eduard Roussel
- Department of Urology, University Hospitals Leuven, 3000 Leuven, Belgium; (E.R.); (M.A.)
| | - Diether Lambrechts
- Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium; (D.L.); (B.B.)
- VIB Center for Cancer Biology, VIB, 3000 Leuven, Belgium
| | - Bram Boeckx
- Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium; (D.L.); (B.B.)
- VIB Center for Cancer Biology, VIB, 3000 Leuven, Belgium
| | - Loïc Vanginderhuysen
- Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, 3000 Leuven, Belgium; (L.K.); (L.V.); (A.V.)
| | - Maarten Albersen
- Department of Urology, University Hospitals Leuven, 3000 Leuven, Belgium; (E.R.); (M.A.)
| | | | - Osvaldo Graña-Castro
- Centro Nacional de Investigaciones Oncológicas (CNIO), 28040 Madrid, Spain; (C.R.-A.); (O.G.-C.)
| | - Lucía Inglada-Pérez
- Department of Statistics and Operational Research, Faculty of Medicine, Complutense University, 28040 Madrid, Spain;
| | - Annelies Verbiest
- Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, 3000 Leuven, Belgium; (L.K.); (L.V.); (A.V.)
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006 Paris, France; (J.Z.-R.); (G.C.); (S.C.)
| | - Gabrielle Couchy
- Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006 Paris, France; (J.Z.-R.); (G.C.); (S.C.)
| | - Stefano Caruso
- Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006 Paris, France; (J.Z.-R.); (G.C.); (S.C.)
| | | | | | - Benoit Beuselinck
- Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, 3000 Leuven, Belgium; (L.K.); (L.V.); (A.V.)
- Correspondence: ; Tel.: +32-16-346900
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7
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Curtaz CJ, Schmitt C, Blecharz-Lang KG, Roewer N, Wöckel A, Burek M. Circulating MicroRNAs and Blood-Brain-Barrier Function in Breast Cancer Metastasis. Curr Pharm Des 2020; 26:1417-1427. [PMID: 32175838 PMCID: PMC7475800 DOI: 10.2174/1381612826666200316151720] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 02/26/2020] [Indexed: 12/24/2022]
Abstract
Brain metastases are a major cause of death in breast cancer patients. A key event in the metastatic progression of breast cancer in the brain is the migration of cancer cells across the blood-brain barrier (BBB). The BBB is a natural barrier with specialized functions that protect the brain from harmful substances, including anti-tumor drugs. Extracellular vesicles (EVs) sequestered by cells are mediators of cell-cell communication. EVs carry cellular components, including microRNAs that affect the cellular processes of target cells. Here, we summarize the knowledge about microRNAs known to play a significant role in breast cancer and/or in the BBB function. In addition, we describe previously established in vitro BBB models, which are a useful tool for studying molecular mechanisms involved in the formation of brain metastases.
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Affiliation(s)
- Carolin J Curtaz
- Department of Gynecology and Obstetrics, University of Würzburg, Würzburg, Germany
| | - Constanze Schmitt
- Department of Anaesthesia and Critical Care, University of Würzburg, 97080 Würzburg, Germany
| | - Kinga G Blecharz-Lang
- Department of Experimental Neurosurgery, Charite - Universitätsmedizin, Berlin, Germany
| | - Norbert Roewer
- Department of Anaesthesia and Critical Care, University of Würzburg, 97080 Würzburg, Germany
| | - Achim Wöckel
- Department of Gynecology and Obstetrics, University of Würzburg, Würzburg, Germany
| | - Malgorzata Burek
- Department of Anaesthesia and Critical Care, University of Würzburg, 97080 Würzburg, Germany
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8
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Legrand MA, Millet M, Merle B, Rousseau JC, Hemmendinger A, Gineyts E, Sornay-Rendu E, Szulc P, Borel O, Croset M, Chapurlat R. A Signature of Circulating miRNAs Associated With Fibrous Dysplasia of Bone: the mirDys Study. J Bone Miner Res 2020; 35:1881-1892. [PMID: 32526052 DOI: 10.1002/jbmr.4111] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 05/05/2020] [Accepted: 06/07/2020] [Indexed: 12/21/2022]
Abstract
Fibrous dysplasia (FD) is a rare bone disease caused by activating mutations of GNAS encoding the Gsα protein, enhancing cyclic adenosine monophosphate (cAMP) production by overstimulation of adenylyl cyclase and impairing osteoblastic differentiation. The clinical presentation ranges from asymptomatic to polyostotic forms with severe disability, explained by the mosaic distribution of the GNAS mutation. Physicians have to deal with the gap of knowledge in FD pathogenesis, the absence of prognostic markers and the lack of specific treatment. The identification of specific biomarkers for FD is an important step to improve the clinical and therapeutic approaches. An epigenetic regulation driven by microRNAs (miRNAs), known as promising biomarkers in bone disease, could be involved in FD. We have sought circulating miRNAs that are differentially expressed in FD patients compared to controls and would reflect dysregulations of osteogenesis-related genes and bone disorder. The global miRNA profiling was performed using Next Generation Sequencing in patient serum collected from a discovery cohort of 20 patients (10 polyostotic and 10 monostotic) and 10 controls. From these, we selected 19 miRNAs for a miRNA validation phase from serum of 82 patients and 82 controls, using real-time qPCR. Discovery screening identified 111 miRNAs differentially expressed in patient serum, after adjusting for the false discovery rate (FDR). Among the 82 patients, 55% were polyostotic, and 73% were women with a mean age of 42 years. Six miRNAs (miR-25-3p, miR-93-5p, miR-182-5p, miR-324-5p, miR-363-3p, and miR-451a) were significantly overexpressed in serum, with FDR <0.05. The expression level of these six miRNAs was not associated with the FD severity. In conclusion, we identified a signature of circulating miRNAs associated with FD. These miRNAs are potential negative regulators of gene expression in bone cell progenitors, suggesting their activity in FD by interfering with osteoblastic and osteoclastic differentiation to impair bone mineralization and remodeling processes. © 2020 American Society for Bone and Mineral Research.
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Affiliation(s)
- Mélanie A Legrand
- Department of Rheumatology, Edouard Herriot University Hospital, Lyon, France.,INSERM UMR 1033, Université de Lyon, Lyon, France
| | | | | | | | | | | | | | - Pawel Szulc
- INSERM UMR 1033, Université de Lyon, Lyon, France
| | | | | | - Roland Chapurlat
- Department of Rheumatology, Edouard Herriot University Hospital, Lyon, France.,INSERM UMR 1033, Université de Lyon, Lyon, France
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9
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Wang M, Xia F, Wei Y, Wei X. Molecular mechanisms and clinical management of cancer bone metastasis. Bone Res 2020; 8:30. [PMID: 32793401 PMCID: PMC7391760 DOI: 10.1038/s41413-020-00105-1] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 09/03/2019] [Accepted: 10/23/2019] [Indexed: 02/05/2023] Open
Abstract
As one of the most common metastatic sites of malignancies, bone has a unique microenvironment that allows metastatic tumor cells to grow and flourish. The fenestrated capillaries in the bone, bone matrix, and bone cells, including osteoblasts and osteoclasts, together maintain the homeostasis of the bone microenvironment. In contrast, tumor-derived factors act on bone components, leading to subsequent bone resorption or excessive bone formation. The various pathways involved also provide multiple targets for therapeutic strategies against bone metastases. In this review, we summarize the current understanding of the mechanism of bone metastases. Based on the general process of bone metastases, we specifically highlight the complex crosstalk between tumor cells and the bone microenvironment and the current management of cancer bone metastases.
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Affiliation(s)
- Manni Wang
- Laboratory of Aging Research and Cancer Drug Targets, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan P.R. China
| | - Fan Xia
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan P.R. China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Drug Targets, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan P.R. China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Targets, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan P.R. China
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10
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Wood SL, Brown JE. Personal Medicine and Bone Metastases: Biomarkers, Micro-RNAs and Bone Metastases. Cancers (Basel) 2020; 12:cancers12082109. [PMID: 32751181 PMCID: PMC7465268 DOI: 10.3390/cancers12082109] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 07/24/2020] [Accepted: 07/24/2020] [Indexed: 02/06/2023] Open
Abstract
Bone metastasis is a major cause of morbidity within solid tumours of the breast, prostate, lung and kidney. Metastasis to the skeleton is associated with a wide range of complications including bone fractures, spinal cord compression, hypercalcaemia and increased bone pain. Improved treatments for bone metastasis, such as the use of anti-bone resorptive bisphosphonate agents, within post-menopausal women have improved disease-free survival; however, these treatments are not without side effects. There is thus a need for biomarkers, which will predict the risk of developing the spread to bone within these cancers. The application of molecular profiling techniques, together with animal model systems and engineered cell-lines has enabled the identification of a series of potential bone-metastasis biomarker molecules predictive of bone metastasis risk. Some of these biomarker candidates have been validated within patient-derived samples providing a step towards clinical utility. Recent developments in multiplex biomarker quantification now enable the simultaneous measurement of up to 96 micro-RNA/protein molecules in a spatially defined manner with single-cell resolution, thus enabling the characterisation of the key molecules active at the sites of pre-metastatic niche formation as well as tumour-stroma signalling. These technologies have considerable potential to inform biomarker discovery. Additionally, a potential future extension of these discoveries could also be the identification of novel drug targets within cancer spread to bone. This chapter summarises recent findings in biomarker discovery within the key bone metastatic cancers (breast, prostate, lung and renal cell carcinoma). Tissue-based and circulating blood-based biomarkers are discussed from the fields of genomics, epigenetic regulation (micro-RNAs) and protein/cell-signalling together with a discussion of the potential future development of these markers towards clinical development.
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Affiliation(s)
- Steven L. Wood
- Department of Oncology and Metabolism, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
- Correspondence:
| | - Janet E. Brown
- Department of Oncology and Metabolism, Weston Park Hospital, Whitham Road, Sheffield S10 2SJ, UK;
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11
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Ma X, Yu J. Role of the bone microenvironment in bone metastasis of malignant tumors - therapeutic implications. Cell Oncol (Dordr) 2020; 43:751-761. [PMID: 32623700 DOI: 10.1007/s13402-020-00512-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/27/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Bone is one of the most common sites for solid tumor metastasis. Bone metastasis of a malignant tumor seriously affects the quality of life and the overall survival of patients. Evidence has suggested that bone provides a favorable microenvironment that enables disseminated tumor cells to home, proliferate and colonize, leading to the formation of metastases. In the process of bone metastasis the bone microenvironment may be considered as an orchestra that plays a dissonant melody through blending (e.g. cross-talk between osteoclasts, osteoblasts and/or other cells), adding (e.g. a variety of biological factors) or taking away (e.g. blocking a specific pathway) players. CONCLUSIONS Here, we review the normal bone microenvironment, bone microenvironment-related factors that promote bone metastasis, as well as mechanisms underlying bone metastasis. In addition, we elude on directions for clinical bone metastasis management, focusing on potential therapeutic approaches to target bone microenvironment-related factors, including bisphosphonate, denosumab, CXCR4/CXCL12 antagonists and cathepsin K inhibitors.
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Affiliation(s)
- Xiaoting Ma
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, No.95 Yong An Road, Xi Cheng District, Beijing, 100050, China
| | - Jing Yu
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, No.95 Yong An Road, Xi Cheng District, Beijing, 100050, China.
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12
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Puppo M, Taipaleenmäki H, Hesse E, Clézardin P. Non-coding RNAs in bone remodelling and bone metastasis: Mechanisms of action and translational relevance. Br J Pharmacol 2019; 178:1936-1954. [PMID: 31423566 DOI: 10.1111/bph.14836] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 07/26/2019] [Accepted: 08/07/2019] [Indexed: 12/17/2022] Open
Abstract
Bone metastases are frequent complications in patients with advanced cancer, which can be fatal or may rapidly impede the quality of life of patients. Current treatments for patients with bone metastases are palliative. Therefore, a better understanding of the molecular mechanisms that precede the overt development of skeletal lesions could lead to better therapeutic interventions. In this review, we present evidence that non-coding RNAs (ncRNAs) such as long ncRNAs, microRNAs, and circular RNAs are emerging as master regulators of bone metastasis formation. We highlight potential opportunities for the therapeutic targeting of ncRNAs. Furthermore, we discuss the possibility that ncRNAs may be used as biomarkers in the context of bone metastases, which might provide insight for improving the response to current bone-targeting therapies. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.
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Affiliation(s)
- Margherita Puppo
- Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, UK
| | - Hanna Taipaleenmäki
- Molecular Skeletal Biology Laboratory, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eric Hesse
- Molecular Skeletal Biology Laboratory, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Institute of Molecular Musculoskeletal Research, Faculty of Medicine, LMU Munich, Planegg-Martinsried, Germany
| | - Philippe Clézardin
- Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, UK.,INSERM, Research Unit UMR_S1033, LyOS, Faculty of Medicine Lyon-Est, University of Lyon 1, Lyon, France
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13
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Gomez-Cambronero J. Lack of effective translational regulation of PLD expression and exosome biogenesis in triple-negative breast cancer cells. Cancer Metastasis Rev 2019; 37:491-507. [PMID: 30091053 DOI: 10.1007/s10555-018-9753-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is difficult to treat since cells lack the three receptors (ES, PR, or HER) that the most effective treatments target. We have used a well-established TNBC cell line (MDA-MB-231) from which we found evidence in support for a phospholipase D (PLD)-mediated tumor growth and metastasis: high levels of expression of PLD, as well as the absence of inhibitory miRs (such as miR-203) and 3'-mRNA PARN deadenylase activity in these cells. Such findings are not present in a luminal B cell line, MCF-7, and we propose a new miR•PARN•PLD node that is not uniform across breast cancer molecular subtypes and as such TNBC could be pharmacologically targeted differentially. We review the participation of PLD and phosphatidic acid (PA), its enzymatic product, as new "players" in breast cancer biology, with the aspects of regulation of the tumor microenvironment, macrophage polarization, regulation of PLD transcripts by specific miRs and deadenylases, and PLD-regulated exosome biogenesis. A new signaling miR•PARN•PLD node could serve as new biomarkers for TNBC abnormal signaling and metastatic disease staging, potentially before metastases are able to be visualized using conventional imaging.
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Affiliation(s)
- Julian Gomez-Cambronero
- Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, 3640 Colonel Glenn Highway, Dayton, OH, 45435, USA.
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14
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Vahidian F, Mohammadi H, Ali-Hasanzadeh M, Derakhshani A, Mostaan M, Hemmatzadeh M, Baradaran B. MicroRNAs and breast cancer stem cells: Potential role in breast cancer therapy. J Cell Physiol 2018; 234:3294-3306. [PMID: 30362508 DOI: 10.1002/jcp.27246] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Accepted: 07/24/2018] [Indexed: 12/19/2022]
Abstract
MicroRNAs (miRNAs) can control cancer and cancer stem cells (CSCs), and this topic has drawn immense attention recently. Stem cells are a tiny population of a bulk of tumor cells that have enormous potential in expansion and metastasis of the tumor. miRNA have a crucial role in the management of the function of stem cells. This role is to either promote or suppress the tumor. In this review, we investigated the function and different characteristics of CSCs and function of the miRNAs that are related to them. We also demonstrated the role and efficacy of these miRNAs in breast cancer and breast cancer stem cells (BCSC). Eventually, we revealed the metastasis, tumor formation, and their role in the apoptosis process. Also, the therapeutic potential of miRNA as an effective method for the treatment of BCSC was described. Extensive research is required to investigate the employment or suppression of these miRNAs for therapeutics approached in different cancers in the future.
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Affiliation(s)
- Fatemeh Vahidian
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Ali-Hasanzadeh
- Department of Immunology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Afshin Derakhshani
- Department of Immunology, Birjand University of Medical Sciences, Birjand, Iran.,Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Masoud Mostaan
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Islamic Azad university, Tabriz, Iran
| | - Maryam Hemmatzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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15
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孟 超, 汤 传, 梁 军. [Progress of Biomarkers in Diagnosis of Bone Metastases of Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2018; 21:615-619. [PMID: 30172269 PMCID: PMC6105350 DOI: 10.3779/j.issn.1009-3419.2018.08.07] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 06/06/2018] [Accepted: 06/08/2018] [Indexed: 12/02/2022]
Abstract
Bone is one of the most metastatic sites of advanced malignant tumors. With the continuous improvement of diagnosis and treatment of malignant tumors, the survival time of patients is prolonged and incidence of bone metastases also increases. Lung cancer is the leading cause of cancer-related mortality worldwide. It is estimated that the incidence of bone metastases in patients advanced lung cancer is about 30%-40%. The traditional diagnosis of bone metastases in lung cancer is based on clinical symptoms, X ray, computed tomography (CT), magnetic resonance imaging (MRI) and pathology. Recently, a large number of exploratory studies have reported blood biomarkers as indicators of bone metastasis screening and efficacy evaluation. In this review, we summarize the progress of biomarkers in diagnosis of bone metastases of lung cancer.
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Affiliation(s)
- 超 孟
- />102206 北京，北京大学国际医院肿瘤内科Department of Oncology, Peking University International Hospital, Beijing 102206, China
| | - 传昊 汤
- />102206 北京，北京大学国际医院肿瘤内科Department of Oncology, Peking University International Hospital, Beijing 102206, China
| | - 军 梁
- />102206 北京，北京大学国际医院肿瘤内科Department of Oncology, Peking University International Hospital, Beijing 102206, China
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16
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Croset M, Pantano F, Kan CWS, Bonnelye E, Descotes F, Alix-Panabières C, Lecellier CH, Bachelier R, Allioli N, Hong SS, Bartkowiak K, Pantel K, Clézardin P. miRNA-30 Family Members Inhibit Breast Cancer Invasion, Osteomimicry, and Bone Destruction by Directly Targeting Multiple Bone Metastasis-Associated Genes. Cancer Res 2018; 78:5259-5273. [PMID: 30042152 DOI: 10.1158/0008-5472.can-17-3058] [Citation(s) in RCA: 137] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 05/10/2018] [Accepted: 07/13/2018] [Indexed: 11/16/2022]
Abstract
miRNAs are master regulators of gene expression that play key roles in cancer metastasis. During bone metastasis, metastatic tumor cells must rewire their biology and express genes that are normally expressed by bone cells (a process called osteomimicry), which endow tumor cells with full competence for outgrowth in the bone marrow. Here, we establish miR-30 family members miR-30a, miR-30b, miR-30c, miR-30d, and miR-30e as suppressors of breast cancer bone metastasis that regulate multiple pathways, including osteomimicry. Low expression of miR-30 in primary tumors from patients with breast cancer were associated with poor relapse-free survival. In addition, estrogen receptor (ER)-negative/progesterone receptor (PR)-negative breast cancer cells expressed lower miR-30 levels than their ER/PR-positive counterparts. Overexpression of miR-30 in ER/PR-negative breast cancer cells resulted in the reduction of bone metastasis burden in vivoIn vitro, miR-30 did not affect tumor cell proliferation, but did inhibit tumor cell invasion. Furthermore, overexpression of miR-30 restored bone homeostasis by reversing the effects of tumor cell-conditioned medium on osteoclastogenesis and osteoblastogenesis. A number of genes associated with osteoclastogenesis stimulation (IL8, IL11), osteoblastogenesis inhibition (DKK-1), tumor cell osteomimicry (RUNX2, CDH11), and invasiveness (CTGF, ITGA5, ITGB3) were identified as targets for repression by miR-30. Among these genes, silencing CDH11 or ITGA5 in ER-/PR-negative breast cancer cells recapitulated inhibitory effects of miR-30 on skeletal tumor burden in vivo Overall, our findings provide evidence that miR-30 family members employ multiple mechanisms to impede breast cancer bone metastasis and may represent attractive targets for therapeutic intervention.Significance: These findings suggest miR-30 family members may serve as an effective means to therapeutically attenuate metastasis in triple-negative breast cancer. Cancer Res; 78(18); 5259-73. ©2018 AACR.
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Affiliation(s)
| | - Francesco Pantano
- INSERM, UMR_S1033, University Lyon 1, Lyon, France.,Medical Oncology Department, Campus Bio-Medico University of Rome, Rome, Italy
| | | | | | - Françoise Descotes
- Service de Biochimie Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France
| | | | | | | | - Nathalie Allioli
- Institut des Sciences Pharmaceutiques et Biologiques (ISPB)-Faculté de Pharmacie de Lyon, University Claude Bernard Lyon 1. Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Lyon, France
| | - Saw-See Hong
- University Lyon 1, UMR 754-INRA-EPHE, Lyon, France
| | - Kai Bartkowiak
- Department of Tumor Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Klaus Pantel
- Department of Tumor Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
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17
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An Y, Gao S, Zhao WC, Qiu BA, Xia NX, Zhang PJ, Fan ZP. Novel serum microRNAs panel on the diagnostic and prognostic implications of hepatocellular carcinoma. World J Gastroenterol 2018; 24:2596-2604. [PMID: 29962816 PMCID: PMC6021775 DOI: 10.3748/wjg.v24.i24.2596] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 04/26/2018] [Accepted: 05/05/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To determine a panel of serum microRNAs (miRNAs) that could be used as novel biomarkers for diagnosis of hepatocellular carcinoma (HCC).
METHODS We initially screened 9 out of 754 serum miRNAs by TaqMan Low Density Array in two pooled samples respectively from 35 HCC and 35 normal controls, and then validated individually by RT-qPCR in another 114 patients and 114 controls arranged in two phases. The changes of the selected miRNAs after operation and their prognostic value were examined.
RESULTS miR-375, miR-10a, miR-122 and miR-423 were found to be significantly higher in HCC than in controls (P < 0.0001), and the area under the receiver-operating-characteristic curve for the 4-miRNA panel was 0.995 (95%CI: 0.985-1). All the four miRNAs were significantly reduced after surgical removal of the tumors (P < 0.0001), while still higher than normal controls (at least P < 0.05)
CONCLUSION The four serum miRNAs (miR-375, miR-10a, miR-122 and miR-423) could potentially serve as novel biomarkers for the diagnostic and prognostic of HCC.
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Affiliation(s)
- Yang An
- Department of Hepato-Biliary-Pancreatic Surgey, Navy General Hospital of Chinese People’s Liberation Army, Beijing 100048, China
| | - Song Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Interventional Therapy Department, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Wen-Chao Zhao
- Department of Hepato-Biliary-Pancreatic Surgey, Navy General Hospital of Chinese People’s Liberation Army, Beijing 100048, China
| | - Bao-An Qiu
- Department of Hepato-Biliary-Pancreatic Surgey, Navy General Hospital of Chinese People’s Liberation Army, Beijing 100048, China
| | - Nian-Xin Xia
- Department of Hepato-Biliary-Pancreatic Surgey, Navy General Hospital of Chinese People’s Liberation Army, Beijing 100048, China
| | - Peng-Jun Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Interventional Therapy Department, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhen-Ping Fan
- The Liver Disease Center for Cadre Medical Care, Beijing 302 Military Hospital, Beijing 100039, China
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18
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Graham N, Qian BZ. Mesenchymal Stromal Cells: Emerging Roles in Bone Metastasis. Int J Mol Sci 2018; 19:E1121. [PMID: 29642534 PMCID: PMC5979535 DOI: 10.3390/ijms19041121] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 03/25/2018] [Accepted: 03/29/2018] [Indexed: 12/13/2022] Open
Abstract
Bone metastasis is the most advanced stage of many cancers and indicates a poor prognosis for patients due to resistance to anti-tumor therapies. The establishment of metastasis within the bone is a multistep process. To ensure survival within the bone marrow, tumor cells must initially colonize a niche in which they can enter dormancy. Subsequently, reactivation permits the proliferation and growth of the tumor cells, giving rise to a macro-metastasis displayed clinically as a bone metastatic lesion. Here, we review the evidences that suggest mesenchymal stromal cells play an important role in each of these steps throughout the development of bone metastasis. Similarities between the molecular mechanisms implicated in these processes and those involved in the homeostasis of the bone indicate that the metastatic cells may exploit the homeostatic processes to their own advantage. Identifying the molecular interactions between the mesenchymal stromal cells and tumor cells that promote tumor development may offer insight into potential therapeutic targets that could be utilized to treat bone metastasis.
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Affiliation(s)
- Nicola Graham
- Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
| | - Bin-Zhi Qian
- Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
- Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh EH4 2XR, UK.
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19
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Taipaleenmäki H, Farina NH, van Wijnen AJ, Stein JL, Hesse E, Stein GS, Lian JB. Antagonizing miR-218-5p attenuates Wnt signaling and reduces metastatic bone disease of triple negative breast cancer cells. Oncotarget 2018; 7:79032-79046. [PMID: 27738322 PMCID: PMC5346696 DOI: 10.18632/oncotarget.12593] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2016] [Accepted: 09/19/2016] [Indexed: 01/02/2023] Open
Abstract
Wnt signaling is implicated in bone formation and activated in breast cancer cells promoting primary and metastatic tumor growth. A compelling question is whether osteogenic miRNAs that increase Wnt activity for bone formation are aberrantly expressed in breast tumor cells to support metastatic bone disease. Here we report that miR-218-5p is highly expressed in bone metastases from breast cancer patients, but is not detected in normal mammary epithelial cells. Furthermore, inhibition of miR-218-5p impaired the growth of bone metastatic MDA-MB-231 cells in the bone microenvironment in vivo. These findings indicate a positive role for miR-218-5p in bone metastasis. Bioinformatic and biochemical analyses revealed a positive correlation between aberrant miR-218-5p expression and activation of Wnt signaling in breast cancer cells. Mechanistically, miR-218-5p targets the Wnt inhibitors Sclerostin (SOST) and sFRP-2, which highly enhances Wnt signaling. In contrast, delivery of antimiR-218-5p decreased Wnt activity and the expression of metastasis-related genes, including bone sialoprotein (BSP/IBSP), osteopontin (OPN/SPP1) and CXCR-4, implicating a Wnt/miR-218-5p regulatory network in bone metastatic breast cancer. Furthermore, miR-218-5p also mediates the Wnt-dependent up-regulation of PTHrP, a key cytokine promoting cancer-induced osteolysis. Antagonizing miR-218-5p reduced the expression of PTHrP and Rankl, inhibited osteoclast differentiation in vitro and in vivo, and prevented the development of osteolytic lesions in a preclinical metastasis model. We conclude that pathological elevation of miR-218-5p in breast cancer cells activates Wnt signaling to enhance metastatic properties of breast cancer cells and cancer-induced osteolytic disease, suggesting that miR-218-5p could be an attractive therapeutic target for preventing disease progression.
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Affiliation(s)
- Hanna Taipaleenmäki
- Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA.,Heisenberg-Group for Molecular Skeletal Biology, Department of Trauma, Hand & Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nicholas H Farina
- Department of Biochemistry & Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA
| | - Andre J van Wijnen
- Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA.,Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Janet L Stein
- Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA.,Department of Biochemistry & Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA
| | - Eric Hesse
- Heisenberg-Group for Molecular Skeletal Biology, Department of Trauma, Hand & Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Gary S Stein
- Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA.,Department of Biochemistry & Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA
| | - Jane B Lian
- Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA.,Department of Biochemistry & Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA
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20
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Haider MT, Taipaleenmäki H. Targeting the Metastatic Bone Microenvironment by MicroRNAs. Front Endocrinol (Lausanne) 2018; 9:202. [PMID: 29780354 PMCID: PMC5946017 DOI: 10.3389/fendo.2018.00202] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 04/11/2018] [Indexed: 01/08/2023] Open
Abstract
Bone metastases are a common and devastating feature of late-stage breast cancer. Metastatic bone disease is a consequence of disturbed bone remodeling due to pathological interactions between cancer cells and the bone microenvironment (BME). In the BME, breast cancer cells severely alter the balanced bone formation and bone resorption driven by osteoblasts and osteoclasts. The complex cellular cross talk in the BME is governed by secreted molecules, signaling pathways and epigenetic cues including non-coding RNAs. MicroRNAs (miRNAs) are small non-coding RNAs that reduce protein abundance and regulate several biological processes, including bone remodeling. Under pathological conditions, abnormal miRNA signaling contributes to the progression of diseases, such as bone metastasis. Recently miRNAs have been demonstrated to regulate several key drivers of bone metastasis. Furthermore, miRNAs are implicated as important regulators of cellular interactions within the metastatic BME. As a consequence, targeting the BME by miRNA delivery or antagonism has been reported to limit disease progression in experimental and preclinical conditions positioning miRNAs as emerging novel therapeutic tools in metastatic bone disease. This review will summarize our current understanding on the composition and function of the metastatic BME and discuss the recent advances how miRNAs can modulate pathological interactions in the bone environment.
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21
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Boucher J, Monvoisin A, Vix J, Mesnil M, Thuringer D, Debiais F, Cronier L. Connexins, important players in the dissemination of prostate cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2017; 1860:202-215. [PMID: 28693897 DOI: 10.1016/j.bbamem.2017.06.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 06/22/2017] [Accepted: 06/29/2017] [Indexed: 12/25/2022]
Abstract
Over the past 50years, increasing experimental evidences have established that connexins (Cxs) and gap junctional intercellular communication (GJIC) ensure an important role in both the onset and development of cancerous processes. In the present review, we focus on the impact of Cxs and GJIC during the development of prostate cancer (PCa), from the primary growth mainly localized in acinar glands and ducts to the distant metastasis mainly concentrated in bone. As observed in several other types of solid tumours, Cxs and especially Cx43 exhibit an ambivalent role with a tumour suppressor effect in the early stages and, conversely, a rather pro-tumoural profile for most of invasion and dissemination steps to secondary sites. We report here the current knowledge on the function of Cxs during PCa cells migration, cytoskeletal dynamics, proteinases activities and the cross talk with the surrounding stromal cells in the microenvironment of the tumour and the bones. In addition, we discuss the role of Cxs in the bone tropism even if the prostate model is rarely used to study the complete sequence of cancer dissemination compared to breast cancer or melanoma. Even if not yet fully understood, these recent findings on Cxs provide new insights into their molecular mechanisms associated with progression and bone targeted behaviour of PCa. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.
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Affiliation(s)
- Jonathan Boucher
- Laboratory Signalisation et Transports Ioniques Membranaires (STIM), ERL7368 - CNRS, University of Poitiers, Poitiers, France
| | - Arnaud Monvoisin
- Laboratory Signalisation et Transports Ioniques Membranaires (STIM), ERL7368 - CNRS, University of Poitiers, Poitiers, France
| | - Justine Vix
- Laboratory Signalisation et Transports Ioniques Membranaires (STIM), ERL7368 - CNRS, University of Poitiers, Poitiers, France; Department of Rheumatology, C.H.U. la Milétrie, Poitiers, France
| | - Marc Mesnil
- Laboratory Signalisation et Transports Ioniques Membranaires (STIM), ERL7368 - CNRS, University of Poitiers, Poitiers, France
| | | | - Françoise Debiais
- Laboratory Signalisation et Transports Ioniques Membranaires (STIM), ERL7368 - CNRS, University of Poitiers, Poitiers, France; Department of Rheumatology, C.H.U. la Milétrie, Poitiers, France
| | - Laurent Cronier
- Laboratory Signalisation et Transports Ioniques Membranaires (STIM), ERL7368 - CNRS, University of Poitiers, Poitiers, France.
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22
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Clézardin P. Pathophysiology of bone metastases from solid malignancies. Joint Bone Spine 2017; 84:677-684. [PMID: 28499894 DOI: 10.1016/j.jbspin.2017.05.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2016] [Indexed: 02/03/2023]
Abstract
Bone metastases are common complications of many cancers. Among the mechanisms that set the scene for the development of bone metastases, several are shared by all forms of metastatic dissemination (pre-metastatic niche formation and chemotactic attraction of malignant cells, which invade the host tissue) and others are specific of bone tissue (homing of malignant cells to bone marrow niches and acquisition of an osteomimetic cell phenotype). After a latency period that can last several years, the malignant cells can proliferate into tumors that alter the normal bone remodeling process by inducing dysregulation of osteoblast and osteoclast function. These metastases may be lytic, characterized by major bone destruction; sclerotic, with excess bone formation; or mixed. Osteolysis occurs when the tumor cells stimulate osteoclast activity and inhibit osteoblast activity, whereas the opposite effects lead to bone sclerosis. Moreover, the mineralized bone matrix plays a major role in the formation of bone metastases, as its degradation releases growth factors and calcium that exert mitogenic effects on tumor cells. Thus, bone metastases are the site of a vicious circle in which mechanisms involved in bone resorption/formation promote tumor growth and vice versa.
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Affiliation(s)
- Philippe Clézardin
- Inserm, UMR 1033, UFR de médecine Lyon-Est, 69372 Lyon cedex 08, France; Université Claude-Bernard Lyon-1, 69622 Villeurbanne, France.
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23
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Abstract
MicroRNAs are small, noncoding single-stranded RNAs that have emerged as important posttranscriptional regulators of gene expression, with an essential role in vertebrate development and different biological processes. This review highlights the recent advances in the function of miRNAs and their roles in bone remodeling and bone diseases. MicroRNAs (miRNAs) are a class of small (∼22 nt), noncoding single-stranded RNAs that have emerged as important posttranscriptional regulators of gene expression. They are essential for vertebrate development and play critical roles in different biological processes related to cell differentiation, activity, metabolism, and apoptosis. A rising number of experimental reports now indicate that miRNAs contribute to every step of osteogenesis and bone homeostasis, from embryonic skeletal development to maintenance of adult bone tissue, by regulating the growth, differentiation, and activity of different cell systems inside and outside the skeleton. Importantly, emerging information from animal studies suggests that targeting miRNAs might become an attractive and new therapeutic approach for osteoporosis or other skeletal diseases, even though there are still major concerns related to potential off target effects and the need of efficient delivery methods in vivo. Moreover, besides their recognized effects at the cellular level, evidence is also gathering that miRNAs are excreted and can circulate in the blood or other body fluids with potential paracrine or endocrine functions. Thus, they could represent suitable candidates for becoming sensitive disease biomarkers in different pathologic conditions, including skeletal disorders. Despite these promising perspectives more work remains to be done until miRNAs can serve as robust therapeutic targets or established diagnostic tools for precision medicine in skeletal disorders.
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Affiliation(s)
- L Gennari
- Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Santa Maria alle Scotte, Viale Bracci, 53100, Siena, Italy.
| | - S Bianciardi
- Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Santa Maria alle Scotte, Viale Bracci, 53100, Siena, Italy
| | - D Merlotti
- Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Santa Maria alle Scotte, Viale Bracci, 53100, Siena, Italy
- Division of Genetics and Cell Biology, Age Related Diseases, San Raffaele Scientific Institute, Milan, Italy
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24
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Role of Runx2 in breast cancer-mediated bone metastasis. Int J Biol Macromol 2017; 99:608-614. [PMID: 28268169 DOI: 10.1016/j.ijbiomac.2017.03.021] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 03/02/2017] [Accepted: 03/03/2017] [Indexed: 12/21/2022]
Abstract
Breast cancer is one of the most prevalent forms of cancer in women. The currently available treatment for breast cancer is mostly curative except when it becomes metastatic. One of the major sites for metastasis of breast cancer is the bone. Homing of the circulating tumor cells is tightly regulated including a number of factors present in the cells and their microenvironment. Runx2, a transcription factor plays an important role in osteogenesis and breast cancer mediated bone metastases. One of the recent advances in molecular therapy includes the discovery of the small, non-coding microRNAs (miRNAs) and they target specific genes to reduce their expression at the post-transcriptional level. This review provides an outline of breast cancer mediated bone metastasis and summarizes the recent development on the regulation of Runx2 expression by miRNAs which can lead to novel molecular therapeutics for the same.
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25
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Fang Y, Zhang L, Li Z, Li Y, Huang C, Lu X. MicroRNAs in DNA Damage Response, Carcinogenesis, and Chemoresistance. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2017; 333:1-49. [DOI: 10.1016/bs.ircmb.2017.03.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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26
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Kan C, Vargas G, Pape FL, Clézardin P. Cancer Cell Colonisation in the Bone Microenvironment. Int J Mol Sci 2016; 17:ijms17101674. [PMID: 27782035 PMCID: PMC5085707 DOI: 10.3390/ijms17101674] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 09/27/2016] [Accepted: 09/28/2016] [Indexed: 02/06/2023] Open
Abstract
Bone metastases are a common complication of epithelial cancers, of which breast, prostate and lung carcinomas are the most common. The establishment of cancer cells to distant sites such as the bone microenvironment requires multiple steps. Tumour cells can acquire properties to allow epithelial-to-mesenchymal transition, extravasation and migration. Within the bone metastatic niche, disseminated tumour cells may enter a dormancy stage or proliferate to adapt and survive, interacting with bone cells such as hematopoietic stem cells, osteoblasts and osteoclasts. Cross-talk with the bone may alter tumour cell properties and, conversely, tumour cells may also acquire characteristics of the surrounding microenvironment, in a process known as osteomimicry. Alternatively, these cells may also express osteomimetic genes that allow cell survival or favour seeding to the bone marrow. The seeding of tumour cells in the bone disrupts bone-forming and bone-resorbing activities, which can lead to macrometastasis in bone. At present, bone macrometastases are incurable with only palliative treatment available. A better understanding of how these processes influence the early onset of bone metastasis may give insight into potential therapies. This review will focus on the early steps of bone colonisation, once disseminated tumour cells enter the bone marrow.
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Affiliation(s)
- Casina Kan
- National Institute of Health and Medical Research (INSERM), UMR 1033, Lyon 69372, France.
- Faculty of Medicine RTH Laennec, University of Lyon, Villeurbanne 69372, France.
| | - Geoffrey Vargas
- National Institute of Health and Medical Research (INSERM), UMR 1033, Lyon 69372, France.
- Faculty of Medicine RTH Laennec, University of Lyon, Villeurbanne 69372, France.
| | - François Le Pape
- National Institute of Health and Medical Research (INSERM), UMR 1033, Lyon 69372, France.
- Faculty of Medicine RTH Laennec, University of Lyon, Villeurbanne 69372, France.
| | - Philippe Clézardin
- National Institute of Health and Medical Research (INSERM), UMR 1033, Lyon 69372, France.
- Faculty of Medicine RTH Laennec, University of Lyon, Villeurbanne 69372, France.
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27
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Casimiro S, Ferreira AR, Mansinho A, Alho I, Costa L. Molecular Mechanisms of Bone Metastasis: Which Targets Came from the Bench to the Bedside? Int J Mol Sci 2016; 17:E1415. [PMID: 27618899 PMCID: PMC5037694 DOI: 10.3390/ijms17091415] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 08/06/2016] [Accepted: 08/19/2016] [Indexed: 12/31/2022] Open
Abstract
Bone metastases ultimately result from a complex interaction between cancer cells and bone microenvironment. However, prior to the colonization of the bone, cancer cells must succeed through a series of steps that will allow them to detach from the primary tumor, enter into circulation, recognize and adhere to specific endothelium, and overcome dormancy. We now know that as important as the metastatic cascade, tumor cells prime the secondary organ microenvironment prior to their arrival, reflecting the existence of specific metastasis-initiating cells in the primary tumor and circulating osteotropic factors. The deep comprehension of the molecular mechanisms of bone metastases may allow the future development of specific anti-tumoral therapies, but so far the approved and effective therapies for bone metastatic disease are mostly based in bone-targeted agents, like bisphosphonates, denosumab and, for prostate cancer, radium-223. Bisphosphonates and denosumab have proven to be effective in blocking bone resorption and decreasing morbidity; furthermore, in the adjuvant setting, these agents can decrease bone relapse after breast cancer surgery in postmenopausal women. In this review, we will present and discuss some examples of applied knowledge from the bench to the bed side in the field of bone metastasis.
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Affiliation(s)
- Sandra Casimiro
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
| | - Arlindo R Ferreira
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
- Oncology Division, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, 1649-028 Lisbon, Portugal.
| | - André Mansinho
- Oncology Division, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, 1649-028 Lisbon, Portugal.
| | - Irina Alho
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
| | - Luis Costa
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
- Oncology Division, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, 1649-028 Lisbon, Portugal.
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28
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The role of osteoclasts in breast cancer bone metastasis. J Bone Oncol 2016; 5:93-95. [PMID: 27761364 PMCID: PMC5063222 DOI: 10.1016/j.jbo.2016.02.008] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 02/26/2016] [Accepted: 02/26/2016] [Indexed: 02/06/2023] Open
Abstract
Breast cancer frequently metastasises to the skeleton, interfering with the normal bone remodelling process and inducing bone degradation. Bone degradation is caused by osteoclasts, the normal bone-resorbing cells. Osteoclast-mediated bone degradation subsequently leads to the release of bone-derived factors that promote skeletal tumour growth. Osteoclasts themselves stimulate tumour growth. This Review describes the molecular mechanisms through which osteoclasts and breast cancer cells collaborate with each other, triggering the formation of osteolytic bone metastasis.
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29
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Hiraga T. Targeted Agents in Preclinical and Early Clinical Development for the Treatment of Cancer Bone Metastases. Expert Opin Investig Drugs 2016; 25:319-34. [DOI: 10.1517/13543784.2016.1142972] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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30
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Shimono Y, Mukohyama J, Nakamura SI, Minami H. MicroRNA Regulation of Human Breast Cancer Stem Cells. J Clin Med 2015; 5:jcm5010002. [PMID: 26712794 PMCID: PMC4730127 DOI: 10.3390/jcm5010002] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 12/01/2015] [Accepted: 12/21/2015] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) are involved in virtually all biological processes, including stem cell maintenance, differentiation, and development. The dysregulation of miRNAs is associated with many human diseases including cancer. We have identified a set of miRNAs differentially expressed between human breast cancer stem cells (CSCs) and non-tumorigenic cancer cells. In addition, these miRNAs are similarly upregulated or downregulated in normal mammary stem/progenitor cells. In this review, we mainly describe the miRNAs that are dysregulated in human breast CSCs directly isolated from clinical specimens. The miRNAs and their clusters, such as the miR-200 clusters, miR-183 cluster, miR-221-222 cluster, let-7, miR-142 and miR-214, target the genes and pathways important for stem cell maintenance, such as the self-renewal gene BMI1, apoptosis, Wnt signaling, Notch signaling, and epithelial-to-mesenchymal transition. In addition, the current evidence shows that metastatic breast CSCs acquire a phenotype that is different from the CSCs in a primary site. Thus, clarifying the miRNA regulation of the metastatic breast CSCs will further advance our understanding of the roles of human breast CSCs in tumor progression.
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Affiliation(s)
- Yohei Shimono
- Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
- Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
| | - Junko Mukohyama
- Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
| | - Shun-Ichi Nakamura
- Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
- Division of Biochemistry, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
| | - Hironobu Minami
- Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
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31
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Reagan MR, Rosen CJ. Navigating the bone marrow niche: translational insights and cancer-driven dysfunction. Nat Rev Rheumatol 2015; 12:154-68. [PMID: 26607387 DOI: 10.1038/nrrheum.2015.160] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The bone marrow niche consists of stem and progenitor cells destined to become mature cells such as haematopoietic elements, osteoblasts or adipocytes. Marrow cells, influenced by endocrine, paracrine and autocrine factors, ultimately function as a unit to regulate bone remodelling and haematopoiesis. Current evidence highlights that the bone marrow niche is not merely an anatomic compartment; rather, it integrates the physiology of two distinct organ systems, the skeleton and the marrow. The niche has a hypoxic microenvironment that maintains quiescent haematopoietic stem cells (HSCs) and supports glycolytic metabolism. In response to biochemical cues and under the influence of neural, hormonal, and biochemical factors, marrow stromal elements, such as mesenchymal stromal cells (MSCs), differentiate into mature, functioning cells. However, disruption of the niche can affect cellular differentiation, resulting in disorders ranging from osteoporosis to malignancy. In this Review, we propose that the niche reflects the vitality of two tissues - bone and blood - by providing a unique environment for stem and stromal cells to flourish while simultaneously preventing disproportionate proliferation, malignant transformation or loss of the multipotent progenitors required for healing, functional immunity and growth throughout an organism's lifetime. Through a fuller understanding of the complexity of the niche in physiologic and pathologic states, the successful development of more-effective therapeutic approaches to target the niche and its cellular components for the treatment of rheumatic, endocrine, neoplastic and metabolic diseases becomes achievable.
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Affiliation(s)
- Michaela R Reagan
- Center for Molecular Medicine, Maine Medical Centre Research Institute, 81 Research Drive, Scarborough, Maine 04074, USA
| | - Clifford J Rosen
- Center for Molecular Medicine, Maine Medical Centre Research Institute, 81 Research Drive, Scarborough, Maine 04074, USA
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32
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Terpos E, Confavreux CB, Clézardin P. Bone antiresorptive agents in the treatment of bone metastases associated with solid tumours or multiple myeloma. BONEKEY REPORTS 2015; 4:744. [PMID: 26512321 DOI: 10.1038/bonekey.2015.113] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 07/14/2015] [Indexed: 12/16/2022]
Abstract
Skeletal lesions contribute substantially to morbidity and mortality in patients with cancer. The disease manifestation course during metastatic bone disease is driven by tumour cells in the bone marrow, which alter the functions of bone-resorbing (osteoclasts) and bone-forming (osteoblasts) cells, promoting skeletal destruction. Successful therapeutic strategies for the treatment of metastatic bone disease include bisphosphonates and denosumab that inhibit osteoclast-mediated bone resorption. Inhibitors of cathepsin K, Src and activin A are under clinical investigation as potential anti-osteolytics. In this review, we describe current knowledge and future directions of antiresorptive therapies that may reduce or prevent destructive bone lesions from solid tumours and multiple myeloma.
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Affiliation(s)
- Evangelos Terpos
- National and Kapodistrian University of Athens, School of Medicine , Athens, Greece
| | - Cyrille B Confavreux
- Department of Rheumatology, Edouard Herriot Hospital, Hospices Civils de Lyon , Lyon, France ; INSERM, Research Unit UMR1033, UFR de Médecine Lyon-Est (domaine Laennec) , Lyon, France ; Université de Lyon , Lyon, France
| | - Philippe Clézardin
- INSERM, Research Unit UMR1033, UFR de Médecine Lyon-Est (domaine Laennec) , Lyon, France ; Université de Lyon , Lyon, France
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