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Ljubić A, Dinić M, Švraka D, Vujović S. Dual-Double Stem Cell Ovarian Therapy: A Comprehensive Approach in Regenerative Medicine. Int J Mol Sci 2024; 26:69. [PMID: 39795929 PMCID: PMC11719681 DOI: 10.3390/ijms26010069] [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: 09/23/2024] [Revised: 11/10/2024] [Accepted: 11/27/2024] [Indexed: 01/13/2025] Open
Abstract
Dual-double stem cell therapy, which integrates mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), represents a cutting-edge approach in regenerative medicine, particularly for conditions such as ovarian decline, premature ovarian insufficiency (POI), and induced ovarian failure. This therapy leverages the unique properties of MSCs and HSCs, enhancing tissue repair, immune modulation, and overall regenerative outcomes. MSCs, known for their ability to differentiate into various cell types, provide a supportive microenvironment and secrete bioactive molecules that promote angiogenesis and reduce inflammation. HSCs, crucial for hematopoiesis and immune function, further enhance this environment by supporting hematopoietic processes and immune regulation. Clinical evidence increasingly supports the effectiveness of stem cell therapy in ovarian regeneration. Studies have demonstrated improved folliculogenesis, normalization of hormone profiles, and successful pregnancies in patients with POI. Furthermore, recent clinical trials in various medical fields underline the superior potential of dual-double therapy compared to monotherapies involving MSCs or HSCs alone, enhancing tissue repair and functional outcomes. However, despite these benefits, the therapy presents risks that require careful consideration. For autologous MSC therapy involving expanded cell populations, risks include tumorigenic potential, with evidence of sarcoma formation in certain cases of cultured MSCs. In contrast, autologous non-expanded MSC and HSC therapies may be limited by low cell yields, potentially compromising therapeutic efficacy. Additionally, non-expanded HSC therapy poses risks of insufficient cell numbers for successful engraftment and delayed immune reconstitution. These considerations underscore the importance of quality control and rigorous screening to optimize safety and efficacy. This article explores the mechanisms of action, clinical applications, and potential complications of dual-double stem cell therapy, underscoring the need for continued research and optimized protocols to enhance safety and outcomes in ovarian insufficiency and related conditions, offering new hope for affected women.
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Affiliation(s)
- Aleksandar Ljubić
- Pronatal Hospital, 11000 Belgrade, Serbia;
- Academy of Sciences and Arts of Bosnia and Herzegovina, 71000 Sarajevo, Bosnia and Herzegovina
- Medigroup Health System, Dubrovnik International University, 20000 Dubrovnik, Croatia
| | - Marija Dinić
- Department of Therapeutic Apheresis, University Clinical Center of Serbia, 11000 Belgrade, Serbia;
| | | | - Svetlana Vujović
- Clinic of Endocrinology, Diabetes and Diseases of National Center for Infertility and Endocrinology of Gender, 11000 Belgrade, Serbia;
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
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Tvrdik T, Gjeorgjievski SG, Wong P, Oskouei S, Read W, Bahrami A. Genomic Insights Into High-Grade Infarct-Associated Bone Sarcomas. Mod Pathol 2024; 37:100572. [PMID: 39033963 DOI: 10.1016/j.modpat.2024.100572] [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: 05/20/2024] [Revised: 07/06/2024] [Accepted: 07/14/2024] [Indexed: 07/23/2024]
Abstract
Sarcomas rarely develop in bones previously compromised by infarcts. These infarct-associated sarcomas often present as undifferentiated pleomorphic sarcomas (UPS), and their genetic characteristics are poorly understood. High-grade UPS of bone are typically treated with a combination of surgery and chemotherapy, similar to osteosarcoma. We conducted a detailed clinicopathologic and genomic analysis of 6 cases of intraosseous sarcomas arising from histologically and radiographically confirmed bone infarcts. We analyzed 523 genes for sequence-level mutations using next-generation sequencing with the TruSight Oncology 500 panel and utilized whole-genome single nucleotide polymorphism Microarray (OncoScan CNV) to detect copy number alterations and loss of heterozygosity (LOH). Genomic instability was assessed through homologous recombination deficiency (HRD) metrics, incorporating LOH, telomeric allelic imbalance, and large-scale state transitions. Fluorescence in situ hybridization and immunohistochemistry validated the findings. The cohort included 3 men and 3 women, with a median age of 70 years, and tumors located in the femur and tibia. Five of the 6 patients developed distant metastases. Treatment involved surgery and chemotherapy or immune checkpoint inhibitors. Genomic analysis revealed significant complexity and high HRD scores, ranging from 32 to 57 (with a cutoff of 32). Chromosome 12 alterations, including segmental amplification or chromothripsis, were observed in 4 cases. Notably, MDM2 amplification, confirmed by fluorescence in situ hybridization, was detected in 2 cases. Homozygous deletion of CDKN2A/B was observed in all six cases. Tumor mutational burden levels ranged from 2.4 to 7.9 mutations per megabase. Notable pathogenic mutations included H3-3A mutations (p.G35R and p.G35W), and mutations in HRAS, DNMT3A, NF2, PIK3CA, POLE, and TP53, each in one case. These results suggest that high-grade infarct-associated sarcomas of bone, whereas sharing high levels of structural variations with osteosarcoma, may exhibit potentially less frequent TP53 mutations and more common CDKN2A/B deletions. This points to the possibility that the mutation spectrum and disrupted pathways could be distinct from conventional osteosarcoma.
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Affiliation(s)
- Tatiana Tvrdik
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.
| | | | - Philip Wong
- Department of Diagnostic Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia
| | - Shervin Oskouei
- Department of Orthopedic Surgery, Emory University School of Medicine, Atlanta, Georgia
| | - William Read
- Department of Hematology Oncology, Emory University School of Medicine, Atlanta, Georgia
| | - Armita Bahrami
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.
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Song P, Gao Z, Bao Y, Chen L, Huang Y, Liu Y, Dong Q, Wei X. Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy. J Hematol Oncol 2024; 17:46. [PMID: 38886806 PMCID: PMC11184729 DOI: 10.1186/s13045-024-01563-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 05/31/2024] [Indexed: 06/20/2024] Open
Abstract
The Wnt/β-catenin signaling pathway plays a crucial role in various physiological processes, encompassing development, tissue homeostasis, and cell proliferation. Under normal physiological conditions, the Wnt/β-catenin signaling pathway is meticulously regulated. However, aberrant activation of this pathway and downstream target genes can occur due to mutations in key components of the Wnt/β-catenin pathway, epigenetic modifications, and crosstalk with other signaling pathways. Consequently, these dysregulations contribute significantly to tumor initiation and progression. Therapies targeting the Wnt/β-catenin signaling transduction have exhibited promising prospects and potential for tumor treatment. An increasing number of medications targeting this pathway are continuously being developed and validated. This comprehensive review aims to summarize the latest advances in our understanding of the role played by the Wnt/β-catenin signaling pathway in carcinogenesis and targeted therapy, providing valuable insights into acknowledging current opportunities and challenges associated with targeting this signaling pathway in cancer research and treatment.
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Affiliation(s)
- Pan Song
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, China
| | - Zirui Gao
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yige Bao
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, China
| | - Li Chen
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yuhe Huang
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yanyan Liu
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Qiang Dong
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, China.
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China.
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Zheng S, Cheng X, Ke S, Zhang L, Wu H, He D, Cheng X. Bioinformatics analysis and validation of mesenchymal stem cells related gene MT1G in osteosarcoma. Aging (Albany NY) 2024; 16:8155-8170. [PMID: 38747739 PMCID: PMC11131992 DOI: 10.18632/aging.205809] [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: 10/05/2023] [Accepted: 03/18/2024] [Indexed: 05/21/2024]
Abstract
BACKGROUND Osteosarcoma (OS) is a primary malignant bone tumor arising from mesenchymal cells. The standard clinical treatment for OS involves extensive tumor resection combined with neoadjuvant chemotherapy or radiotherapy. OS's invasiveness, lung metastasis, and drug resistance contribute to a low cure rate and poor prognosis with this treatment. Metallothionein 1G (MT1G), observed in various cancers, may serve as a potential therapeutic target for OS. METHODS OS samples in GSE33382 and TARGET datasets were selected as the test cohorts. As the external validation cohort, 13 OS tissues and 13 adjacent cancerous tissues from The Second Affiliated Hospital of Nanchang University were collected. Patients with OS were divided into high and low MT1G mRNA-expression groups; differentially expressed genes (DEGs) were identified as MT1G-related genes. The biological function of MT1G was annotated using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) and gene set enrichment analysis (GSEA). Gene expression correlation analysis and competing endogenous RNA (ceRNA) regulatory network construction were used to determine potential biological regulatory relationships of DEGs. Survival analysis assessed the prognostic value of MT1G. RESULTS MT1G expression increased in OS samples and presented higher in metastatic OS compared with non-metastatic OS. Functional analyses indicated that MT1G was mainly associated with spliceosome. A ceRNA network with DEGs was constructed. MT1G is an effective biomarker predicting survival and correlated with increased recurrence rates and poorer survival. CONCLUSIONS This research identified MT1G as a potential biomarker for OS prognosis, highlighting its potential as a therapy target.
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Affiliation(s)
- Sikuan Zheng
- The Second Affiliated Hospital of Nanchang University, Nanchang, China
- The Second Clinical College, Medical College of Nanchang University, Nanchang, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, China
| | - Xifu Cheng
- School of Ophthalmology and Optometry, Nanchang University, Nanchang, China
| | - Sulun Ke
- Nanchang University Queen Mary School, Jiangxi Medical College of Nanchang University, Nanchang University, Nanchang, China
| | - Linyi Zhang
- School of Ophthalmology and Optometry, Nanchang University, Nanchang, China
| | - Hui Wu
- The Second Affiliated Hospital of Nanchang University, Nanchang, China
- The Second Clinical College, Medical College of Nanchang University, Nanchang, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, China
| | - Dingwen He
- The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, China
| | - Xigao Cheng
- The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, China
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Silver KI, Mannheimer JD, Saba C, Hendricks WPD, Wang G, Day K, Warrier M, Beck JA, Mazcko C, LeBlanc AK. Clinical, pathologic and molecular findings in 2 Rottweiler littermates with appendicular osteosarcoma. RESEARCH SQUARE 2024:rs.3.rs-4223759. [PMID: 38659878 PMCID: PMC11042397 DOI: 10.21203/rs.3.rs-4223759/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
Appendicular osteosarcoma was diagnosed and treated in a pair of littermate Rottweiler dogs, resulting in distinctly different clinical outcomes despite similar therapy within the context of a prospective, randomized clinical trial (NCI-COTC021/022). Histopathology, immunohistochemistry, mRNA sequencing, and targeted DNA hotspot sequencing techniques were applied to both dogs' tumors to define factors that could underpin their differential response to treatment. We describe the comparison of their clinical, histologic and molecular features, as well as those from a companion cohort of Rottweiler dogs, providing new insight into potential prognostic biomarkers for canine osteosarcoma.
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Affiliation(s)
| | | | | | - William P D Hendricks
- Vidium Animal Health, A Subsidiary of The Translational Genomics Research Institute (TGen)
| | - Guannan Wang
- Vidium Animal Health, A Subsidiary of The Translational Genomics Research Institute (TGen)
| | - Kenneth Day
- Vidium Animal Health, A Subsidiary of The Translational Genomics Research Institute (TGen)
| | - Manisha Warrier
- Vidium Animal Health, A Subsidiary of The Translational Genomics Research Institute (TGen)
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Miyashita Y, Kanou T, Fukui E, Matsui T, Kimura T, Ose N, Funaki S, Shintani Y. A Novel Peroxisome Proliferator-Activated Receptor Gamma/Nuclear Factor-Kappa B Activation Pathway is Involved in the Protective Effect of Adipose-Derived Mesenchymal Stem Cells Against Ischemia-Reperfusion Lung Injury. Transplant Proc 2024; 56:369-379. [PMID: 38320873 DOI: 10.1016/j.transproceed.2024.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 10/04/2023] [Accepted: 01/16/2024] [Indexed: 02/08/2024]
Abstract
BACKGROUND Adipose-derived stem cells (ADSCs) are well-recognized for their remarkable ability to suppress ischemia-reperfusion lung injury (IRLI). The primary objective of this investigation was to elucidate the underlying mechanism through which ADSCs exert protective effects against IRLI. METHODS A warm hilar occlusion model in C57BL6J mice was used. Hilar occlusion was achieved for 1 hour (ischemic), and after 1 hour the occlusion was released (reperfusion) to recover for 3 hours. RNA sequencing, the physiological function, pathway activation, and expression of inflammatory cytokines were evaluated. RESULTS Lung gas exchange and pulmonary edema were significantly improved in the IRLI/ADSCs group compared with the IRLI group. RNA sequencing results suggested that the peroxisome proliferator-activated receptor gamma (PPARγ)/nuclear factor-kappa B (NF-κB) pathway was involved in the effect of the ADSCs. Administration of a PPARγ antagonist in the IRLI/ADSC group resulted in the deterioration of the physiological function. Furthermore, the PPARγ protein expression level decreased, the NF-κB protein expression level increased, and inflammatory cytokine parameters from lung tissue and blood sample worsened in the PPARγ antagonist-administered group. CONCLUSION Administration of ADSCs exerted a significant protective effect against IRLI in mice, and the effect is attributed to the activation of the PPARγ/NF-κB pathway.
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Affiliation(s)
- Yudai Miyashita
- Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takashi Kanou
- Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
| | - Eriko Fukui
- Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takahiro Matsui
- Department of Pathology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Toru Kimura
- Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Naoko Ose
- Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Soichiro Funaki
- Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yasushi Shintani
- Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
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Barba-Rosado LV, Carrascal-Hernández DC, Insuasty D, Grande-Tovar CD. Graphene Oxide (GO) for the Treatment of Bone Cancer: A Systematic Review and Bibliometric Analysis. NANOMATERIALS (BASEL, SWITZERLAND) 2024; 14:186. [PMID: 38251150 PMCID: PMC10820493 DOI: 10.3390/nano14020186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/03/2024] [Accepted: 01/08/2024] [Indexed: 01/23/2024]
Abstract
Cancer is a severe disease that, in 2022, caused more than 9.89 million deaths worldwide. One worrisome type of cancer is bone cancer, such as osteosarcoma and Ewing tumors, which occur more frequently in infants. This study shows an active interest in the use of graphene oxide and its derivatives in therapy against bone cancer. We present a systematic review analyzing the current state of the art related to the use of GO in treating osteosarcoma, through evaluating the existing literature. In this sense, studies focused on GO-based nanomaterials for potential applications against osteosarcoma were reviewed, which has revealed that there is an excellent trend toward the use of GO-based nanomaterials, based on their thermal and anti-cancer activities, for the treatment of osteosarcoma through various therapeutic approaches. However, more research is needed to develop highly efficient localized therapies. It is suggested, therefore, that photodynamic therapy, photothermal therapy, and the use of nanocarriers should be considered as non-invasive, more specific, and efficient alternatives in the treatment of osteosarcoma. These options present promising approaches to enhance the effectiveness of therapy while also seeking to reduce side effects and minimize the damage to surrounding healthy tissues. The bibliometric analysis of photothermal and photochemical treatments of graphene oxide and reduced graphene oxide from January 2004 to December 2022 extracted 948 documents with its search strategy, mainly related to research papers, review papers, and conference papers, demonstrating a high-impact field supported by the need for more selective and efficient bone cancer therapies. The central countries leading the research are the United States, Iran, Italy, Germany, China, South Korea, and Australia, with strong collaborations worldwide. At the same time, the most-cited papers were published in journals with impact factors of more than 6.0 (2021), with more than 290 citations. Additionally, the journals that published the most on the topic are high impact factor journals, according to the analysis performed, demonstrating the high impact of the research field.
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Affiliation(s)
- Lemy Vanessa Barba-Rosado
- Grupo de Investigación en Fotoquímica y Fotobiología, Programa de Química, Facultad de Ciencias Básicas, Universidad del Atlántico, Puerto Colombia 081008, Colombia; (L.V.B.-R.); (D.C.C.-H.)
| | - Domingo César Carrascal-Hernández
- Grupo de Investigación en Fotoquímica y Fotobiología, Programa de Química, Facultad de Ciencias Básicas, Universidad del Atlántico, Puerto Colombia 081008, Colombia; (L.V.B.-R.); (D.C.C.-H.)
- Departamento de Química y Biología, División de Ciencias Básicas, Universidad del Norte, Km 5 Vía Puerto Colombia, Barranquilla 081007, Colombia;
| | - Daniel Insuasty
- Departamento de Química y Biología, División de Ciencias Básicas, Universidad del Norte, Km 5 Vía Puerto Colombia, Barranquilla 081007, Colombia;
| | - Carlos David Grande-Tovar
- Grupo de Investigación en Fotoquímica y Fotobiología, Programa de Química, Facultad de Ciencias Básicas, Universidad del Atlántico, Puerto Colombia 081008, Colombia; (L.V.B.-R.); (D.C.C.-H.)
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Difilippo V, Saba KH, Styring E, Magnusson L, Nilsson J, Nathrath M, Baumhoer D, Nord KH. Osteosarcomas With Few Chromosomal Alterations or Adult Onset Are Genetically Heterogeneous. J Transl Med 2024; 104:100283. [PMID: 37931683 DOI: 10.1016/j.labinv.2023.100283] [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: 06/22/2023] [Revised: 10/30/2023] [Accepted: 11/01/2023] [Indexed: 11/08/2023] Open
Abstract
Osteosarcoma is the most common primary bone malignancy, often detected in children and adolescents and commonly associated with TP53 alterations along with a high number of chromosomal rearrangements. However, osteosarcoma can affect patients of any age, and some tumors display less genetic complexity. Besides TP53 variants, data on key driving mutations are lacking for many osteosarcomas, particularly those affecting adults. To detect osteosarcoma-specific alterations, we screened transcriptomic and genomic sequencing and copy number data from 150 bone tumors originally diagnosed as osteosarcomas. To increase the precision in gene fusion detection, we developed a bioinformatic tool denoted as NAFuse, which extracts gene fusions that are verified at both the genomic and transcriptomic levels. Apart from the already reported genetic subgroups of osteosarcoma with TP53 structural variants, or MDM2 and/or CDK4 amplification, we did not identify any recurrent genetic driver that signifies the remaining cases. Among the plethora of mutations identified, we found genetic alterations characteristic of, or similar to, those of other bone and soft tissue tumors in 8 cases. These mutations were found in tumors with relatively few other genetic alterations or in adults. Due to the lack of clinical context and available tissue, we can question the diagnosis only on a genetic basis. However, our findings support the notion that osteosarcomas with few chromosomal alterations or adult onset seem genetically distinct from conventional osteosarcomas of children and adolescents.
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Affiliation(s)
- Valeria Difilippo
- Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden
| | - Karim H Saba
- Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden
| | - Emelie Styring
- Department of Orthopedics, Lund University, Skåne University Hospital, Lund, Sweden
| | - Linda Magnusson
- Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden
| | - Jenny Nilsson
- Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden
| | - Michaela Nathrath
- Children's Cancer Research Centre and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Department of Pediatric Oncology, Klinikum Kassel, Kassel, Germany
| | - Daniel Baumhoer
- Bone Tumour Reference Centre at the Institute of Pathology, University Hospital and University of Basel, Basel, Switzerland
| | - Karolin H Nord
- Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden.
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Locquet MA, Brahmi M, Blay JY, Dutour A. Radiotherapy in bone sarcoma: the quest for better treatment option. BMC Cancer 2023; 23:742. [PMID: 37563551 PMCID: PMC10416357 DOI: 10.1186/s12885-023-11232-3] [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: 02/22/2023] [Accepted: 07/26/2023] [Indexed: 08/12/2023] Open
Abstract
Bone sarcomas are rare tumors representing 0.2% of all cancers. While osteosarcoma and Ewing sarcoma mainly affect children and young adults, chondrosarcoma and chordoma have a preferential incidence in people over the age of 40. Despite this range in populations affected, all bone sarcoma patients require complex transdisciplinary management and share some similarities. The cornerstone of all bone sarcoma treatment is monobloc resection of the tumor with adequate margins in healthy surrounding tissues. Adjuvant chemo- and/or radiotherapy are often included depending on the location of the tumor, quality of resection or presence of metastases. High dose radiotherapy is largely applied to allow better local control in case of incomplete primary tumor resection or for unresectable tumors. With the development of advanced techniques such as proton, carbon ion therapy, radiotherapy is gaining popularity for the treatment of bone sarcomas, enabling the delivery of higher doses of radiation, while sparing surrounding healthy tissues. Nevertheless, bone sarcomas are radioresistant tumors, and some mechanisms involved in this radioresistance have been reported. Hypoxia for instance, can potentially be targeted to improve tumor response to radiotherapy and decrease radiation-induced cellular toxicity. In this review, the benefits and drawbacks of radiotherapy in bone sarcoma will be addressed. Finally, new strategies combining a radiosensitizing agent and radiotherapy and their applicability in bone sarcoma will be presented.
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Affiliation(s)
- Marie-Anaïs Locquet
- Cell Death and Pediatric Cancer Team, Cancer Initiation and Tumor Cell Identity Department, INSERM1052, CNRS5286, Cancer Research Center of Lyon, F-69008, Lyon, France
| | - Mehdi Brahmi
- Department of Medical Oncology, Centre Leon Berard, Unicancer Lyon, 69008, Lyon, France
| | - Jean-Yves Blay
- Cell Death and Pediatric Cancer Team, Cancer Initiation and Tumor Cell Identity Department, INSERM1052, CNRS5286, Cancer Research Center of Lyon, F-69008, Lyon, France
- Department of Medical Oncology, Centre Leon Berard, Unicancer Lyon, 69008, Lyon, France
- Université Claude Bernard Lyon I, Lyon, France
| | - Aurélie Dutour
- Cell Death and Pediatric Cancer Team, Cancer Initiation and Tumor Cell Identity Department, INSERM1052, CNRS5286, Cancer Research Center of Lyon, F-69008, Lyon, France.
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Feng J, Hsu PF, Esteva E, Labella R, Wang Y, Khodadadi-Jamayran A, Pucella J, Liu CZ, Arbini AA, Tsirigos A, Kousteni S, Reizis B. Haplodeficiency of the 9p21 tumor suppressor locus causes myeloid disorders driven by the bone marrow microenvironment. Blood 2023; 142:460-476. [PMID: 37267505 PMCID: PMC12022840 DOI: 10.1182/blood.2022018512] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 05/18/2023] [Accepted: 05/20/2023] [Indexed: 06/04/2023] Open
Abstract
The chromosome 9p21 locus comprises several tumor suppressor genes including MTAP, CDKN2A, and CDKN2B, and its homo- or heterozygous deletion is associated with reduced survival in multiple cancer types. We report that mice with germ line monoallelic deletion or induced biallelic deletion of the 9p21-syntenic locus (9p21s) developed a fatal myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN)-like disease associated with aberrant trabecular bone formation and/or fibrosis in the bone marrow (BM). Reciprocal BM transfers and conditional targeting of 9p21s suggested that the disease originates in the BM stroma. Single-cell analysis of 9p21s-deficient BM stroma revealed the expansion of chondrocyte and osteogenic precursors, reflected in increased osteogenic differentiation in vitro. It also showed reduced expression of factors maintaining hematopoietic stem/progenitor cells, including Cxcl12. Accordingly, 9p21s-deficient mice showed reduced levels of circulating Cxcl12 and concomitant upregulation of the profibrotic chemokine Cxcl13 and the osteogenesis- and fibrosis-related multifunctional glycoprotein osteopontin/Spp1. Our study highlights the potential of mutations in the BM microenvironment to drive MDS/MPN-like disease.
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Affiliation(s)
- Jue Feng
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
| | - Pei-Feng Hsu
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
| | - Eduardo Esteva
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
| | - Rossella Labella
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY
- Edward P. Evans Center for Myelodysplastic Syndromes, Columbia University Medical Center, New York, NY
| | - Yueyang Wang
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
| | - Alireza Khodadadi-Jamayran
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
- Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, New York, NY
| | - Joseph Pucella
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
| | - Cynthia Z. Liu
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
| | - Arnaldo A. Arbini
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
| | - Aristotelis Tsirigos
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
- Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, New York, NY
| | - Stavroula Kousteni
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY
- Edward P. Evans Center for Myelodysplastic Syndromes, Columbia University Medical Center, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY
| | - Boris Reizis
- Department of Pathology, New York University Grossman School of Medicine, New York, NY
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11
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Todosenko N, Khlusov I, Yurova K, Khaziakhmatova O, Litvinova L. Signal Pathways and microRNAs in Osteosarcoma Growth and the Dual Role of Mesenchymal Stem Cells in Oncogenesis. Int J Mol Sci 2023; 24:ijms24108993. [PMID: 37240338 DOI: 10.3390/ijms24108993] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/10/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
The major challenges in Osteosarcoma (OS) therapy are its heterogeneity and drug resistance. The development of new therapeutic approaches to overcome the major growth mechanisms of OS is urgently needed. The search for specific molecular targets and promising innovative approaches in OS therapy, including drug delivery methods, is an urgent problem. Modern regenerative medicine focuses on harnessing the potential of mesenchymal stem cells (MSCs) because they have low immunogenicity. MSCs are important cells that have received considerable attention in cancer research. Currently, new cell-based methods for using MSCs in medicine are being actively investigated and tested, especially as carriers for chemotherapeutics, nanoparticles, and photosensitizers. However, despite the inexhaustible regenerative potential and known anticancer properties of MSCs, they may trigger the development and progression of bone tumors. A better understanding of the complex cellular and molecular mechanisms of OS pathogenesis is essential to identify novel molecular effectors involved in oncogenesis. The current review focuses on signaling pathways and miRNAs involved in the development of OS and describes the role of MSCs in oncogenesis and their potential for antitumor cell-based therapy.
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Affiliation(s)
- Natalia Todosenko
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
| | - Igor Khlusov
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
- Laboratory of Cellular and Microfluidic Technologies, Siberian State Medical University, 2, Moskovskii Trakt, 634050 Tomsk, Russia
| | - Kristina Yurova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
| | - Olga Khaziakhmatova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
| | - Larisa Litvinova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
- Laboratory of Cellular and Microfluidic Technologies, Siberian State Medical University, 2, Moskovskii Trakt, 634050 Tomsk, Russia
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12
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Martins-Neves SR, Sampaio-Ribeiro G, Gomes CMF. Self-Renewal and Pluripotency in Osteosarcoma Stem Cells' Chemoresistance: Notch, Hedgehog, and Wnt/β-Catenin Interplay with Embryonic Markers. Int J Mol Sci 2023; 24:8401. [PMID: 37176108 PMCID: PMC10179672 DOI: 10.3390/ijms24098401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/28/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023] Open
Abstract
Osteosarcoma is a highly malignant bone tumor derived from mesenchymal cells that contains self-renewing cancer stem cells (CSCs), which are responsible for tumor progression and chemotherapy resistance. Understanding the signaling pathways that regulate CSC self-renewal and survival is crucial for developing effective therapies. The Notch, Hedgehog, and Wnt/β-Catenin developmental pathways, which are essential for self-renewal and differentiation of normal stem cells, have been identified as important regulators of osteosarcoma CSCs and also in the resistance to anticancer therapies. Targeting these pathways and their interactions with embryonic markers and the tumor microenvironment may be a promising therapeutic strategy to overcome chemoresistance and improve the prognosis for osteosarcoma patients. This review focuses on the role of Notch, Hedgehog, and Wnt/β-Catenin signaling in regulating CSC self-renewal, pluripotency, and chemoresistance, and their potential as targets for anti-cancer therapies. We also discuss the relevance of embryonic markers, including SOX-2, Oct-4, NANOG, and KLF4, in osteosarcoma CSCs and their association with the aforementioned signaling pathways in overcoming drug resistance.
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Affiliation(s)
- Sara R. Martins-Neves
- iCBR—Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (S.R.M.-N.)
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Gabriela Sampaio-Ribeiro
- iCBR—Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (S.R.M.-N.)
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3000-548 Coimbra, Portugal
- CACC—Clinical Academic Center of Coimbra, 3000-075 Coimbra, Portugal
| | - Célia M. F. Gomes
- iCBR—Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (S.R.M.-N.)
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3000-548 Coimbra, Portugal
- CACC—Clinical Academic Center of Coimbra, 3000-075 Coimbra, Portugal
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13
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Alatrash R, Golubenko M, Martynova E, Garanina E, Mukhamedshina Y, Khaiboullina S, Rizvanov A, Salafutdinov I, Arkhipova S. Genetically Engineered Artificial Microvesicles Carrying Nerve Growth Factor Restrains the Progression of Autoimmune Encephalomyelitis in an Experimental Mouse Model. Int J Mol Sci 2023; 24:ijms24098332. [PMID: 37176039 PMCID: PMC10179478 DOI: 10.3390/ijms24098332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 04/27/2023] [Accepted: 05/02/2023] [Indexed: 05/15/2023] Open
Abstract
Multiple sclerosis (MS) is an incurable, progressive chronic autoimmune demyelinating disease. Therapy for MS is based on slowing down the processes of neurodegeneration and suppressing the immune system of patients. MS is accompanied by inflammation, axon-degeneration and neurogliosis in the central nervous system. One of the directions for a new effective treatment for MS is cellular, subcellular, as well as gene therapy. We investigated the therapeutic potential of adipose mesenchymal stem cell (ADMSC) derived, cytochalasin B induced artificial microvesicles (MVs) expressing nerve growth factor (NGF) on a mouse model of multiple sclerosis experimental autoimmune encephalomyelitis (EAE). These ADMSC-MVs-NGF were tested using histological, immunocytochemical and molecular genetic methods after being injected into the tail vein of animals on the 14th and 21st days post EAE induction. ADMSC-MVs-NGF contained the target protein inside the cytoplasm. Their injection into the caudal vein led to a significant decrease in neurogliosis at the 14th and 21st days post EAE induction. Artificial ADMSC-MVs-NGF stimulate axon regeneration and can modulate gliosis in the EAE model.
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Affiliation(s)
- Reem Alatrash
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Maria Golubenko
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Ekaterina Martynova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Ekaterina Garanina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Yana Mukhamedshina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
- Department of Medical Biology and Genetics, Kazan State Medical University, 420012 Kazan, Russia
| | - Svetlana Khaiboullina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Albert Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Ilnur Salafutdinov
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
- Department of Medical Biology and Genetics, Kazan State Medical University, 420012 Kazan, Russia
| | - Svetlana Arkhipova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
- Department of Medical Biology and Genetics, Kazan State Medical University, 420012 Kazan, Russia
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14
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Oliinyk D, Eigenberger A, Felthaus O, Haerteis S, Prantl L. Chorioallantoic Membrane Assay at the Cross-Roads of Adipose-Tissue-Derived Stem Cell Research. Cells 2023; 12:cells12040592. [PMID: 36831259 PMCID: PMC9953848 DOI: 10.3390/cells12040592] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 02/15/2023] Open
Abstract
With a history of more than 100 years of different applications in various scientific fields, the chicken chorioallantoic membrane (CAM) assay has proven itself to be an exceptional scientific model that meets the requirements of the replacement, reduction, and refinement principle (3R principle). As one of three extraembryonic avian membranes, the CAM is responsible for fetal respiration, metabolism, and protection. The model provides a unique constellation of immunological, vascular, and extracellular properties while being affordable and reliable at the same time. It can be utilized for research purposes in cancer biology, angiogenesis, virology, and toxicology and has recently been used for biochemistry, pharmaceutical research, and stem cell biology. Stem cells and, in particular, mesenchymal stem cells derived from adipose tissue (ADSCs) are emerging subjects for novel therapeutic strategies in the fields of tissue regeneration and personalized medicine. Because of their easy accessibility, differentiation profile, immunomodulatory properties, and cytokine repertoire, ADSCs have already been established for different preclinical applications in the files mentioned above. In this review, we aim to highlight and identify some of the cross-sections for the potential utilization of the CAM model for ADSC studies with a focus on wound healing and tissue engineering, as well as oncological research, e.g., sarcomas. Hereby, the focus lies on the combination of existing evidence and experience of such intersections with a potential utilization of the CAM model for further research on ADSCs.
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Affiliation(s)
- Dmytro Oliinyk
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
- Correspondence:
| | - Andreas Eigenberger
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | - Oliver Felthaus
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | - Silke Haerteis
- Institute for Molecular and Cellular Anatomy, Faculty for Biology and Preclinical Medicine, University of Regensburg, Universitätsstraße 31, 93053 Regensburg, Germany
| | - Lukas Prantl
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
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15
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Sun Y, Zhang C, Fang Q, Zhang W, Liu W. Abnormal signal pathways and tumor heterogeneity in osteosarcoma. J Transl Med 2023; 21:99. [PMID: 36759884 PMCID: PMC9912612 DOI: 10.1186/s12967-023-03961-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 02/01/2023] [Indexed: 02/11/2023] Open
Abstract
BACKGROUND Osteosarcoma (OS) is the most frequent and aggressive primary malignant sarcoma among adolescents and chemotherapy has not substantially progressed for decades. New insights into OS development and therapeutic strategies are urgently needed. METHODS We analyzed integrated single-cell transcriptomes, bulk RNA-seq, and microarray data from Gene Expression Omnibus (GEO) datasets. We also used Weighted Gene Co-expression Network Analysis (WGCNA), Gene set enrichment analysis (GSEA), and Gene set variation analysis (GSVA), along with Simple ClinVar and Enrichr web servers. RESULTS The findings of integrated single-cell analysis showed that OS arises from imperfect osteogenesis during development. Novel abnormalities comprised deficient TGFβ and P53 signal pathways, and cell cycle pathway activation, and a potentially new driver mutation in the interferon induced transmembrane protein 5 (IFITM5) that might function as a pathogenic factor in OS. Osteosarcoma is characterized by oncocyte heterogeneity, especially in immunogenic and adipocyte-like subtypes that respectively promote and hamper OS treatment. Etoposide is a promising chemotherapeutic that provides palliation by affecting the subtype of OS and correcting the abnormal pathways. CONCLUSION Various abnormal signal pathways play indispensable roles in OS development. We explored the heterogeneity and underlying mechanisms of OS and generated findings that will assist with OS assessment and selecting optimal therapies.
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Affiliation(s)
- Yifeng Sun
- grid.452422.70000 0004 0604 7301Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, 250014 Shandong People’s Republic of China ,grid.410712.10000 0004 0473 882XDepartment of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany
| | - Chunming Zhang
- grid.452422.70000 0004 0604 7301Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, 250014 Shandong People’s Republic of China
| | - Qiongxuan Fang
- grid.11135.370000 0001 2256 9319MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, 100871 China
| | - Wenqiang Zhang
- grid.452422.70000 0004 0604 7301Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, 250014 Shandong People’s Republic of China
| | - Wei Liu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, 250014, Shandong, People's Republic of China.
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16
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Park SJ, Kim DS, Choi M, Han KH, Han JS, Yoo KH, Moon KS. Preclinical Evaluation of interferon-gamma primed human Wharton's jelly-derived mesenchymal stem cells. Hum Exp Toxicol 2023; 42:9603271231171650. [PMID: 37092667 DOI: 10.1177/09603271231171650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
The potential of human mesenchymal stem cells (MSCs) for cell therapy has been investigated in numerous immune-mediated conditions; MSCs are considered one of the most promising cellular therapeutics to treat intractable diseases. Recently, approaches to prime MSCs have been investigated, thereby generating cellular products with enhanced potential for a variety of clinical applications. Interferon-gamma (IFN-γ) priming is a current approach used to increase the therapeutic efficacy of MSCs. In this study, we determined the systemic toxicity, tumorigenicity and biodistribution of IFN-γ-primed Wharton's jelly-derived (WJ)-MSCs in male and female BALB/c-nu/nu mice. There were no deaths or pathologic lesions in the mice treated with 5 × 106 cells/kg IFN-γ-primed MSCs in the repeated dose study. In the tumorigenicity study, one of the subcutaneously treated mice showed bronchioloalveolar adenoma in the lung but tested negative for human-specific anti-mitochondrial antibody, suggesting the spontaneous murine origin of the adenoma. A biodistribution study using real-time quantitative polymerase chain reaction demonstrated the systemic IFN-γ-primed MSC clearance by day 28. Based on the toxicity, biodistribution, and tumorigenicity studies, we concluded that IFN-γ-primed MSCs at 5 × 106 cells/kg do not induce tumor formation and adverse changes.
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Affiliation(s)
- Sang-Jin Park
- Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Dae Seong Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea
- Division of Clinical Development, CELLnLIFE Research Center, CELLnLIFE Inc., Seoul, Republic of Korea
| | - Myeongjin Choi
- Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Kang-Hyun Han
- Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Ji-Seok Han
- Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Keon Hee Yoo
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea
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17
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The Role of Tumor Microenvironment in Regulating the Plasticity of Osteosarcoma Cells. Int J Mol Sci 2022; 23:ijms232416155. [PMID: 36555795 PMCID: PMC9788144 DOI: 10.3390/ijms232416155] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/07/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Osteosarcoma (OS) is a malignancy that is becoming increasingly common in adolescents. OS stem cells (OSCs) form a dynamic subset of OS cells that are responsible for malignant progression and chemoradiotherapy resistance. The unique properties of OSCs, including self-renewal, multilineage differentiation and metastatic potential, 149 depend closely on their tumor microenvironment. In recent years, the likelihood of its dynamic plasticity has been extensively studied. Importantly, the tumor microenvironment appears to act as the main regulatory component of OS cell plasticity. For these reasons aforementioned, novel strategies for OS treatment focusing on modulating OS cell plasticity and the possibility of modulating the composition of the tumor microenvironment are currently being explored. In this paper, we review recent studies describing the phenomenon of OSCs and factors known to influence phenotypic plasticity. The microenvironment, which can regulate OSC plasticity, has great potential for clinical exploitation and provides different perspectives for drug and treatment design for OS.
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18
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Jimenez IA, Pool RR, Gabrielson KL. Canine Idiopathic Arteriopathy, Appendicular Bone Infarcts, and Neoplastic Transformation of Bone Infarcts in 108 Dogs ( Canis lupus familiaris). Comp Med 2022; 72:306-319. [PMID: 36113969 PMCID: PMC9827601 DOI: 10.30802/aalas-cm-22-000037] [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: 04/09/2022] [Revised: 05/27/2022] [Accepted: 07/26/2022] [Indexed: 01/27/2023]
Abstract
Osteosarcoma (OSA) is the most common primary bone tumor in both dogs and humans. The dog is an important research model for OSA, yet dogs have much higher prevalence of bone tumors than do humans, a disparity that has yet to be explained. Neoplastic transformation of cells within or adjacent to bone infarcts into primary bone tumors has been described in humans but only sparsely characterized in the veterinary literature. In this study, 653 cases of canine bone infarcts were received through a referral veterinary osteopathology service over a 14-y period. We identified an idiopathic disorder affecting the nutrient artery, termed canine idiopathic arteriopathy (CIA), which to our knowledge has no direct counterpart in human medicine. This disorder was documented alongside ischemic necrosis of the medullary cavity in 114 bone infarcts in 108 dogs. We hypothesize that CIA precipitated an ischemic environment, resulting in development of a bone infarct down- stream of the abnormal artery. In 52% (59 of 114) of cases, bone infarcts demonstrated evidence of repair (termed reparative bone infarcts [RBI]), while in 48% (55 of 114) of infarcts, a bone tumor was also present, including pleomorphic sarcoma, OSA, fibrosarcoma, and chondrosarcoma. In some cases, a spectrum of tumors was present. We hypothesize that the ischemic infarct environment provoked bone marrow mesenchymal stem cells (MSCs) to attempt repair of the stroma, and in approximately half of cases, MSCs underwent neoplastic transformation (BINT) to produce tumors. The most common sites of bone infarcts were the distal femur, distal radius, proximal humerus, and distal tibia, coinciding with common sites of canine OSA. The authors propose that CIA leading to bone infarcts and infarct-derived tumors, in combination with possible underdiagnosis of canine bone infarcts and misdiagnosis of some RBI as neoplasia, may contribute to the higher reported proportion of bone tumors in dogs compared with humans.
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Affiliation(s)
- Isabel A Jimenez
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland;,
| | - Roy R Pool
- Department of Veterinary Pathobiology, Texas A&M College of Veterinary Medicine & Biomedical Sciences, College Station, Texas
| | - Kathleen L Gabrielson
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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19
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Guo J, Fang X, Zhou J, Zeng L, Yu B. Identification and validation of miR-509-5p as a prognosticator for favorable survival in osteosarcoma. Medicine (Baltimore) 2022; 101:e29705. [PMID: 35984199 PMCID: PMC9387993 DOI: 10.1097/md.0000000000029705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Osteosarcoma (OS) is the most common primary bone cancer diagnosed in children. This study aims to explore the aberrantly expressed miRNAs that are prognostically related and to provide potential biomarkers for the prognosis prediction of OS. The miRNA profiles of OS and adjacent normal controls were obtained from 2 gene expression omnibus cohorts (i.e., GSE28423 and GSE65071). GSE39058 and Therapeutically Applicable Research to Generate Effective Treatments cohorts, which respectively contained 91 and 85 OS samples with both miRNA expression and clinical characteristics, were employed to perform survival and multivariate Cox regression analyses. Lymphocyte infiltration abundance between distinct subgroups was evaluated with the CIBERSORT algorithm and a previously proposed method. Gene set enrichment analysis was used to infer the dysregulated signaling pathways within each subgroup. Of the 31 differentially expressed miRNAs, miR-509-5p (miR-509) was the most significantly prognostic miRNA in the GSE39058 cohort and its high expression was associated with the better OS prognosis (Log-rank P = .008). In the Therapeutically Applicable Research to Generate Effective Treatments validation cohort, the association of high miR-509 expression with favorable survival was also observed (Log-rank P = .014). The results remained still significant even adjusted for clinical confounding factors in multivariate Cox regression models. Further immunology analyses demonstrated that elevated infiltration of lymphocytes, decreased infiltration of immune-suppressive cells, and immune response-related pathways were significantly enriched in patients with miR-509 high expression. Our study suggests that miR-509 may serve as a potential biomarker for evaluating OS prognosis and provides clues for tailoring OS immunotherapy strategies.
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Affiliation(s)
- Jiekun Guo
- Department of Orthopedic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Orthopedic Surgery, Yuebei People’s Hospital, Shantou University, Guangdong, China
| | - Xiang Fang
- Department of Orthopedic Surgery, Yuebei People’s Hospital, Shantou University, Guangdong, China
| | - Jun Zhou
- Department of Orthopedic Surgery, Yuebei People’s Hospital, Shantou University, Guangdong, China
| | - LingGuo Zeng
- Department of Orthopedic Surgery, Yuebei People’s Hospital, Shantou University, Guangdong, China
| | - Bin Yu
- Department of Orthopedic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
- *Correspondence: Bin Yu, Department of Orthopedic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China (e-mail: )
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20
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No Effect on Tumorigenesis in MG63 Cells Induced by Co-Cultured Mesenchymal Stem Cells. JOURNAL OF ONCOLOGY 2022; 2022:4202439. [PMID: 35847369 PMCID: PMC9279036 DOI: 10.1155/2022/4202439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/24/2022] [Accepted: 05/26/2022] [Indexed: 11/27/2022]
Abstract
Osteosarcoma is a kind of bone tumor with an extremely high malignant degree and often occurs in adolescents. Mesenchymal stem cells are believed to play an important role in the microenvironment of osteosarcoma, but whether they promote or inhibit the development of osteosarcoma is controversial. In this study, the coexpression of mesenchymal stem cells (MSCs) with osteosarcoma cell MG63 was used to explore the effect of MSCs on MG63. We found that co-culture of MSCs with MG63 did not affect the proliferation, invasion, and migration of MG63 cells, nor did it significantly affect the epithelial- and glial-mesenchymal transformation of MG63 cells. Therefore, in this study, we obtained a new concept that MSCs neither promote nor inhibit the occurrence and development of osteosarcoma.
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21
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Jimenez IA, Pool RR, Fischetti AJ, Gabrielson K, Canapp SO. Neoplastic transformation of arteriopathy‐derived bone infarct into nascent osteosarcoma in the proximal tibia of a miniature schnauzer. VETERINARY RECORD CASE REPORTS 2022. [DOI: 10.1002/vrc2.293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Isabel A. Jimenez
- Veterinary Orthopedic and Sports Medicine Group Annapolis Junction Maryland USA
- Department of Molecular and Comparative Pathobiology The Johns Hopkins University School of Medicine Baltimore Maryland USA
| | - Roy R. Pool
- Department of Veterinary Pathobiology Texas A&M College of Veterinary Medicine & Biomedical Sciences College Station Texas USA
| | | | - Kathy Gabrielson
- Department of Molecular and Comparative Pathobiology The Johns Hopkins University School of Medicine Baltimore Maryland USA
| | - Sherman O. Canapp
- Veterinary Orthopedic and Sports Medicine Group Annapolis Junction Maryland USA
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22
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Franceschini N, Gaeta R, Krimpenfort P, Briaire-de Bruijn I, Kruisselbrink AB, Szuhai K, Palubeckaitė I, Cleton-Jansen AM, Bovée JVMG. A murine mesenchymal stem cell model for initiating events in osteosarcomagenesis points to CDK4/CDK6 inhibition as a therapeutic target. J Transl Med 2022; 102:391-400. [PMID: 34921235 PMCID: PMC8964417 DOI: 10.1038/s41374-021-00709-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 11/07/2021] [Accepted: 11/19/2021] [Indexed: 12/04/2022] Open
Abstract
Osteosarcoma is a high-grade bone-forming neoplasm, with a complex genome. Tumours frequently show chromothripsis, many deletions, translocations and copy number alterations. Alterations in the p53 or Rb pathway are the most common genetic alterations identified in osteosarcoma. Using spontaneously transformed murine mesenchymal stem cells (MSCs) which formed sarcoma after subcutaneous injection into mice, it was previously demonstrated that p53 is most often involved in the transformation towards sarcomas with complex genomics, including osteosarcoma. In the current study, not only loss of p53 but also loss of p16Ink4a is shown to be a driver of osteosarcomagenesis: murine MSCs with deficient p15Ink4b, p16Ink4a, or p19Arf transform earlier compared to wild-type murine MSCs. Furthermore, in a panel of nine spontaneously transformed murine MSCs, alterations in p15Ink4b, p16Ink4a, or p19Arf were observed in eight out of nine cases. Alterations in the Rb/p16 pathway could indicate that osteosarcoma cells are vulnerable to CDK4/CDK6 inhibitor treatment. Indeed, using two-dimensional (n = 7) and three-dimensional (n = 3) cultures of human osteosarcoma cell lines, it was shown that osteosarcoma cells with defective p16INK4A are sensitive to the CDK4/CDK6 inhibitor palbociclib after 72-hour treatment. A tissue microarray analysis of 109 primary tumour biopsies revealed a subset of patients (20-23%) with intact Rb, but defective p16 or overexpression of CDK4 and/or CDK6. These patients might benefit from CDK4/CDK6 inhibition, therefore our results are promising and might be translated to the clinic.
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Affiliation(s)
- Natasja Franceschini
- grid.10419.3d0000000089452978Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Raffaele Gaeta
- grid.5395.a0000 0004 1757 3729Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Paul Krimpenfort
- grid.430814.a0000 0001 0674 1393Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Inge Briaire-de Bruijn
- grid.10419.3d0000000089452978Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Alwine B. Kruisselbrink
- grid.10419.3d0000000089452978Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Karoly Szuhai
- grid.10419.3d0000000089452978Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
| | - Ieva Palubeckaitė
- grid.10419.3d0000000089452978Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Anne-Marie Cleton-Jansen
- grid.10419.3d0000000089452978Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Judith V. M. G. Bovée
- grid.10419.3d0000000089452978Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
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23
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Brozovich AA, Lenna S, Paradiso F, Serpelloni S, McCulloch P, Weiner B, Yustein JT, Taraballi F. Osteogenesis in the presence of chemotherapy: A biomimetic approach. J Tissue Eng 2022; 13:20417314221138945. [PMID: 36451687 PMCID: PMC9703557 DOI: 10.1177/20417314221138945] [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] [Received: 07/18/2022] [Accepted: 10/29/2022] [Indexed: 07/13/2024] Open
Abstract
Osteosarcoma (OS) is the most common bone tumor in pediatrics. After resection, allografts or metal endoprostheses reconstruct bone voids, and systemic chemotherapy is used to prevent recurrence. This urges the development of novel treatment options for the regeneration of bone after excision. We utilized a previously developed biomimetic, biodegradable magnesium-doped hydroxyapatite/type I collagen composite material (MHA/Coll) to promote bone regeneration in the presence of chemotherapy. We also performed experiments to determine if human mesenchymal stem cells (hMSCs) seeded on MHA/Coll scaffold migrate less toward OS cells, suggesting that hMSCs will not contribute to tumor growth and therefore the potential of oncologic safety in vitro. Also, hMSCs seeded on MHA/Coll had increased expression of osteogenic genes (BGLAP, SPP1, ALP) compared to hMSCs in the 2D condition, even when exposed to chemotherapeutics. This is the first study to demonstrate that a highly osteogenic scaffold can potentially be oncologically safe because hMSCs on MHA/Coll tend to differentiate and lose the ability to migrate toward tumor cells. Therefore, hMSCs on MHA/Coll could potentially be utilized for bone regeneration after OS excision.
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Affiliation(s)
- Ava A Brozovich
- Texas A&M College of Medicine, Bryan, TX, USA
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Orthopedics & Sports Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Stefania Lenna
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Orthopedics & Sports Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Francesca Paradiso
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Orthopedics & Sports Medicine, Houston Methodist Hospital, Houston, TX, USA
- Reproductive Biology and Gynaecological Oncology Group, Swansea University Medical School, Singleton Park, Swansea, UK
| | - Stefano Serpelloni
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Orthopedics & Sports Medicine, Houston Methodist Hospital, Houston, TX, USA
- Politecnico di Milano, Department of Electronics, Informatics, and Bioengineering (DEIB), Milan, Italy
| | - Patrick McCulloch
- Houston Methodist Orthopedics & Sports Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Bradley Weiner
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Orthopedics & Sports Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Jason T Yustein
- Texas Children’s Cancer and Hematology Center and The Faris D. Virani Ewing Sarcoma Center, Baylor College of Medicine, Houston, TX, USA
| | - Francesca Taraballi
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Orthopedics & Sports Medicine, Houston Methodist Hospital, Houston, TX, USA
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24
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Zhang W, Wei L, Weng J, Yu F, Qin H, Wang D, Zeng H. Advances in the Research of Osteosarcoma Stem Cells and its Related Genes. Cell Biol Int 2021; 46:336-343. [PMID: 34941001 DOI: 10.1002/cbin.11752] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 11/29/2021] [Accepted: 12/12/2021] [Indexed: 11/07/2022]
Abstract
Osteosarcoma is a malignant tumor that often occurs in adolescents. There is an urgent need of new treatment options for osteosarcoma due to its poor prognosis after metastasis. Cancer stem cell theory states that cancer stem cells represent a small proportion of cancer cells. These cancer stem cells have self-renewal ability and are closely associated with cancer growth and metastasis as well as chemotherapy resistance. Similarly, osteosarcoma stem cells (OSCs) play an important role in the growth, metastasis, and chemotherapy resistance of osteosarcoma cells. Targeting OSCs may represent a future treatment of osteosarcoma. Furthermore, some genes have shown to regulate the growth, metastasis, and chemotherapy resistance of osteosarcoma cells by altering the stemness of OSCs. Targeting these genes may help in the treatment of osteosarcoma. This review mainly discusses recent advances in the research of OSCs and its related genes. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Weifei Zhang
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Liangchen Wei
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Jian Weng
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Fei Yu
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Haotian Qin
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Deli Wang
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Hui Zeng
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
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25
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LIM Kinases in Osteosarcoma Development. Cells 2021; 10:cells10123542. [PMID: 34944050 PMCID: PMC8699892 DOI: 10.3390/cells10123542] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 12/06/2021] [Accepted: 12/10/2021] [Indexed: 12/17/2022] Open
Abstract
Tumorigenesis is a long-term and multistage process that often leads to the formation of metastases. During this pathological course, two major events appear to be crucial: primary tumour growth and metastatic expansion. In this context, despite research and clinical advances during the past decades, bone cancers remain a leading cause of death worldwide among paediatric cancer patients. Osteosarcomas are the most common malignant bone tumours in children and adolescents. Notwithstanding advances in therapeutic treatments, many patients succumb to these diseases. In particular, less than 30% of patients who demonstrate metastases at diagnosis or are poor responders to chemotherapy survive 5 years after initial diagnosis. LIM kinases (LIMKs), comprising LIMK1 and LIMK2, are common downstream effectors of several signalization pathways, and function as a signalling node that controls cytoskeleton dynamics through the phosphorylation of the cofilin family proteins. In recent decades, several reports have indicated that the functions of LIMKs are mainly implicated in the regulation of actin microfilament and the control of microtubule dynamics. Previous studies have thus identified LIMKs as cancer-promoting regulators in multiple organ cancers, such as breast cancer or prostate cancer. This review updates the current understanding of LIMK involvement in osteosarcoma progression.
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26
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Xu C, Wang M, Zandieh-Doulabi B, Sun W, Wei L, Liu Y. To B (Bone Morphogenic Protein-2) or Not to B (Bone Morphogenic Protein-2): Mesenchymal Stem Cells May Explain the Protein's Role in Osteosarcomagenesis. Front Cell Dev Biol 2021; 9:740783. [PMID: 34869325 PMCID: PMC8635864 DOI: 10.3389/fcell.2021.740783] [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: 07/13/2021] [Accepted: 10/11/2021] [Indexed: 12/14/2022] Open
Abstract
Osteosarcoma (OS), a primary malignant bone tumor, stems from bone marrow-derived mesenchymal stem cells (BMSCs) and/or committed osteoblast precursors. Distant metastases, in particular pulmonary and skeletal metastases, are common in patients with OS. Moreover, extensive resection of the primary tumor and bone metastases usually leads to bone defects in these patients. Bone morphogenic protein-2 (BMP-2) has been widely applied in bone regeneration with the rationale that BMP-2 promotes osteoblastic differentiation of BMSCs. Thus, BMP-2 might be useful after OS resection to repair bone defects. However, the potential tumorigenicity of BMP-2 remains a concern that has impeded the administration of BMP-2 in patients with OS and in populations susceptible to OS with severe bone deficiency (e.g., in patients with genetic mutation diseases and aberrant activities of bone metabolism). In fact, some studies have drawn the opposite conclusion about the effect of BMP-2 on OS progression. Given the roles of BMSCs in the origination of OS and osteogenesis, we hypothesized that the responses of BMSCs to BMP-2 in the tumor milieu may be responsible for OS development. This review focuses on the relationship among BMSCs, BMP-2, and OS cells; a better understanding of this relationship may elucidate the accurate mechanisms of actions of BMP-2 in osteosarcomagenesis and thereby pave the way for clinically safer and broader administration of BMP-2 in the future. For example, a low dosage of and a slow-release delivery strategy for BMP-2 are potential topics for exploration to treat OS.
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Affiliation(s)
- Chunfeng Xu
- Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Mingjie Wang
- Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Behrouz Zandieh-Doulabi
- Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Wei Sun
- Department of Mechanical Engineering, Drexel University, Philadelphia, PA, United States.,Department of Mechanical Engineering, Tsinghua University, Beijing, China
| | - Lingfei Wei
- Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands.,Department of Oral Implantology, Yantai Stomatological Hospital, Yantai, China
| | - Yuelian Liu
- Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands
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27
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Qi J, Zhang R, Wang Y. Exosomal miR-21-5p derived from bone marrow mesenchymal stem cells promote osteosarcoma cell proliferation and invasion by targeting PIK3R1. J Cell Mol Med 2021; 25:11016-11030. [PMID: 34741385 PMCID: PMC8642676 DOI: 10.1111/jcmm.17024] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 10/06/2021] [Accepted: 10/14/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are a class of pluripotent cells that can release a large number of exosomes which act as paracrine mediators in tumour-associated microenvironment. However, the role of MSC-derived exosomes in pathogenesis and progression of cancer cells especially osteosarcoma has not been thoroughly clarified until now. In this study, we established a co-culture model for human bone marrow-derived MSCs with osteosarcoma cells, then extraction of exosomes from induced MSCs and study the role of MSC-derived exosomes in the progression of osteosarcoma cell. The aim of this study was to address potential cell biological effects between MSCs and osteosarcoma cells. The results showed that MSC-derived exosomes can significantly promote osteosarcoma cells' proliferation and invasion. We also found that miR-21-5p was significantly over-expressed in MSCs and MSC-derived exosomes by quantitative real-time polymerase chain reaction (qRT-PCR), compared with human foetal osteoblastic cells hFOB1.19. MSC-derived exosomes transfected with miR-21-5p could significantly enhance the proliferation and invasion of osteosarcoma cells in vitro and in vivo. Bioinformatics analysis and dual-luciferase reporter gene assays validated the targeted relationship between exosomal miR-21-5p and PIK3R1; we further demonstrated that miR-21-5p-abundant exosomes derived human bone marrow MSCs could activate PI3K/Akt/mTOR pathway by suppressing PIK3R1 expression in osteosarcoma cells. In summary, our study provides new insights into the interaction between human bone marrow MSCs and osteosarcoma cells in tumour-associated microenvironment.
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Affiliation(s)
- Jin Qi
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, People's Republic of China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, People's Republic of China
| | - Ruihao Zhang
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, People's Republic of China
| | - Yapeng Wang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, People's Republic of China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, People's Republic of China
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28
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Ban J, Fock V, Aryee DNT, Kovar H. Mechanisms, Diagnosis and Treatment of Bone Metastases. Cells 2021; 10:2944. [PMID: 34831167 PMCID: PMC8616226 DOI: 10.3390/cells10112944] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/22/2021] [Accepted: 10/27/2021] [Indexed: 12/24/2022] Open
Abstract
Bone and bone marrow are among the most frequent metastatic sites of cancer. The occurrence of bone metastasis is frequently associated with a dismal disease outcome. The prevention and therapy of bone metastases is a priority in the treatment of cancer patients. However, current therapeutic options for patients with bone metastatic disease are limited in efficacy and associated with increased morbidity. Therefore, most current therapies are mainly palliative in nature. A better understanding of the underlying molecular pathways of the bone metastatic process is warranted to develop novel, well-tolerated and more successful treatments for a significant improvement of patients' quality of life and disease outcome. In this review, we provide comparative mechanistic insights into the bone metastatic process of various solid tumors, including pediatric cancers. We also highlight current and innovative approaches to biologically targeted therapy and immunotherapy. In particular, we discuss the role of the bone marrow microenvironment in the attraction, homing, dormancy and outgrowth of metastatic tumor cells and the ensuing therapeutic implications. Multiple signaling pathways have been described to contribute to metastatic spread to the bone of specific cancer entities, with most knowledge derived from the study of breast and prostate cancer. However, it is likely that similar mechanisms are involved in different types of cancer, including multiple myeloma, primary bone sarcomas and neuroblastoma. The metastatic rate-limiting interaction of tumor cells with the various cellular and noncellular components of the bone-marrow niche provides attractive therapeutic targets, which are already partially exploited by novel promising immunotherapies.
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Affiliation(s)
- Jozef Ban
- St. Anna Children’s Cancer Research Institute, 1090 Vienna, Austria; (J.B.); (V.F.); (D.N.T.A.)
| | - Valerie Fock
- St. Anna Children’s Cancer Research Institute, 1090 Vienna, Austria; (J.B.); (V.F.); (D.N.T.A.)
| | - Dave N. T. Aryee
- St. Anna Children’s Cancer Research Institute, 1090 Vienna, Austria; (J.B.); (V.F.); (D.N.T.A.)
- Department of Pediatrics, Medical University Vienna, 1090 Vienna, Austria
| | - Heinrich Kovar
- St. Anna Children’s Cancer Research Institute, 1090 Vienna, Austria; (J.B.); (V.F.); (D.N.T.A.)
- Department of Pediatrics, Medical University Vienna, 1090 Vienna, Austria
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29
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Xu A, Qian C, Lin J, Yu W, Jin J, Liu B, Tao H. Cell Differentiation Trajectory-Associated Molecular Classification of Osteosarcoma. Genes (Basel) 2021; 12:genes12111685. [PMID: 34828292 PMCID: PMC8625454 DOI: 10.3390/genes12111685] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/19/2021] [Accepted: 10/21/2021] [Indexed: 01/01/2023] Open
Abstract
This study aims to investigate the differentiation trajectory of osteosarcoma cells and to construct molecular subtypes with their respective characteristics and generate a multi-gene signature for predicting prognosis. Integrated single-cell RNA-sequencing (scRNA-seq) data, bulk RNA-seq data and microarray data from osteosarcoma samples were used for analysis. Via scRNA-seq data, time-related as well as differentiation-related genes were recognized as osteosarcoma tumor stem cell-related genes (OSCGs). In Gene Expression Omnibus (GEO) cohort, osteosarcoma patients were classified into two subtypes based on prognostic OSCGs and it was found that molecular typing successfully predicted overall survival, tumor microenvironment and immune infiltration status. Further, available drugs for influencing osteosarcoma via prognostic OSCGs were revealed. A 3-OSCG-based prognostic risk score signature was generated and by combining other clinic-pathological independent prognostic factor, stage at diagnosis, a nomogram was established to predict individual survival probability. In external independent TARGET cohort, the molecular types, the 3-gene signature as well as nomogram were validated. In conclusion, osteosarcoma cell differentiation occupies a crucial position in many facets, such as tumor prognosis and microenvironment, suggesting promising therapeutic targets for this disease.
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Affiliation(s)
- Ankai Xu
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88, Jiefang Road, Hangzhou 310009, China; (A.X.); (C.Q.); (J.L.); (W.Y.); (J.J.); (B.L.)
- Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Chao Qian
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88, Jiefang Road, Hangzhou 310009, China; (A.X.); (C.Q.); (J.L.); (W.Y.); (J.J.); (B.L.)
- Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Jinti Lin
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88, Jiefang Road, Hangzhou 310009, China; (A.X.); (C.Q.); (J.L.); (W.Y.); (J.J.); (B.L.)
- Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Wei Yu
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88, Jiefang Road, Hangzhou 310009, China; (A.X.); (C.Q.); (J.L.); (W.Y.); (J.J.); (B.L.)
- Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Jiakang Jin
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88, Jiefang Road, Hangzhou 310009, China; (A.X.); (C.Q.); (J.L.); (W.Y.); (J.J.); (B.L.)
- Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Bing Liu
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88, Jiefang Road, Hangzhou 310009, China; (A.X.); (C.Q.); (J.L.); (W.Y.); (J.J.); (B.L.)
- Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Huimin Tao
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88, Jiefang Road, Hangzhou 310009, China; (A.X.); (C.Q.); (J.L.); (W.Y.); (J.J.); (B.L.)
- Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
- Correspondence:
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30
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Mullard M, Lavaud M, Regnier L, Tesfaye R, Ory B, Rédini F, Verrecchia F. Ubiquitin-specific proteases as therapeutic targets in paediatric primary bone tumours? Biochem Pharmacol 2021; 194:114797. [PMID: 34678225 DOI: 10.1016/j.bcp.2021.114797] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/08/2021] [Accepted: 10/11/2021] [Indexed: 01/04/2023]
Abstract
In children and young adults, primary malignant bone tumours are mainly composed of osteosarcoma and Ewing's sarcoma. Despite advances in treatments, nearly 40% of patients succumb to these diseases. In particular, the clinical outcome of metastatic osteosarcoma or Ewing's sarcoma remains poor, with less than 30% of patients who develop metastases surviving five years after initial diagnosis. Over the last decade, the cancer research community has shown considerable interest in the processes of protein ubiquitination and deubiquitination. In particular, a growing number of studies show the relevance to target the ubiquitin-specific protease (USP) family in various cancers. This review provides an update on the current knowledge regarding the implication of these USPs in the progression of bone sarcoma: osteosarcoma and Ewing's sarcoma.
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Affiliation(s)
- Mathilde Mullard
- INSERM, Université de Nantes, UMR1238, "Bone Sarcoma and Remodelling of Calcified Tissues", 44000 Nantes, France
| | - Mélanie Lavaud
- INSERM, Université de Nantes, UMR1238, "Bone Sarcoma and Remodelling of Calcified Tissues", 44000 Nantes, France
| | - Laura Regnier
- INSERM, Université de Nantes, UMR1238, "Bone Sarcoma and Remodelling of Calcified Tissues", 44000 Nantes, France
| | - Robel Tesfaye
- INSERM, Université de Nantes, UMR1238, "Bone Sarcoma and Remodelling of Calcified Tissues", 44000 Nantes, France
| | - Benjamin Ory
- INSERM, Université de Nantes, UMR1238, "Bone Sarcoma and Remodelling of Calcified Tissues", 44000 Nantes, France
| | - Françoise Rédini
- INSERM, Université de Nantes, UMR1238, "Bone Sarcoma and Remodelling of Calcified Tissues", 44000 Nantes, France
| | - Franck Verrecchia
- INSERM, Université de Nantes, UMR1238, "Bone Sarcoma and Remodelling of Calcified Tissues", 44000 Nantes, France.
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31
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Wang JY, Chen CM, Chen CF, Wu PK, Chen WM. Suppression of Estrogen Receptor Alpha Inhibits Cell Proliferation, Differentiation and Enhances the Chemosensitivity of P53-Positive U2OS Osteosarcoma Cell. Int J Mol Sci 2021; 22:ijms222011238. [PMID: 34681897 PMCID: PMC8540067 DOI: 10.3390/ijms222011238] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/24/2021] [Accepted: 10/15/2021] [Indexed: 11/26/2022] Open
Abstract
Osteosarcoma is a highly malignant musculoskeletal tumor that is commonly noticed in adolescent children, young children, and elderly adults. Due to advances in surgery, chemotherapy and imaging technology, survival rates have improved to 70–80%, but chemical treatments do not enhance patient survival; in addition, the survival rate after chemical treatments is still low. The most obvious clinical feature of osteosarcoma is new bone formation, which is called “sun burst”. Estrogen receptor alpha (ERα) is an essential feature of osteogenesis and regulates cell growth in various tumors, including osteosarcoma. In this study, we sought to investigate the role of ERα in osteosarcoma and to determine if ERα can be used as a target to facilitate the chemosensitivity of osteosarcoma to current treatments. The growth rate of each cell clone was assayed by MTT and trypan blue cell counting, and cell cycle analysis was conducted by flow cytometry. Osteogenic differentiation was induced by osteogenic induction medium and quantified by ARS staining. The effects of ERα on the chemoresponse of OS cells treated with doxorubicin were evaluated by colony formation assay. Mechanistic studies were conducted by examining the levels of proteins by Western blot. The role of ERα on OS prognosis was investigated by an immunohistochemical analysis of OS tissue array. The results showed an impaired growth rate and a decreased osteogenesis ability in the ERα-silenced P53(+) OS cell line U2OS, but not in P53(−) SAOS2 cells, compared with the parental cell line. Cotreatment with tamoxifen, an estrogen receptor inhibitor, increased the sensitivity to doxorubicin, which decreased the colony formation of P53(+) U2OS cells. Cell cycle arrest in the S phase was observed in P53(+) U2OS cells cotreated with low doses of doxorubicin and tamoxifen, while increased levels of apoptosis factors indicated cell death. Moreover, patients with ER−/P53(+) U2OS showed better chemoresponse rates (necrosis rate > 90%) and impaired tumor sizes, which were compatible with the findings of basic research. Taken together, ERα may be a potential target of the current treatments for osteosarcoma that can control tumor growth and improve chemosensitivity. In addition, the expression of ERα in osteosarcoma can be a prognostic factor to predict the response to chemotherapy.
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Affiliation(s)
- Jir-You Wang
- Department of Orthopaedics, Taipei Veterans General Hospital, Taipei City 112, Taiwan; (J.-Y.W.); (C.-M.C.); (C.-F.C.); (W.-M.C.)
- Department of Orthopaedics, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei City 112, Taiwan
- Institute of Traditional Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Chao-Ming Chen
- Department of Orthopaedics, Taipei Veterans General Hospital, Taipei City 112, Taiwan; (J.-Y.W.); (C.-M.C.); (C.-F.C.); (W.-M.C.)
- Department of Orthopaedics, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei City 112, Taiwan
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Cheng-Fong Chen
- Department of Orthopaedics, Taipei Veterans General Hospital, Taipei City 112, Taiwan; (J.-Y.W.); (C.-M.C.); (C.-F.C.); (W.-M.C.)
- Department of Orthopaedics, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei City 112, Taiwan
| | - Po-Kuei Wu
- Department of Orthopaedics, Taipei Veterans General Hospital, Taipei City 112, Taiwan; (J.-Y.W.); (C.-M.C.); (C.-F.C.); (W.-M.C.)
- Department of Orthopaedics, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei City 112, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Correspondence:
| | - Wei-Ming Chen
- Department of Orthopaedics, Taipei Veterans General Hospital, Taipei City 112, Taiwan; (J.-Y.W.); (C.-M.C.); (C.-F.C.); (W.-M.C.)
- Department of Orthopaedics, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei City 112, Taiwan
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Giordano F, Lenna S, Rampado R, Brozovich A, Hirase T, Tognon MG, Martini F, Agostini M, Yustein JT, Taraballi F. Nanodelivery Systems Face Challenges and Limitations in Bone Diseases Management. ADVANCED THERAPEUTICS 2021. [DOI: 10.1002/adtp.202100152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Federica Giordano
- Center for Musculoskeletal Regeneration Houston Methodist Academic Institute, Houston Methodist 6670 Bertner Ave Houston TX 77030 USA
- Orthopedics and Sports Medicine Houston Methodist Hospital Houston Methodist, 6565 Fannin Street Houston TX 77030 USA
| | - Stefania Lenna
- Center for Musculoskeletal Regeneration Houston Methodist Academic Institute, Houston Methodist 6670 Bertner Ave Houston TX 77030 USA
- Orthopedics and Sports Medicine Houston Methodist Hospital Houston Methodist, 6565 Fannin Street Houston TX 77030 USA
| | - Riccardo Rampado
- Center for Musculoskeletal Regeneration Houston Methodist Academic Institute, Houston Methodist 6670 Bertner Ave Houston TX 77030 USA
- Orthopedics and Sports Medicine Houston Methodist Hospital Houston Methodist, 6565 Fannin Street Houston TX 77030 USA
- First Surgical Clinic Section, Department of Surgical Oncological and Gastroenterological Sciences, University of Padua Padua 35124 Italy
- Nano‐Inspired Biomedicine Laboratory Institute of Pediatric Research—Città della Speranza Padua Italy
| | - Ava Brozovich
- Center for Musculoskeletal Regeneration Houston Methodist Academic Institute, Houston Methodist 6670 Bertner Ave Houston TX 77030 USA
- Orthopedics and Sports Medicine Houston Methodist Hospital Houston Methodist, 6565 Fannin Street Houston TX 77030 USA
- Texas A&M College of Medicine 8447 Highway 47 Bryan TX 77807 USA
| | - Takashi Hirase
- Center for Musculoskeletal Regeneration Houston Methodist Academic Institute, Houston Methodist 6670 Bertner Ave Houston TX 77030 USA
- Orthopedics and Sports Medicine Houston Methodist Hospital Houston Methodist, 6565 Fannin Street Houston TX 77030 USA
| | - Mauro G. Tognon
- Section of Experimental Medicine, Department of Medical Sciences, School of Medicine University of Ferrara Ferrara Italy
| | - Fernanda Martini
- Section of Experimental Medicine, Department of Medical Sciences, School of Medicine University of Ferrara Ferrara Italy
| | - Marco Agostini
- First Surgical Clinic Section, Department of Surgical Oncological and Gastroenterological Sciences, University of Padua Padua 35124 Italy
- Nano‐Inspired Biomedicine Laboratory Institute of Pediatric Research—Città della Speranza Padua Italy
| | - Jason T. Yustein
- Texas Children's Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center Baylor College of Medicine Houston TX 77030 USA
| | - Francesca Taraballi
- Center for Musculoskeletal Regeneration Houston Methodist Academic Institute, Houston Methodist 6670 Bertner Ave Houston TX 77030 USA
- Orthopedics and Sports Medicine Houston Methodist Hospital Houston Methodist, 6565 Fannin Street Houston TX 77030 USA
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Sarhadi VK, Daddali R, Seppänen-Kaijansinkko R. Mesenchymal Stem Cells and Extracellular Vesicles in Osteosarcoma Pathogenesis and Therapy. Int J Mol Sci 2021; 22:11035. [PMID: 34681692 PMCID: PMC8537935 DOI: 10.3390/ijms222011035] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/01/2021] [Accepted: 10/09/2021] [Indexed: 12/29/2022] Open
Abstract
Osteosarcoma (OS) is an aggressive bone tumor that mainly affects children and adolescents. OS has a strong tendency to relapse and metastasize, resulting in poor prognosis and survival. The high heterogeneity and genetic complexity of OS make it challenging to identify new therapeutic targets. Mesenchymal stem cells (MSCs) are multipotent stem cells that can differentiate into adipocytes, osteoblasts, or chondroblasts. OS is thought to originate at some stage in the differentiation process of MSC to pre-osteoblast or from osteoblast precursors. MSCs contribute to OS progression by interacting with tumor cells via paracrine signaling and affect tumor cell proliferation, invasion, angiogenesis, immune response, and metastasis. Extracellular vesicles (EVs), secreted by OS cells and MSCs in the tumor microenvironment, are crucial mediators of intercellular communication, driving OS progression by transferring miRNAs/RNA and proteins to other cells. MSC-derived EVs have both pro-tumor and anti-tumor effects on OS progression. MSC-EVs can be also engineered to deliver anti-tumor cargo to the tumor site, which offers potential applications in MSC-EV-based OS treatment. In this review, we highlight the role of MSCs in OS, with a focus on EV-mediated communication between OS cells and MSCs and their role in OS pathogenesis and therapy.
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Chang X, Ma Z, Zhu G, Lu Y, Yang J. New perspective into mesenchymal stem cells: Molecular mechanisms regulating osteosarcoma. J Bone Oncol 2021; 29:100372. [PMID: 34258182 PMCID: PMC8254115 DOI: 10.1016/j.jbo.2021.100372] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/14/2021] [Accepted: 06/02/2021] [Indexed: 02/05/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells with significant potential for regenerative medicine. The tumorigenesis of osteosarcoma is an intricate system and MSCs act as an indispensable part of this, interacting with the tumor microenvironment (TME) during the process. MSCs link to cells by acting on each component in the TME via autocrine or paracrine extracellular vesicles for cellular communication. Because of their unique characteristics, MSCs can be modified and processed into good biological carriers, loaded with drugs, and transfected with anticancer genes for the targeted treatment of osteosarcoma. Previous high-quality reviews have described the biological characteristics of MSCs; this review will discuss the effects of MSCs on the components of the TME and cellular communication and the prospects for clinical applications of MSCs.
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Key Words
- 3TSR, Three type 1 repeats
- 5 FC, 5-fluorocytosine
- AD-MSCs, Adipose-derived MSCs
- AQP1, Aquaporin-1
- BMSC-derived exosomes, BMSC-Exos
- BMSCs, Bone marrow mesenchymal stem cells
- CAFs, Carcinoma-associated-fibroblasts
- CRC, Colorectal cancer
- CSF, Colony-stimulating factor
- Cellular communication
- Clinical application
- DOX, Doxorubicin
- DP-MSCs, Dental pulp-derived MSCs, hUC-MSCs, Human umbilical cord MSCs
- ECM, Extracellular matrix
- ESCs, embryonic stem cells
- EVs, Extracellular vesicles
- GBM, Glioblastoma
- HCC, hepatocellular carcinoma
- LINE-1, Long interspersing element 1
- MCP-1, Monocyte chemoattractant protein-1
- MSC-Exos, MSC-derived exosomes
- MSC-MVs, MSC microvesicles
- MSCs
- MSCs, Mesenchymal stem cells
- OPG, osteoprotegerin
- OS, osteosarcoma
- Osteosarcoma
- PDGFRα, Platelet derived growth factor receptor α
- PDGFRβ, Platelet derived growth factor receptor β
- PDGFα, Platelet derived growth factor α
- S TRAIL, Secretable variant of the TNF-related apoptosis-inducing ligand
- SD-MSCs, stressed MSCs
- SDF-1, Stromal cell-derived factor 1
- TGF, Transforming growth factor
- TME
- TME, Tumor microenvironment
- TNF, Tumor necrosis factor
- TRA2B, Transformer 2β
- VEGF, Vascular endothelial growth factor
- hASCs, human adipose stem cells
- iPSCs, induced pluripotent stem cells
- yCD::UPRT, Yeast cytosine deaminase::uracil phosphoribosyl transferase
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Affiliation(s)
- Xingyu Chang
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Zhanjun Ma
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Guomao Zhu
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Yubao Lu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Jingjing Yang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730000, China
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35
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Metwally AM, Li H, Houghton JM. Alterations of epigenetic regulators and P53 mutations in murine mesenchymal stem cell cultures: A possible mechanism of spontaneous transformation. Cancer Biomark 2021; 32:327-337. [PMID: 34151835 DOI: 10.3233/cbm-203121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Recent studies demonstrated the involvement of mesenchymal stem/stromal cells (MSCs) in carcinogenesis, but the molecular mechanism behind this transformation is still obscured. OBJECTIVE To screen both the expression levels of polycomb and trithorax epigenetic regulators and TrP53 mutations in early and late MSC culture passages in an attempt to decipher the mechanism of spontaneous transformation. METHODS The study was conducted on early and late passages of MSC culture model from C57BL/6J mice. The expression profile of 84 epigenetic regulators was examined using RT2 profiler PCR array. TrP53 mutations in the DNA binding domain was screened. Codons, amino acids positions and the corresponding human variants were detected in P53 sequences. RESULTS Sixty-two epigenetic regulators were dysregulated. Abnormalities were detected starting the third passage. Nine regulators were dysregulated in all passages. (C>G) substitution P53 mutation was detected in passage 3 resulting in Ser152Arg substitution. Passages 6, 9, 12 and the last passage showed T>C substitution resulting in Cys235Arg substitution. The last passage had T deletion and A insertion resulting in frame shift mutations changing the p.Phe286Ser and p.Asn103Lys respectively. CONCLUSION In vitro expanded MSCs undergo transformation through alteration of epigenetic regulators which results in genomic instability and frequent P53 mutations.
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Affiliation(s)
- Ayman Mohamed Metwally
- Technology of Medical Laboratory Department, College of Applied Health Science Technology, Misr University for Science and Technology, Egypt.,Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Hanchen Li
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Jean Marie Houghton
- Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
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36
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Kovac M, Ameline B, Ribi S, Kovacova M, Cross W, Barenboim M, Witt O, Bielack S, Krieg A, Hartmann W, Nathrath M, Baumhoer D. The early evolutionary landscape of osteosarcoma provides clues for targeted treatment strategies. J Pathol 2021; 254:556-566. [PMID: 33963544 PMCID: PMC8361660 DOI: 10.1002/path.5699] [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: 12/17/2020] [Revised: 04/12/2021] [Accepted: 05/04/2021] [Indexed: 12/26/2022]
Abstract
Osteosarcomas are aggressive primary tumors of bone that are typically detected in locally advanced stages; however, which genetic mutations drive the cancer before its clinical detection remain unknown. To identify these events, we performed longitudinal genome-sequencing analysis of 12 patients with metastatic or refractory osteosarcoma. Phylogenetic and molecular clock analyses were carried out next to identify actionable mutations, and these were validated by integrating data from additional 153 osteosarcomas and pre-existing functional evidence from mouse PDX models. We found that the earliest and thus clinically most promising mutations affect the cell cycle G1 transition, which is guarded by cyclins D3, E1, and cyclin-dependent kinases 2, 4, and 6. Cell cycle G1 alterations originate no more than a year before the primary tumor is clinically detected and occur in >90% and 50% of patients of the discovery and validation cohorts, respectively. In comparison, other cancer driver mutations could be acquired at any evolutionary stage and often do not become pervasive. Consequently, our data support that the repertoire of actionable mutations present in every osteosarcoma cell is largely limited to cell cycle G1 mutations. Since they occur in mutually exclusive combinations favoring either CDK2 or CDK4/6 pathway activation, we propose a new genomically-based algorithm to direct patients to correct clinical trial options. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Michal Kovac
- Bone Tumor Reference Centre, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.,Faculty of Informatics and Information Technologies, Slovak University of Technology, Bratislava, Slovakia
| | - Baptiste Ameline
- Bone Tumor Reference Centre, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Sebastian Ribi
- Bone Tumor Reference Centre, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Monika Kovacova
- Faculty of Informatics and Information Technologies, Slovak University of Technology, Bratislava, Slovakia
| | - William Cross
- Evolution and Cancer Laboratory, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Barbican, London, UK
| | - Maxim Barenboim
- Department of Pediatrics and Children's Cancer Research Center, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Olaf Witt
- Hopp Children's Cancer Center Heidelberg, German Cancer Research Center and University Hospital Heidelberg, Heidelberg, Germany
| | - Stefan Bielack
- Klinikum Stuttgart - Olgahospital, Stuttgart Cancer Center, Stuttgart, Germany
| | - Andreas Krieg
- Paediatric Orthopaedic Department, University Children's Hospital Basel, Basel, Switzerland
| | - Wolfgang Hartmann
- Division of Translational Pathology, Gerhard-Domagk-Institut of Pathology, University Hospital Münster, Münster, Germany
| | | | - Daniel Baumhoer
- Bone Tumor Reference Centre, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
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Kannan S, Lock I, Ozenberger BB, Jones KB. Genetic drivers and cells of origin in sarcomagenesis. J Pathol 2021; 254:474-493. [DOI: 10.1002/path.5617] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 12/01/2020] [Accepted: 01/06/2021] [Indexed: 02/06/2023]
Affiliation(s)
- Sarmishta Kannan
- Departments of Orthopaedics and Oncological Sciences Huntsman Cancer Institute, University of Utah School of Medicine Salt Lake City UT USA
| | - Ian Lock
- Departments of Orthopaedics and Oncological Sciences Huntsman Cancer Institute, University of Utah School of Medicine Salt Lake City UT USA
| | - Benjamin B Ozenberger
- Departments of Orthopaedics and Oncological Sciences Huntsman Cancer Institute, University of Utah School of Medicine Salt Lake City UT USA
| | - Kevin B Jones
- Departments of Orthopaedics and Oncological Sciences Huntsman Cancer Institute, University of Utah School of Medicine Salt Lake City UT USA
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38
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Al-Khan AA, Al Balushi NR, Richardson SJ, Danks JA. Roles of Parathyroid Hormone-Related Protein (PTHrP) and Its Receptor (PTHR1) in Normal and Tumor Tissues: Focus on Their Roles in Osteosarcoma. Front Vet Sci 2021; 8:637614. [PMID: 33796580 PMCID: PMC8008073 DOI: 10.3389/fvets.2021.637614] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 02/17/2021] [Indexed: 12/17/2022] Open
Abstract
Osteosarcoma (OS) is the most common primary bone tumor and originates from bone forming mesenchymal cells and primarily affects children and adolescents. The 5-year survival rate for OS is 60 to 65%, with little improvement in prognosis during the last four decades. Studies have demonstrated the evolving roles of parathyroid hormone-related protein (PTHrP) and its receptor (PTHR1) in bone formation, bone remodeling, regulation of calcium transport from blood to milk, regulation of maternal calcium transport to the fetus and reabsorption of calcium in kidneys. These two molecules also play critical roles in the development, progression and metastasis of several tumors such as breast cancer, lung carcinoma, chondrosarcoma, squamous cell carcinoma, melanoma and OS. The protein expression of both PTHrP and PTHR1 have been demonstrated in OS, and their functions and proposed signaling pathways have been investigated yet their roles in OS have not been fully elucidated. This review aims to discuss the latest research with PTHrP and PTHR1 in OS tumorigenesis and possible mechanistic pathways. This review is dedicated to Professor Michael Day who died in May 2020 and was a very generous collaborator.
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Affiliation(s)
- Awf A Al-Khan
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia.,Department of Pathology, Sohar Hospital, Sohar, Oman
| | - Noora R Al Balushi
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia
| | - Samantha J Richardson
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia.,School of Science, RMIT University, Bundoora, VIC, Australia
| | - Janine A Danks
- School of Science, RMIT University, Bundoora, VIC, Australia.,The University of Melbourne, Department of Medicine, Austin Health, Heidelberg, VIC, Australia
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39
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Franceschini N, Verbruggen B, Tryfonidou MA, Kruisselbrink AB, Baelde H, de Visser KE, Szuhai K, Cleton-Jansen AM, Bovée JVMG. Transformed Canine and Murine Mesenchymal Stem Cells as a Model for Sarcoma with Complex Genomics. Cancers (Basel) 2021; 13:cancers13051126. [PMID: 33807947 PMCID: PMC7961539 DOI: 10.3390/cancers13051126] [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: 01/27/2021] [Revised: 02/23/2021] [Accepted: 02/28/2021] [Indexed: 12/21/2022] Open
Abstract
Simple Summary Sarcomas are rare cancers of mesenchymal origin, the majority of which are characterized by many copy number alterations, amplifications, or deletions. Because of these complex genomics, it is notoriously difficult to identify driver events of malignant transformation. In this study, we show that murine and canine mesenchymal stem cells (MSCs) can be used to model spontaneous malignant transformation towards sarcomas with complex genomics. We show that these MSCs have an abnormal karyotype, many structural variants, and point mutations at whole genome sequencing analysis, and form sarcomas after injection into mice. Our cross-species analysis reveals that p53 loss is an early event in sarcomagenesis, and it was shown that MSCs with a knock-out in Trp53 transform earlier compared to wild-type MSCs. Our study points to the importance of p53 loss in the transformation process towards sarcomas with complex genomics. Abstract Sarcomas are rare mesenchymal tumors with a broad histological spectrum, but they can be divided into two groups based on molecular pathology: sarcomas with simple or complex genomics. Tumors with complex genomics can have aneuploidy and copy number gains and losses, which hampers the detection of early, initiating events in tumorigenesis. Often, no benign precursors are known, which is why good models are essential. The mesenchymal stem cell (MSC) is the presumed cell of origin of sarcoma. In this study, MSCs of murine and canine origin are used as a model to identify driver events for sarcomas with complex genomic alterations as they transform spontaneously after long-term culture. All transformed murine but not canine MSCs formed sarcomas after subcutaneous injection in mice. Using whole genome sequencing, spontaneously transformed murine and canine MSCs displayed a complex karyotype with aneuploidy, point mutations, structural variants, inter-chromosomal translocations, and copy number gains and losses. Cross-species analysis revealed that point mutations in Tp53/Trp53 are common in transformed murine and canine MSCs. Murine MSCs with a cre-recombinase induced deletion of exon 2–10 of Trp53 transformed earlier compared to wild-type murine MSCs, confirming the contribution of loss of p53 to spontaneous transformation. Our comparative approach using transformed murine and canine MSCs points to a crucial role for p53 loss in the formation of sarcomas with complex genomics.
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Affiliation(s)
- Natasja Franceschini
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (N.F.); (B.V.); (A.B.K.); (H.B.); (A.-M.C.-J.)
| | - Bas Verbruggen
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (N.F.); (B.V.); (A.B.K.); (H.B.); (A.-M.C.-J.)
| | - Marianna A. Tryfonidou
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands;
| | - Alwine B. Kruisselbrink
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (N.F.); (B.V.); (A.B.K.); (H.B.); (A.-M.C.-J.)
| | - Hans Baelde
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (N.F.); (B.V.); (A.B.K.); (H.B.); (A.-M.C.-J.)
| | - Karin E. de Visser
- Division of Tumour Biology & Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;
- Oncode Institute, Office Jaarbeurs Innovation Mile (JIM), Jaarbeursplein 6, 3521 AL Utrecht, The Netherlands
| | - Karoly Szuhai
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
| | - Anne-Marie Cleton-Jansen
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (N.F.); (B.V.); (A.B.K.); (H.B.); (A.-M.C.-J.)
| | - Judith V. M. G. Bovée
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (N.F.); (B.V.); (A.B.K.); (H.B.); (A.-M.C.-J.)
- Correspondence: ; Tel.: +31-715266622
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40
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Chu S, Skidmore ZL, Kunisaki J, Walker JR, Griffith M, Griffith OL, Bryan JN. Unraveling the chaotic genomic landscape of primary and metastatic canine appendicular osteosarcoma with current sequencing technologies and bioinformatic approaches. PLoS One 2021; 16:e0246443. [PMID: 33556121 PMCID: PMC7870011 DOI: 10.1371/journal.pone.0246443] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 01/19/2021] [Indexed: 12/03/2022] Open
Abstract
Osteosarcoma is a rare disease in children but is one of the most common cancers in adult large breed dogs. The mutational landscape of both the primary and pulmonary metastatic tumor in two dogs with appendicular osteosarcoma (OSA) was comprehensively evaluated using an automated whole genome sequencing, exome and RNA-seq pipeline that was adapted for this study for use in dogs. Chromosomal lesions were the most common type of mutation. The mutational landscape varied substantially between dogs but the lesions within the same patient were similar. Copy number neutral loss of heterozygosity in mutant TP53 was the most significant driver mutation and involved a large region in the middle of chromosome 5. Canine and human OSA is characterized by loss of cell cycle checkpoint integrity and DNA damage response pathways. Mutational profiling of individual patients with canine OSA would be recommended prior to targeted therapy, given the heterogeneity seen in our study and previous studies.
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Affiliation(s)
- Shirley Chu
- Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO, United States of America
- * E-mail:
| | - Zachary L. Skidmore
- McDonnell Genome Institute, Washington University, St. Louis, MO, United States of America
| | - Jason Kunisaki
- McDonnell Genome Institute, Washington University, St. Louis, MO, United States of America
| | - Jason R. Walker
- McDonnell Genome Institute, Washington University, St. Louis, MO, United States of America
| | - Malachi Griffith
- McDonnell Genome Institute, Washington University, St. Louis, MO, United States of America
- Department of Medicine, Washington University, St. Louis, MO, United States of America
| | - Obi L. Griffith
- McDonnell Genome Institute, Washington University, St. Louis, MO, United States of America
- Department of Medicine, Washington University, St. Louis, MO, United States of America
| | - Jeffrey N. Bryan
- Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO, United States of America
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41
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Bertin H, Gomez-Brouchet A, Rédini F. Osteosarcoma of the jaws: An overview of the pathophysiological mechanisms. Crit Rev Oncol Hematol 2020; 156:103126. [PMID: 33113487 DOI: 10.1016/j.critrevonc.2020.103126] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 09/18/2020] [Accepted: 10/02/2020] [Indexed: 01/24/2023] Open
Abstract
Osteosarcoma (OS) is the most common cancer of bone. Jaw osteosarcoma (JOS) is rare and it differs from long-bone OS (LBOS) in terms of the time of onset (two decades later), lower metastatic spread, and better survival. OS is characterized by the proliferation of osteoblastic precursor cells and the production of osteoid or immature bone. OS arises from a combination of genetic aberrations and a favourable microenvironment. This local microenvironment includes bone cells, blood vessels, stromal cells, and immune infiltrates, all of which may constitute potential targets for anti-cancer drugs. Differences in the clinical and biological behaviour of JOS versus LBOS are likely to at least in part be due to differences in the microenvironment between the two sites. The present review provides a brief overview of the known pathophysiological parameters involved in JOS.
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Affiliation(s)
- Hélios Bertin
- Department of Maxillofacial Surgery, Nantes University Hospital, 1 Place Alexis Ricordeau, 44093 Nantes Cedex 1, France; Bone Sarcoma and Remodeling of Calcified Tisues (PhyOs, UMR 1238), Nantes Medical School, 1 Rue Gaston Veil, 44035 Nantes Cedex, France.
| | - A Gomez-Brouchet
- Department of Pathology, IUCT Oncopole, Toulouse University Hospital, 1 Avenue Irène Joliot-Curie, 31059 Toulouse Cedex 9, France.
| | - F Rédini
- Bone Sarcoma and Remodeling of Calcified Tisues (PhyOs, UMR 1238), Nantes Medical School, 1 Rue Gaston Veil, 44035 Nantes Cedex, France.
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42
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Bone Microenvironment and Osteosarcoma Metastasis. Int J Mol Sci 2020; 21:ijms21196985. [PMID: 32977425 PMCID: PMC7582690 DOI: 10.3390/ijms21196985] [Citation(s) in RCA: 169] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 09/14/2020] [Accepted: 09/22/2020] [Indexed: 01/10/2023] Open
Abstract
The bone microenvironment is an ideal fertile soil for both primary and secondary tumors to seed. The occurrence and development of osteosarcoma, as a primary bone tumor, is closely related to the bone microenvironment. Especially, the metastasis of osteosarcoma is the remaining challenge of therapy and poor prognosis. Increasing evidence focuses on the relationship between the bone microenvironment and osteosarcoma metastasis. Many elements exist in the bone microenvironment, such as acids, hypoxia, and chemokines, which have been verified to affect the progression and malignance of osteosarcoma through various signaling pathways. We thoroughly summarized all these regulators in the bone microenvironment and the transmission cascades, accordingly, attempting to furnish hints for inhibiting osteosarcoma metastasis via the amelioration of the bone microenvironment. In addition, analysis of the cross-talk between the bone microenvironment and osteosarcoma will help us to deeply understand the development of osteosarcoma. The cellular and molecular protagonists presented in the bone microenvironment promoting osteosarcoma metastasis will accelerate the exploration of novel therapeutic strategies towards osteosarcoma.
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43
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Hass R. Role of MSC in the Tumor Microenvironment. Cancers (Basel) 2020; 12:2107. [PMID: 32751163 PMCID: PMC7464647 DOI: 10.3390/cancers12082107] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/24/2020] [Accepted: 07/25/2020] [Indexed: 12/24/2022] Open
Abstract
The tumor microenvironment represents a dynamically composed matrix in which tissue-associated cancer cells are embedded together with a variety of further cell types to form a more or less separate organ-like structure. Constantly mutual interactions between cells of the tumor microenvironment promote continuous restructuring and growth in the tumor. A distinct organization of the tumor stroma also facilitates the formation of transient cancer stem cell niches, thereby contributing to progressive and dynamic tumor development. An important but heterogeneous mixture of cells that communicates among the cancer cells and the different tumor-associated cell types is represented by mesenchymal stroma-/stem-like cells (MSC). Following recruitment to tumor sites, MSC can change their functionalities, adapt to the tumor's metabolism, undergo differentiation and synergize with cancer cells. Vice versa, cancer cells can alter therapeutic sensitivities and change metastatic behavior depending on the type and intensity of this MSC crosstalk. Thus, close cellular interactions between MSC and cancer cells can eventually promote cell fusion by forming new cancer hybrid cells. Consequently, newly acquired cancer cell functions or new hybrid cancer populations enlarge the plasticity of the tumor and counteract successful interventional strategies. The present review article highlights some important features of MSC within the tumor stroma.
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Affiliation(s)
- Ralf Hass
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany
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Sadykova LR, Ntekim AI, Muyangwa-Semenova M, Rutland CS, Jeyapalan JN, Blatt N, Rizvanov AA. Epidemiology and Risk Factors of Osteosarcoma. Cancer Invest 2020; 38:259-269. [PMID: 32400205 DOI: 10.1080/07357907.2020.1768401] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Osteosarcoma is a rare tumor diagnosed at any age; however younger age is a common risk factor. In addition, multiple factors are believed to contribute to higher rates of osteosarcoma, particularly race and gender. Although diagnosed worldwide, osteosarcoma is found to be more prevalent in Africa with high numbers of cases reported in Nigeria, Uganda, and Sudan. Additionally, higher rates are detected in African Americans, suggesting a genetic predisposition linked to race. This review focuses on identifying high risk factors of osteosarcoma with an emphasis on sarcoma epidemiology and risk factors in African countries.
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Affiliation(s)
| | - Atara I Ntekim
- Department of Radiation Oncology, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | | | - Catrin S Rutland
- SVMS, Faculty of Medicine and Health Science, University of Nottingham Biodiscovery Institute, Nottingham, UK
| | - Jennie N Jeyapalan
- SVMS, Faculty of Medicine and Health Science, University of Nottingham Biodiscovery Institute, Nottingham, UK
| | - Nataliya Blatt
- SVMS, Faculty of Medicine and Health Science, University of Nottingham Biodiscovery Institute, Nottingham, UK
| | - Albert A Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
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Chang QY, Zhang SW, Li PP, Yuan ZW, Tan JC. Safety of menstrual blood-derived stromal cell transplantation in treatment of intrauterine adhesion. World J Stem Cells 2020; 12:368-380. [PMID: 32547685 PMCID: PMC7280865 DOI: 10.4252/wjsc.v12.i5.368] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/03/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Intrauterine adhesion (IUA) can cause serious damage to women's reproductive health, yet current treatment methods are difficult to achieve satisfactory results. In our previous studies, we demonstrated that menstrual-derived stromal stem cells (MenSCs), with high proliferative capacity and self-renewal ability, have a powerful therapeutic effect in patients with severe IUA. However, safety assessment of MenSCs transplantation is essential for its further application.
AIM To evaluate the short-, medium-, and long-term biosafety of MenSCs via intrauterine transplantation in a rat model of IUA, with a focus on toxicity and tumorigenicity.
METHODS MenSCs were injected into the sub-serosal layer of the uterus in an IUA rat model, for 3 d, 3 mo, and 6 mo separately, to monitor the corresponding acute, sub-chronic, and chronic effects. Healthy rats of the same age served as negative controls. Toxicity effects were evaluated by body weight, organ weight, histopathology, hematology, and biochemistry tests. Tumorigenicity of MenSCs was investigated in Balb/c-nu mice in vivo and by colony formation assays in vitro.
RESULTS Compared with the same week-old control group, all of the IUA rats receiving MenSC transplantation demonstrated no obvious changes in body weight, main organ weight, or blood cell composition during the acute, sub-chronic, and chronic observation periods. At the same time, serum biochemical tests showed no adverse effects on metabolism or liver and kidney function. After 4 wk of subcutaneous injection of MenSCs in Balb/c-nu nude mice, no tumor formation or cell metastasis was observed. Moreover, there was no tumor colony formation of MenSCs during soft agar culture in vitro.
CONCLUSION There is no acute, sub-chronic, or chronic poisoning, infection, tumorigenesis, or endometriosis in rats with IUA after MenSC transplantation. The above results suggest that intrauterine transplantation of MenSCs is safe for endometrial treatment.
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Affiliation(s)
- Qi-Yuan Chang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
- Key Laboratory of Reproductive Dysfunction Diseases and Fertility Remodeling of Liaoning Province, Shenyang 110004, Liaoning Province, China
| | - Si-Wen Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
- Key Laboratory of Reproductive Dysfunction Diseases and Fertility Remodeling of Liaoning Province, Shenyang 110004, Liaoning Province, China
| | - Ping-Ping Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
- Key Laboratory of Reproductive Dysfunction Diseases and Fertility Remodeling of Liaoning Province, Shenyang 110004, Liaoning Province, China
| | - Zheng-Wei Yuan
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital of China Medical University, Benxi 117004, Liaoning Province, China
| | - Ji-Chun Tan
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
- Key Laboratory of Reproductive Dysfunction Diseases and Fertility Remodeling of Liaoning Province, Shenyang 110004, Liaoning Province, China
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Jacques C, Tesfaye R, Lavaud M, Georges S, Baud’huin M, Lamoureux F, Ory B. Implication of the p53-Related miR-34c, -125b, and -203 in the Osteoblastic Differentiation and the Malignant Transformation of Bone Sarcomas. Cells 2020; 9:cells9040810. [PMID: 32230926 PMCID: PMC7226610 DOI: 10.3390/cells9040810] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/24/2020] [Accepted: 03/25/2020] [Indexed: 02/07/2023] Open
Abstract
The formation of the skeleton occurs throughout the lives of vertebrates and is achieved through the balanced activities of two kinds of specialized bone cells: the bone-forming osteoblasts and the bone-resorbing osteoclasts. Impairment in the remodeling processes dramatically hampers the proper healing of fractures and can also result in malignant bone diseases such as osteosarcoma. MicroRNAs (miRNAs) are a class of small non-coding single-strand RNAs implicated in the control of various cellular activities such as proliferation, differentiation, and apoptosis. Their post-transcriptional regulatory role confers on them inhibitory functions toward specific target mRNAs. As miRNAs are involved in the differentiation program of precursor cells, it is now well established that this class of molecules also influences bone formation by affecting osteoblastic differentiation and the fate of osteoblasts. In response to various cell signals, the tumor-suppressor protein p53 activates a huge range of genes, whose miRNAs promote genomic-integrity maintenance, cell-cycle arrest, cell senescence, and apoptosis. Here, we review the role of three p53-related miRNAs, miR-34c, -125b, and -203, in the bone-remodeling context and, in particular, in osteoblastic differentiation. The second aim of this study is to deal with the potential implication of these miRNAs in osteosarcoma development and progression.
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Seetharaman R, Mahmood A, Kshatriya P, Patel D, Srivastava A. An Overview on Stem Cells in Tissue Regeneration. Curr Pharm Des 2020; 25:2086-2098. [PMID: 31298159 DOI: 10.2174/1381612825666190705211705] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 06/19/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Deteriorations in tissues and decline in organ functions, due to chronic diseases or with advancing age or sometimes due to infections or injuries, can severely compromise the quality of life of an individual. Regenerative medicine, a field of medical research focuses on replacing non-functional or dead cells or repairing or regenerating tissues and organs to restore normal functions of an impaired organ. Approaches used in regenerative therapy for achieving the objective employ a number of means which include soluble biomolecules, stem cell transplants, tissue engineering, gene therapy and reprogramming of cells according to target tissue types. Stem cells transplant and tissue regeneration methods for treating various diseases have rapidly grown in usage over the past decades or so. There are different types of stem cells such as mesenchymal, hematopoietic, embryonic, mammary, intestinal, endothelial, neural, olfactory, neural crest, testicular and induced pluripotent stem cells. METHODS This review covers the recent advances in tissue regeneration and highlights the application of stem cell transplants in treating many life-threatening diseases or in improving quality of life. RESULTS Remarkable progress in stem cell research has established that the cell-based therapy could be an option for treating diseases which could not be cured by conventional medical means till recent. Stem cells play major roles in regenerative medicine with its exceptional characteristics of self-renewal capacity and potential to differentiate into almost all types of cells of a body. CONCLUSION Vast number of reports on preclinical and clinical application of stem cells revealed its vital role in disease management and many pharmacological industries around the globe working to achieve effective stem cell based products.
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Affiliation(s)
| | | | | | | | - Anand Srivastava
- Global Institute of Stem Cell Therapy and Research, 4660 La Jolla Village Drive, San Diego, CA 92122, United States
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Luo X, Tang J, Xuan H, Liu J, Li X. Identification and Validation of a Potent Multi-miRNA Signature for Prediction of Prognosis of Osteosarcoma Patients. Med Sci Monit 2020; 26:e919272. [PMID: 32098942 PMCID: PMC7060510 DOI: 10.12659/msm.919272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background Osteosarcoma, the most common solid malignancy, has high incidence and mortality rates. We constructed a miRNA-based signature that can be used to assess the prognosis of osteosarcoma patients. Material/Methods The miRNA profile was derived from the Gene Expression Omnibus (GEO) website, with matched clinical records. The miRNA-based overall survival (OS)-predicting signature was established by LASSO Cox regression analysis. Receiver operating characteristic (ROC) curve and Kaplan-Meier (K-M) analyses were performed to examine the stability and discriminatory ability of the OS-predicting signatures. Pathway enrichment analyses were performed to uncover potential mechanisms. Results Three miRNAs (miR-153, miR-212, and miR-591) independently related to the OS were extracted to build a risk score formula. The ROC curve and K-M analyses revealed good discrimination ability of the OS signature for osteosarcoma patients in both the training cohort (P=0.00015, AUC=0.962) and the validation cohort (P=0.0065, AUC=0.793). As shown in multivariate analysis, the classifier showed favorable predictive accuracy similar to the recurrence status to be an independent risk factor for osteosarcoma. Furthermore, the nomogram showed a synergistic effect by combining the clinicopathological features with our classifier. Also, the enrichment analyses of the target genes may contribute to improved treatment of osteosarcoma. Conclusions The 3-miRNA-based classifier serves as an effective prognosis-predicting signature for osteosarcoma patients.
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Affiliation(s)
- Xinle Luo
- Department of Trauma and Joint Orthopedics, The People's Hospital of Longhua, Shenzhen, Guangdong, China (mainland)
| | - Jiuyang Tang
- Department of Trauma and Joint Orthopedics, The People's Hospital of Longhua, Shenzhen, Guangdong, China (mainland)
| | - Huabing Xuan
- Department of Trauma and Joint Orthopedics, The People's Hospital of Longhua, Shenzhen, Guangdong, China (mainland)
| | - Jianlin Liu
- Department of Trauma and Joint Orthopedics, The People's Hospital of Longhua, Shenzhen, Guangdong, China (mainland)
| | - Xi Li
- Department of Trauma and Joint Orthopedics, The People's Hospital of Longhua, Shenzhen, Guangdong, China (mainland)
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Jacques C, Lavaud M, Georges S, Tesfaye R, Baud’huin M, Lamoureux F, Ory B. BET bromodomains’ functions in bone-related pathologies. Epigenomics 2020; 12:127-144. [DOI: 10.2217/epi-2019-0172] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Throughout life, bones are subjected to the so-called ‘bone-remodeling’ process, which is a balanced mechanism between the apposition and the resorption of bone. This remodeling process depends on the activities of bone-specialized cells, namely the osteoblasts and the osteoclasts. Any deregulation in this process results in bone-related pathologies, classified as either metabolic nonmalignant diseases (such as osteoporosis) or malignant primary bone sarcomas. As these pathologies are not characterized by common targetable genetic alterations, epigenetic strategies could be relevant and promising options. Recently, targeting epigenetic regulators such as the bromodomains and extraterminal domains (BET) readers have achieved success in numerous other pathologies, including cancers. In this review, we highlight the current state of the art in terms of the diverse implications of BET bromodomain proteins in the bone’s biology and its defects. Consequently, their role in bone-related pathologies will also be developed, especially in the context of the primary bone sarcomas.
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Affiliation(s)
- Camille Jacques
- Nantes Université, INSERM, Bone sarcomas & remodeling of calcified tissues, UMR 1238, F-44000 Nantes, France
| | - Melanie Lavaud
- Nantes Université, INSERM, Bone sarcomas & remodeling of calcified tissues, UMR 1238, F-44000 Nantes, France
| | - Steven Georges
- Nantes Université, INSERM, Bone sarcomas & remodeling of calcified tissues, UMR 1238, F-44000 Nantes, France
| | - Robel Tesfaye
- Nantes Université, INSERM, Bone sarcomas & remodeling of calcified tissues, UMR 1238, F-44000 Nantes, France
- ‘Niches & Epigenetics of Tumors’ Network from Cancéropôle Grand Ouest
| | - Marc Baud’huin
- Nantes Université, INSERM, Bone sarcomas & remodeling of calcified tissues, UMR 1238, F-44000 Nantes, France
| | - François Lamoureux
- Nantes Université, INSERM, Bone sarcomas & remodeling of calcified tissues, UMR 1238, F-44000 Nantes, France
| | - Benjamin Ory
- Nantes Université, INSERM, Bone sarcomas & remodeling of calcified tissues, UMR 1238, F-44000 Nantes, France
- ‘Niches & Epigenetics of Tumors’ Network from Cancéropôle Grand Ouest
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Franceschini N, Lam SW, Cleton-Jansen AM, Bovée JVMG. What's new in bone forming tumours of the skeleton? Virchows Arch 2020; 476:147-157. [PMID: 31741049 PMCID: PMC6969005 DOI: 10.1007/s00428-019-02683-w] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 09/12/2019] [Accepted: 09/30/2019] [Indexed: 12/15/2022]
Abstract
Bone tumours are difficult to diagnose and treat, as they are rare and over 60 different subtypes are recognised. The emergence of next-generation sequencing has partly elucidated the molecular mechanisms behind these tumours, including the group of bone forming tumours (osteoma, osteoid osteoma, osteoblastoma and osteosarcoma). Increased knowledge on the molecular mechanism could help to identify novel diagnostic markers and/or treatment options. Osteoid osteoma and osteoblastoma are bone forming tumours without malignant potential that have overlapping morphology. They were recently shown to carry FOS and-to a lesser extent-FOSB rearrangements suggesting that these tumours are closely related. The presence of these rearrangements could help discriminate these entities from other lesions with woven bone deposition. Osteosarcoma is a malignant bone forming tumour for which different histological subtypes are recognised. High-grade osteosarcoma is the prototype of a complex karyotype tumour, and extensive research exploring its molecular background has identified phenomena like chromothripsis and kataegis and some recurrent alterations. Due to lack of specificity, this has not led to a valuable novel diagnostic marker so far. Nevertheless, these studies have also pointed towards potential targetable drivers of which the therapeutic merit remains to be further explored.
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Affiliation(s)
- Natasja Franceschini
- Department of Pathology, Leiden University Medical Center, P.O. Box 9600, L1-Q, 2300 RC, Leiden, Netherlands
| | - Suk Wai Lam
- Department of Pathology, Leiden University Medical Center, P.O. Box 9600, L1-Q, 2300 RC, Leiden, Netherlands
| | - Anne-Marie Cleton-Jansen
- Department of Pathology, Leiden University Medical Center, P.O. Box 9600, L1-Q, 2300 RC, Leiden, Netherlands
| | - Judith V M G Bovée
- Department of Pathology, Leiden University Medical Center, P.O. Box 9600, L1-Q, 2300 RC, Leiden, Netherlands.
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