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Zeng H, Feng H, Zhang C, Kang Z, Wu J, Zhao X, Huang A, Xu Y, Huang Y, Xu H, Gong M. Novel intravenous formulation for radiosensitization in osteosarcoma treatment. Mater Today Bio 2025; 32:101682. [PMID: 40206141 PMCID: PMC11979400 DOI: 10.1016/j.mtbio.2025.101682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 02/23/2025] [Accepted: 03/17/2025] [Indexed: 04/11/2025] Open
Abstract
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. While radiotherapy is an adjuvant treatment option for OS, particularly in cases of unresectable recurrent metastases, its efficacy remains limited. Enhancing radiosensitivity in OS cells is therefore crucial for improving treatment outcomes. Hafnium oxide, a known radiosensitizer, has demonstrated potential but its current formulation restricts its use to intratumoral administration, posing challenges for treating intraosseous tumors. The development of an intravenous formulation is thus highly desirable. Furthermore, radiotherapy resistance, driven by tumor hypoxia and an immunosuppressive microenvironment, further compromises its effectiveness. In this study, we synthesized hafnium-doped Prussian blue nanoparticles (HP) coated with a tannic acid-manganese metallophenol network (HPTM) to improve biocompatibility and enable intravenous administration. Following intravenous injection in a murine model of OS tibialis in situ tumors with lung metastases, HPTM effectively localized to the primary tumor. Within the acidic tumor microenvironment, manganese was released, activating the STING pathway and triggering anti-tumor immune responses. Moreover, near-infrared light irradiation of the Prussian blue component induced a photothermal effect, promoting apoptosis. Concurrently, under low-dose X-ray irradiation, HPTM augmented radiation energy deposition, generating reactive oxygen species and inducing DNA damage in tumor cells. This synergistic therapeutic approach significantly increased apoptosis in radiotherapy-resistant OS cells, reduced lung metastases, and suppressed primary tumor growth. These findings suggest a promising avenue for clinical translation, integrating radiosensitization, photothermal therapy, and STING pathway activation to overcome current limitations in OS radiotherapy.
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Affiliation(s)
- Haitao Zeng
- Department of Pediatric Orthopaedics, GuangZhou Women and Children's Medical Center, GuangZhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, GuangZhou, 510623, China
- Bone&Soft Tissue Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430079, China
| | - Huixiong Feng
- Department of Musculoskeletal Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Chong Zhang
- Department of Orthopedics, Renmin Hospital of Wuhan University, 430060 Wuhan, China
| | - Zhe Kang
- Department of Pediatric Orthopaedics, GuangZhou Women and Children's Medical Center, GuangZhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, GuangZhou, 510623, China
| | - Jianping Wu
- Department of Pediatric Orthopaedics, GuangZhou Women and Children's Medical Center, GuangZhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, GuangZhou, 510623, China
| | - Xingqi Zhao
- Department of Pediatric Orthopaedics, GuangZhou Women and Children's Medical Center, GuangZhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, GuangZhou, 510623, China
| | - Anfei Huang
- Department of Pediatric Orthopaedics, GuangZhou Women and Children's Medical Center, GuangZhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, GuangZhou, 510623, China
| | - Yanyang Xu
- Department of Joint Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China
| | - Yufeng Huang
- Department of Cervical Spondylosis and Spine Orthopedics, The First Af Liated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China
| | - Hongwen Xu
- Department of Pediatric Orthopaedics, GuangZhou Women and Children's Medical Center, GuangZhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, GuangZhou, 510623, China
| | - Ming Gong
- Department of Pediatric Orthopaedics, GuangZhou Women and Children's Medical Center, GuangZhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, GuangZhou, 510623, China
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Yanzhang R, Yan M, Yang Z, Zhang H, Yu Y, Li X, Shen R, Chu X, Han S, Zhang Z, Teng J, Li H, Li T, Jin G, Guo Z. Ginger extract inhibits c-MET activation and suppresses osteosarcoma in vitro and in vivo. Cancer Cell Int 2025; 25:130. [PMID: 40186167 PMCID: PMC11971884 DOI: 10.1186/s12935-025-03759-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 03/19/2025] [Indexed: 04/07/2025] Open
Abstract
BACKGROUND Osteosarcoma (OS) as an invasive and lethal malignancy showing a low 5-year survival rate requires novel therapeutic targets and their suppressors to improve prevention and treatment strategies. METHODS Our research served to clarify the therapeutic potential of ginger extract and its underlying antineoplastic mechanisms in OS. In vitro studies were used to detect the anti-proliferation ability of ginger extract towards OS cells. Patient-derived xenograft (PDX) was performed to confirm whether ginger extract suppressed tumor growth. Cancer Heat Shock Protein (HSP) database was utilized to identify the potential target of ginger extract, which was subsequently validated through a computational docking model screening method, molecular dynamics simulations and pull-down assay. Analysis of the Gene Expression Omnibus (GEO) database revealed the c-MET expression among OS samples as well as the potential mechanism. Immunohistochemistry (IHC) staining corroborated the c-MET expression level among OS tissues relative to the controls. Functional studies involving c-MET knockdown among OS cell lines were produced to elucidate the functional role of c-MET in OS cellular processes. RESULTS In vitro studies demonstrated that ginger extract administration impeded OS cell progress while inducing apoptosis and inhibiting migration. Moreover, in vivo tests unveiled that ginger extract prominently inhibited patient-derived xenograft (PDX) tumor development. Cancer HSP database analysis recognized c-MET as an underlying target of ginger extract, which was subsequently validated through a computational docking model screening, molecular dynamics simulations and pull-down assay. Analysis of the Gene Expression Omnibus (GEO) database combined with immunohistochemistry (IHC) staining corroborated the c-MET overexpression among OS tissues in contrast with the controls. Next, our study confirmed the significant suppression of cell progress and anchorage-independent growth, while concomitantly inducing apoptosis after c-MET knockdown, underscoring its prospect for a therapeutic target. CONCLUSION Collectively, our findings show that c-MET is a prospective therapeutic target for OS. Ginger extract, a natural c-MET inhibitor, exhibits potent antineoplastic effects by suppressing OS growth both in vitro and in vivo, highlighting its prospect for a new therapeutic agent of this aggressive malignancy.
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Affiliation(s)
- Ruoping Yanzhang
- Henan Key Laboratory of Chronic Disease, Fuwai Central China Cardiovascular Hospital, Zhengzhou, 450000, China
- Laboratory of Bone Tumor, Luoyang Orthopedic Hospital of Henan Province (Orthopedic Hospital of Henan Province), Zhengzhou, 450000, China
| | - Mingyang Yan
- China-US (Henan) Hormel Cancer Institute, No.126, Dongming street, Jinshui District, Zhengzhou, Henan, 450008, China
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Zhaojie Yang
- Henan Key Laboratory of Chronic Disease, Fuwai Central China Cardiovascular Hospital, Zhengzhou, 450000, China
- Laboratory of Bone Tumor, Luoyang Orthopedic Hospital of Henan Province (Orthopedic Hospital of Henan Province), Zhengzhou, 450000, China
| | - Huijun Zhang
- Henan Key Laboratory of Chronic Disease, Fuwai Central China Cardiovascular Hospital, Zhengzhou, 450000, China
- Laboratory of Bone Tumor, Luoyang Orthopedic Hospital of Henan Province (Orthopedic Hospital of Henan Province), Zhengzhou, 450000, China
| | - Yin Yu
- Henan Key Laboratory of Chronic Disease, Fuwai Central China Cardiovascular Hospital, Zhengzhou, 450000, China
- Laboratory of Bone Tumor, Luoyang Orthopedic Hospital of Henan Province (Orthopedic Hospital of Henan Province), Zhengzhou, 450000, China
| | - Xiangping Li
- Laboratory of Bone Tumor, Luoyang Orthopedic Hospital of Henan Province (Orthopedic Hospital of Henan Province), Zhengzhou, 450000, China
| | - Ruifang Shen
- Laboratory of Bone Tumor, Luoyang Orthopedic Hospital of Henan Province (Orthopedic Hospital of Henan Province), Zhengzhou, 450000, China
| | - Xiao Chu
- Henan Key Laboratory of Chronic Disease, Fuwai Central China Cardiovascular Hospital, Zhengzhou, 450000, China
| | - Siyuan Han
- Henan Key Laboratory of Chronic Disease, Fuwai Central China Cardiovascular Hospital, Zhengzhou, 450000, China
| | - Ziliang Zhang
- Henan Key Laboratory of Chronic Disease, Fuwai Central China Cardiovascular Hospital, Zhengzhou, 450000, China
| | - Junyan Teng
- Laboratory of Bone Tumor, Luoyang Orthopedic Hospital of Henan Province (Orthopedic Hospital of Henan Province), Zhengzhou, 450000, China
| | - Hao Li
- Henan Key Laboratory of Chronic Disease, Fuwai Central China Cardiovascular Hospital, Zhengzhou, 450000, China
| | - Tao Li
- Healthy Management Center, Fuwai Central China Cardiovascular Hospital, No.1 Fuwai Road, Zhengzhou, Henan, 451464, China
| | - Guoguo Jin
- Henan Key Laboratory of Chronic Disease, Fuwai Central China Cardiovascular Hospital, Zhengzhou, 450000, China.
- China-US (Henan) Hormel Cancer Institute, No.126, Dongming street, Jinshui District, Zhengzhou, Henan, 450008, China.
| | - Zhiping Guo
- Henan Key Laboratory of Chronic Disease, Fuwai Central China Cardiovascular Hospital, Zhengzhou, 450000, China.
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Cong M, Li S, Fu Y, Wang T, Wei H, Ma X, Liu F, Sheng X, Long K, Hou H, Sun X, Li W, Zhang L. Ghrelin increases cis-platinum resistance and promotes aggressiveness of osteosarcoma by activating AKT and Wnt/β-catenin pathways. J Orthop Surg Res 2025; 20:253. [PMID: 40059184 PMCID: PMC11892314 DOI: 10.1186/s13018-024-05261-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 11/11/2024] [Indexed: 05/13/2025] Open
Abstract
Osteosarcoma (OS) is the most common primary bone malignancy because of its extra high tendency of metastasis. In-depth research is needed to uncover the pathogenesis of patients with OS cells. We collected 74 tissue samples from patients with OS cells and measured the expression levels of ghrelin by immunohistochemistry. Ghrelin was added into OS cell lines in CCK8 assays, JC-1 staining and Western blot analysis were performed to explore its effect on the aggressiveness of OS cells and drug resistance. To determine its function, ghrelin was overexpressed or knocked down in OS cells and then detect cell proliferation in the xenograft mouse model and orthotopic model. Western blot analysis was performed to explore ghrelin-regulated signal pathways. In this work, we identified the relation between the level of ghrelin expression and poor prognosis of OS patients. As well as promoting proliferation, migration, and invation, ghrelin promotes the survival of OS in vitro as well as in vivo, and reduces the apoptosis of OS cells. What's more, ghrelin increases the resistance of cis-platinum by changing mitochondrial function and decreases the expression of MDR-1. Above all, these results demonstrated ghrelin exerts tumorigenic and metastatic effects and may be a potential therapeutic target.
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Affiliation(s)
- Menglin Cong
- Department of Spine Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Shufeng Li
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Yu Fu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Ting Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Huizhen Wei
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Xiaojie Ma
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Fangming Liu
- Department of Rheumatology and immunology, Shandong Provincial Qianfoshan Hospital, Institute of Anesthesia and Respiratory Critical Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - XieHuang Sheng
- College of Chemistry, Chemical Engineering and Materials Science, Shandong Normal University, Jinan, China
| | - Kehan Long
- Clinical Medical College of Weifang Medical University, Weifang, China
| | - Haocheng Hou
- College of Basic Medicine, Shandong University, Jinan, China
| | - Xuecheng Sun
- Department of Orthopedic Trauma, Weifang People's Hospital, Weifang, China.
| | - Weiwei Li
- Department of Pathology, Qilu Hospital of Shandong University, Jinan, China.
| | - Lei Zhang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.
- Tissue Engineering Laboratory, Department of Radiology, Shandong First Medical University, Jinan, China.
- Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, China.
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Hussein L, Moaness M, Mabrouk M, Farahat MG, Beherei HH. Advancements in mesoporous bioactive glasses for effective bone cancer therapy: Recent developments and future perspectives. BIOMATERIALS AND BIOSYSTEMS 2025; 17:100108. [PMID: 40083816 PMCID: PMC11904600 DOI: 10.1016/j.bbiosy.2025.100108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/04/2025] [Accepted: 02/14/2025] [Indexed: 03/16/2025] Open
Abstract
This review focuses on recent advancements in the effective use of mesoporous bioactive glasses (MBG) in the treatment of bone cancer, focusing on Osteosarcoma (OS). Bone cancers are rare but are associated with significant morbidity and mortality; often, aggressive treatment is required. Conventional treatments such as surgery, radiation, and chemotherapy are often not enough. This is because surgery cannot completely remove the tumor, without creating a critical size which are defects larger than 2 cm that cannot be repaired by physiological mechanisms. As a result, patients often face the additional burden of radiation and chemotherapy. Scientists have been exploring new treatments, including hyperthermia-targeted therapy, polymeric nanoparticles, and stem cell therapy. This could potentially negatively impact healthy tissues and organs. MBG offers a promising alternative to chemotherapeutic agents and ions for disease treatment as it acts as a multifunctional drug delivery system (DDS). In addition, MBG can also be engineered into scaffolds to facilitate local delivery of growth factors and drugs, thus promoting the efficiency of bone healing and restoration. Therefore, the current review highlights various MBG types reported in the past decade and explores potential future paths to enhance their use in bone cancer treatment while also giving insight on the already commercially available BGs that are used in different bone-related disease.
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Affiliation(s)
- Laila Hussein
- Refractories, Ceramics and Building Materials Department, Advanced Materials, Technology and Mineral Resources Research Institute, National Research Centre, 33 El Bohouth St., Dokki, PO Box 12622, Cairo, Egypt
| | - Mona Moaness
- Refractories, Ceramics and Building Materials Department, Advanced Materials, Technology and Mineral Resources Research Institute, National Research Centre, 33 El Bohouth St., Dokki, PO Box 12622, Cairo, Egypt
| | - Mostafa Mabrouk
- Refractories, Ceramics and Building Materials Department, Advanced Materials, Technology and Mineral Resources Research Institute, National Research Centre, 33 El Bohouth St., Dokki, PO Box 12622, Cairo, Egypt
| | - Mohamed G. Farahat
- Botany and Microbiology Department, Faculty of Science, Cairo University, Giza, Egypt
- Biotechnology Department, Faculty of Postgraduate Studies for Nanotechnology, Sheikh Zayed Branch Campus, Cairo University, Sheikh Zayed City 12588, Egypt
| | - Hanan H. Beherei
- Refractories, Ceramics and Building Materials Department, Advanced Materials, Technology and Mineral Resources Research Institute, National Research Centre, 33 El Bohouth St., Dokki, PO Box 12622, Cairo, Egypt
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Aoki Y, Kubota Y, Masaki N, Tome Y, Bouvet M, Nishida K, Hoffman RM. Targeting Methionine Addiction of Osteosarcoma with Methionine Restriction to Overcome Drug Resistance: A New Paradigm for a Recalcitrant Disease. Cancers (Basel) 2025; 17:506. [PMID: 39941872 PMCID: PMC11817422 DOI: 10.3390/cancers17030506] [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: 12/27/2024] [Revised: 01/25/2025] [Accepted: 01/29/2025] [Indexed: 02/16/2025] Open
Abstract
Chemotherapy resistance in osteosarcoma results in a very poor patient prognosis, with the 5-year survival rate of approximately 20%, which not improved for over three decades; thus, the development of novel therapeutic strategies is required. Methionine addiction is a fundamental and general hallmark of cancer, termed the Hoffman effect. Cancer cells need larger amounts of exogenous methionine in order to grow compared to normal cells, despite their ability to synthesize normal or greater amounts of methionine from homocysteine, due to increased transmethylation reactions in cancer cells. Methionine restriction therapy, including recombinant methioninase (rMETase), arrests cancer cells in the late-S/G2 phase of the cell cycle by targeting methionine addiction. First-line chemotherapy for osteosarcoma, including methotrexate (MTX), doxorubicin (DOX), and cisplatinum (CDDP), targets cells in the S/G2-phase, where cancer cells are also inhibited by methionine restriction, resulting in the synergy of methionine restriction to overcome drug resistance. In the present review, we describe the synergistic efficacy of conventional chemotherapy and methionine restriction therapy, including rMETase, in overcoming the drug resistance of osteosarcoma. The clinical potential of this new paradigm to overcome the drug resistance of osteosarcoma is discussed.
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Affiliation(s)
- Yusuke Aoki
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0125, Japan
- AntiCancer Inc., 7917 Ostrow St., Suite B, San Diego, CA 92111, USA
- Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, San Diego, CA 92037, USA
| | - Yutaro Kubota
- AntiCancer Inc., 7917 Ostrow St., Suite B, San Diego, CA 92111, USA
- Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, San Diego, CA 92037, USA
| | - Noriyuki Masaki
- AntiCancer Inc., 7917 Ostrow St., Suite B, San Diego, CA 92111, USA
- Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, San Diego, CA 92037, USA
| | - Yasunori Tome
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0125, Japan
| | - Michael Bouvet
- Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, San Diego, CA 92037, USA
| | - Kotaro Nishida
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0125, Japan
| | - Robert M. Hoffman
- AntiCancer Inc., 7917 Ostrow St., Suite B, San Diego, CA 92111, USA
- Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, San Diego, CA 92037, USA
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Zhang X, Gao X, Xu J, Zhang Z, Lin T, Zhang X, Kang X. The role of lncRNA and miRNA on the effects of occurrence and development of osteosarcoma. Int Immunopharmacol 2025; 144:113726. [PMID: 39615111 DOI: 10.1016/j.intimp.2024.113726] [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: 10/10/2024] [Revised: 11/19/2024] [Accepted: 11/25/2024] [Indexed: 12/15/2024]
Abstract
Osteosarcoma is a common primary malignant bone tumor with a high incidence in children and adolescents, with high invasiveness and lung metastases. Even after traditional surgical excision, chemoradiotherapy, and comprehensive treatment, the survival rate of patients is still low, and the prognosis is not ideal. As an important part of non-coding RNA family, lncRNA and miRNA have significant regulatory effects on the growth, proliferation, metastasis and apoptosis of osteosarcoma cells. Therefore, exploring the roles of lncRNAs and miRNAs in the occurrence and development of osteosarcoma is of great help for the subsequent diagnosis, treatment, and prognosis of osteosarcoma. This paper mainly reviews the current research progress on the effects and mechanisms of lncRNAs and miRNAs on osteosarcoma cells, in order to provide new ideas for future research on the development process, treatment methods, and prognosis of osteosarcoma.
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Affiliation(s)
- Xiaobo Zhang
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiao Tong University, 710054 Xi'an, Shaanxi Province, China
| | - Xidan Gao
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiao Tong University, 710054 Xi'an, Shaanxi Province, China
| | - Jing Xu
- The Second Clinical Medical College of Lanzhou University, 730000 Lanzhou, Gansu, China
| | - Zhuoya Zhang
- The First Clinical Medical College of Lanzhou University, 730000 Lanzhou, Gansu, China
| | - Tingtong Lin
- The Second Clinical Medical College of Lanzhou University, 730000 Lanzhou, Gansu, China
| | - Xueyan Zhang
- Institute of Biochemistry and Molecular Biology and School of Basic Medical Sciences, Lanzhou University, 730000 Lanzhou, Gansu, China
| | - Xin Kang
- Department of Sports Medicine, Honghui Hospital, Xi'an Jiao Tong University, 710054 Xi'an, Shaanxi Province, China.
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Gerrand C, Amary F, Anwar HA, Brennan B, Dileo P, Kalkat MS, McCabe MG, McCullough AL, Parry MC, Patel A, Seddon BM, Sherriff JM, Tirabosco R, Strauss SJ. UK guidelines for the management of bone sarcomas. Br J Cancer 2025; 132:32-48. [PMID: 39550489 PMCID: PMC11723950 DOI: 10.1038/s41416-024-02868-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 09/15/2024] [Accepted: 09/24/2024] [Indexed: 11/18/2024] Open
Abstract
This document is an update of the British Sarcoma Group guidelines (2016) and provides a reference standard for the clinical care of UK patients with primary malignant bone tumours (PMBT) and giant cell tumours (GCTB) of bone. The guidelines recommend treatments that are effective and should be available in the UK, and support decisions about management and service delivery. The document represents a consensus amongst British Sarcoma Group members in 2024. Key recommendations are that bone pain, or a palpable mass should always lead to further investigation and that patients with clinical or radiological findings suggestive of a primary bone tumour at any anatomic site should be referred to a specialist centre and managed by an accredited bone sarcoma multidisciplinary team. Treatment recommendations are provided for the major tumour types and for localised, metastatic and recurrent disease. Follow-up schedules are suggested.
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Affiliation(s)
- Craig Gerrand
- Bone and Soft Tissue Tumour Service, Royal National Orthopaedic Hospital, Stanmore, Middlesex, HA7 4LP, UK.
| | - Fernanda Amary
- Bone and Soft Tissue Tumour Service, Royal National Orthopaedic Hospital, Stanmore, Middlesex, HA7 4LP, UK
| | - Hanny A Anwar
- Bone and Soft Tissue Tumour Service, Royal National Orthopaedic Hospital, Stanmore, Middlesex, HA7 4LP, UK
| | | | - Palma Dileo
- Department of Oncology, University College London Hospital NHS Foundation Trust, London, NW1 2BU, UK
| | | | | | | | - Michael C Parry
- Royal Orthopaedic Hospital, Bristol Road South, Birmingham, B31 2AP, UK
| | - Anish Patel
- Royal Orthopaedic Hospital, Bristol Road South, Birmingham, B31 2AP, UK
| | - Beatrice M Seddon
- Department of Oncology, University College London Hospital NHS Foundation Trust, London, NW1 2BU, UK
| | | | - Roberto Tirabosco
- Bone and Soft Tissue Tumour Service, Royal National Orthopaedic Hospital, Stanmore, Middlesex, HA7 4LP, UK
| | - Sandra J Strauss
- Department of Oncology, University College London Hospital NHS Foundation Trust, London, NW1 2BU, UK
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Suehara Y, Kitada R, Kamio S, Ogura K, Iwata S, Kobayashi E, Kawai A, Khosaka S. Analysis of cancer multigene panel testing for osteosarcoma in pediatric and adults using the center for cancer genomics and advanced therapeutics database in Japan. J Orthop Sci 2024:S0949-2658(24)00209-4. [PMID: 39562182 DOI: 10.1016/j.jos.2024.10.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 09/18/2024] [Accepted: 10/29/2024] [Indexed: 11/21/2024]
Abstract
BACKGROUND Osteosarcoma (OS) is the most common primary malignant bone tumor. Despite advances in multimodal chemotherapy, prognosis for metastatic or recurrent OS remains poor. Next-generation sequencing (NGS) can uncover new therapeutic options by identifying potentially targetable alterations. This study analyzed NGS data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database in Japan, comparing findings with the Memorial Sloan-Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) data from the United States. METHODS We sequenced tumor and/or germline DNA from 223 high-grade OS samples using the FoundationOne® CDx or OncoGuideTM NCC Oncopanel System, and the FoundationOne® Liquid CDx for multigene panel testing (2019-2023). Genomic alterations were interpreted using the Cancer Knowledge Database (CKDB), with potentially actionable genetic events categorized into A-F levels. RESULTS Analysis of 223 high-grade OS samples revealed 1684 somatic mutations in 167 genes and 1114 copy number alterations in 89 genes. Potentially actionable alterations were identified in 94 patients (42.2 %) at CKDB Levels A-C. These included 2 cases with NTRK fusions (0.9 %; Level A), one case with TMB-high (0.4 %; Level A), 3 with ERBB amplifications (1.3 %; Level B), and 88 cases (39.5 %) with alterations such as CDK4 amplification, PTEN deletion/mutation, and others (Level C). Co-occurring amplifications of KIT, KDR, and PDGFRA at the 4q12 locus were found in 8 cases (3.6 %), while VEGFA and CCND3 co-amplifications at the 6p12-21 locus were seen in 33 cases (14.8 %). These gene amplifications, also reported in US studies, are targetable by multi-kinase inhibitors, although the C-CAT cohort's profiles differed from US cohorts like MSK-IMPACT. CONCLUSIONS Precision medicine for rare tumors still poses challenges. In this Japanese cohort, 42.2 % of high-grade OSs had potentially actionable alterations per CKDB. Concurrent gene amplifications of KIT, KDR, and PDGFRA at 4q12, and VEGFA and CCND3 at 6p12-21, might offer promising therapeutic options for patients with recurrent/metastatic OS resistant to conventional chemotherapy.
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Affiliation(s)
- Yoshiyuki Suehara
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan; Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
| | - Rina Kitada
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Satoshi Kamio
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan; Department of Musculoskeletal Oncology and Rehabilitation Medicine, National Cancer Center Hospital, Tokyo, Japan
| | - Koichi Ogura
- Department of Musculoskeletal Oncology and Rehabilitation Medicine, National Cancer Center Hospital, Tokyo, Japan
| | - Shintaro Iwata
- Department of Musculoskeletal Oncology and Rehabilitation Medicine, National Cancer Center Hospital, Tokyo, Japan
| | - Eisuke Kobayashi
- Department of Musculoskeletal Oncology and Rehabilitation Medicine, National Cancer Center Hospital, Tokyo, Japan
| | - Akira Kawai
- Department of Musculoskeletal Oncology and Rehabilitation Medicine, National Cancer Center Hospital, Tokyo, Japan
| | - Shinji Khosaka
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
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Mao J, Li HM, Huang Z. Comprehensive analysis of the expression and prognosis for cyclin-dependent protein kinase family in osteosarcoma. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2024:1-24. [PMID: 39357043 DOI: 10.1080/15257770.2024.2410957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 09/21/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND AND OBJECTIVE Cyclin-dependent protein kinases (CDKs) have been suggested as prospective therapeutic targets because they control processes vital to the survival and growth of cancer cells. However, research on the varied CDK expression profiles and prognostic factors in osteosarcoma is still lacking. METHODS The osteosarcoma microRNA (GSE65071) and gene expression profiles were retrieved from the Gene Expression Omnibus (GEO) database (GSE42352). A substantial variation in prognosis was discovered in CDKs using the TARGET database. Cytoscape was used to construct the miRNAs-CDKs network, and functional and pathway enrichment analyses were completed. It was looked at how immune checkpoint genes, m6A-related genes, and CDKs interact. RESULTS In patients with osteosarcoma compared to normal samples, CDK1-5, CDK18, CDK16, and CDK17 gene expression levels were considerably greater, whereas CDK7-9, CDK11B, CDK16, and CDK20 gene expression levels were significantly lower. Patients with osteosarcoma who had low CDK3 and 18 gene levels or high CDK6, 9 gene levels were predicted to have a favorable prognosis and a long-life expectancy. Immune checkpoint genes, m6A-related gene expression, and CDKs expression all showed some connection. Finally, a network of crucial CDKs and miRNAs was constructed. CONCLUSION According to our research, CDK3, 6, 9, and 18 have been identified as possible therapeutic targets for osteosarcoma, and CDKs may have a role in controlling m6A mutations in tumor cells as well as immune checkpoint regulation.
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Affiliation(s)
- Jianshui Mao
- Department of Orthopedics, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, P R China
| | - Hui-Min Li
- Department of Orthopedics, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, P R China
| | - Zhidan Huang
- Department of Orthopedics, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, P R China
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10
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Blay JY, Penel N, Toulmonde M, Valentin T, Chaigneau L, Rios M, Saada-Bouzid E, Firmin N, Bertucci F, Marec-Berard P, Ray-Coquard I, Lervat C, Rolland F, Thyss A, Conroy T, Brahmi M, Dufresne A, Merrouche Y, Brunat-Mentigny M, Biron P, Bompas E, Perol D. Long term survival in adult osteosarcoma patients treated with a two-drug regimen: Final results of the OSAD93 phase II study of the FSG-GETO. Eur J Cancer 2024; 208:114228. [PMID: 39018632 DOI: 10.1016/j.ejca.2024.114228] [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: 05/12/2024] [Revised: 07/03/2024] [Accepted: 07/07/2024] [Indexed: 07/19/2024]
Abstract
RATIONALE We report a phase II trial (OSAD93) testing CDDP with ifosfamide (IFO), without doxorubicin in neoadjuvant phase, in adult osteosarcoma with a 25 years follow-up. PATIENTS AND METHODS This is a multicentric phase II study of neoadjuvant chemotherapy with IFO and CDDP in localized high-grade osteosarcoma of patients. Patients received 4 pre-operative courses of IFO 9 g/m2 and CDDP 100 mg/m2 on day 4 (SHOC regimen), followed by local treatment. Doxorubicin was added post-operatively (HOCA regimen) in patients with > 10 % residual tumor cells. A Good Histological Response (GHR), ie ≤ 10 % residual tumor cells in > 30 % of patients, was the primary objective. Disease-free survival (DFS), overall survival (OS) and toxicity were secondary objectives. RESULTS From Jan 1994 to Jun 1998, 60 patients were included. Median age was 27 (range: 16-63). Primary tumor sites were limbs (76 %), trunk, head or neck (24 %). After neoadjuvant SHOC, grade 3-4 and febrile neutropenia, thrombopenia, and re-hospitalization occurred in 58 %, 17 %, 17 % and 22 % of SHOC courses and in 76 %, 28 %, 47 %, 47 % of HOCA courses, respectively. GHR was obtained in 16/60 (27.5 %) patients. With a median follow-up of 322 months, the DFS and OS were 51.8 % and 64.4 % at 5 years. At 10 years, DFS and OS were 49.9 % and 64.4 %. At 25 years, DFS and OS were 47.8 % and 55.9 %. No long-term cardiac toxicity was observed. Three patients developed a second malignancy (one fatal) after 300 months. CONCLUSION Though the primary endpoint of OSAD93 was not met, this pre-operative doxorubicin-free regimen led to excellent long-term survival with limited toxicity in localized osteosarcoma.
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Affiliation(s)
- Jean-Yves Blay
- Centre Léon Bérard, CRCL, Unicancer, Lyon Unicancer & UCBL1, Lyon, France.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Mehdi Brahmi
- Centre Léon Bérard, CRCL, Unicancer, Lyon Unicancer & UCBL1, Lyon, France
| | - Armelle Dufresne
- Centre Léon Bérard, CRCL, Unicancer, Lyon Unicancer & UCBL1, Lyon, France
| | | | | | - Pierre Biron
- Centre Léon Bérard, CRCL, Unicancer, Lyon Unicancer & UCBL1, Lyon, France
| | | | - David Perol
- Centre Léon Bérard, CRCL, Unicancer, Lyon Unicancer & UCBL1, Lyon, France
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11
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Zhou C, Qian G, Wang Y, Li H, Shen Z, Zheng S. Safety and efficacy of fruquintinib-based therapy in patients with advanced or metastatic sarcoma. Cancer Med 2024; 13:e7438. [PMID: 38967496 PMCID: PMC11225144 DOI: 10.1002/cam4.7438] [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: 01/08/2024] [Revised: 06/02/2024] [Accepted: 06/18/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND The purpose of this study was to evaluate the efficacy and safety of fruquintinib-based therapy as a salvage therapy for patients with advanced or metastatic sarcoma, including soft tissue sarcoma (STS) and bone sarcoma. METHODS Patients with advanced or metastatic sarcoma were divided into two groups. One group received fruquintinib monotherapy, while the other received fruquintinib combined therapy. Safety and efficacy of fruquintinib-based therapy were recorded and reviewed retrospectively, including progression-free survival (PFS), overall response rate (ORR), and adverse events (AEs). RESULTS Between August 2021 and December 2022, 38 sarcoma patients were retrospectively included. A total of 14 patients received fruquintinib alone (including 6 STS and 8 bone sarcoma), while 24 were treated with fruquintinib combined therapy (including 2 STS and 22 bone sarcoma). The median follow-up was 10.2 months (95% CI, 6.4-11.5). For the entire population, the median PFS was 8.0 months (95% CI, 5.5-13.0). The ORR was 13.1%, while the disease control rate (DCR) was 86.8%. The univariate analysis showed that radiotherapy history (HR, 4.56; 95% CI, 1.70-12.24; p = 0.003), bone sarcoma (HR, 0.34; 95% CI, 0.14-0.87; p = 0.024), and treatment method of fruquintinib (HR, 0.36; 95% CI, 0.15-0.85; p = 0.021) were significantly associated with PFS. The multivariate analysis showed that patients without radiotherapy history were associated with a better PFS (HR, 3.71; 95% CI: 1.31-10.55; p = 0.014) than patients with radiotherapy history. Patients in combination group reported pneumothorax (8.3%), leukopenia (33.3%), thrombocytopenia (12.5%), diarrhea (4.2%), and anemia (4.2%) as the most frequent grade 3 or higher treatment-emergent AEs (TEAEs), while there was no severe TEAEs occurred in the monotherapy group. CONCLUSIONS Fruquintinib-based therapy displayed an optimal tumor control and an acceptable safety profile in patients with advanced or metastatic sarcoma.
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Affiliation(s)
- Chenliang Zhou
- Department of OncologyShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Guowei Qian
- Department of OncologyShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yonggang Wang
- Department of OncologyShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Hongtao Li
- Department of OncologyShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Zan Shen
- Department of OncologyShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Shuier Zheng
- Department of OncologyShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
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12
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Rademacher MJ, Faber ML, Bone KM, Medin JA, Schloemer NJ. Fate control engagement augments NK cell responses in LV/hu-IL-12 transduced sarcoma. Exp Mol Pathol 2024; 137:104898. [PMID: 38729059 DOI: 10.1016/j.yexmp.2024.104898] [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: 10/04/2023] [Revised: 04/23/2024] [Accepted: 05/01/2024] [Indexed: 05/12/2024]
Abstract
INTRODUCTION NK cells are an untapped resource for cancer therapy. Sarcomas transduced with lentiviruses to express human IL-12 are only cleared in mice bearing mature human NK cells. However, systemic inflammation limits IL-12 utilization. Fate control a.k.a. "suicide mechanisms" regulate unchecked systemic inflammation caused by cellular immunotherapies. Despite increasing utilization, there remains limited data on immune consequences or tumor-directed effects of fate control. OBJECTIVES We sought to engage the mutant thymidylate kinase (mTMPK) metabolic fate control system to regulate systemic inflammation and assess the impact on NK cell effector functions. METHODS Primary human sarcoma short-passage samples and cell lines were transduced with LV/hu-IL-12_mTMPK engineering expression of IL-12 and an AZT-associated fate control enzyme. We assessed transduced sarcoma responses to AZT engagement and subsequent modulation of NK cell functions as measured by inflammatory cytokine production and cytotoxicity. RESULTS AZT administration to transduced (LV/hu-IL-12_mTMPK) short-passage primary human sarcomas and human Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma cell lines, abrogated the robust expression of human IL-12. Fate control activation elicited a specific dose-dependent cytotoxic effect measured by metabolic activity (WST-1) and cell death (Incucyte). NK effector functions of IFN-γ and cytotoxic granule release were significantly augmented despite IL-12 abrogation. This correlated with preferentially induced expression of NK cell activation ligands. CONCLUSIONS mTMPK fate control engagement terminates transduced sarcoma IL-12 production and triggers cell death, but also augments an NK cell-mediated response coinciding with metabolic stress activating surface ligand induction. Fate control engagement could offer a novel immune activation method for NK cell-mediated cancer clearance.
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Affiliation(s)
- Mary Jo Rademacher
- Departments of Pediatrics; Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Mary L Faber
- Departments of Pediatrics; Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Kathleen M Bone
- Departments of Pathology; Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Jeffrey A Medin
- Departments of Pediatrics; Medical College of Wisconsin, Milwaukee, WI 53226, USA; Departments of Biochemisty; Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Nathan J Schloemer
- Departments of Pediatrics; Medical College of Wisconsin, Milwaukee, WI 53226, USA.
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13
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Xie P, Jin Q, Zhang L, Zhang H, Montesdeoca N, Karges J, Xiao H, Mao X, Song H, Shang K. Endowing Pt(IV) with Perfluorocarbon Chains and Human Serum Albumin Encapsulation for Highly Effective Antitumor Chemoimmunotherapy. ACS NANO 2024; 18:13683-13695. [PMID: 38749906 DOI: 10.1021/acsnano.4c01352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Tumor metastases and reoccurrence are considered the leading causes of cancer-associated deaths. As an emerging therapeutic method, increasing research efforts have been devoted to immunogenic cell death (ICD)-inducing compounds to solve the challenge. The clinically approved chemotherapeutic Pt complexes are not or are only poorly able to trigger ICD. Herein, the axial functionalization of the Pt(II) complex cisplatin with perfluorocarbon chains into ICD-inducing Pt(IV) prodrugs is reported. Strikingly, while the Pt(II) complex as well as the perfluorocarbon ligands did not induce ICD, the Pt(IV) prodrug demonstrated unexpectantly the induction of ICD through accumulation in the endoplasmic reticulum and generation of reactive oxygen species in this organelle. To enhance the pharmacological properties, the compound was encapsulated with human serum albumin into nanoparticles. While selectively accumulating in the tumorous tissue, the nanoparticles demonstrated a strong tumor growth inhibitory effect against osteosarcoma inside a mouse model. In vivo tumor vaccine analysis also demonstrated the ability of Pt(IV) to be an ideal ICD inducer. Overall, this study reports on axially perfluorocarbon chain-modified Pt(IV) complexes for ICD induction and chemoimmunotherapy in osteosarcoma.
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Affiliation(s)
- Peng Xie
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Qiao Jin
- Department of Oncology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Lingpu Zhang
- Beijing National Laboratory for Molecular Sciences, Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
| | - Hanchen Zhang
- Beijing National Laboratory for Molecular Sciences, Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
| | - Nicolás Montesdeoca
- Faculty of Chemistry and Biochemistry, Ruhr-University Bochum, Universitätsstrasse 150, Bochum 44780, Germany
| | - Johannes Karges
- Faculty of Chemistry and Biochemistry, Ruhr-University Bochum, Universitätsstrasse 150, Bochum 44780, Germany
| | - Haihua Xiao
- Beijing National Laboratory for Molecular Sciences, Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
| | - Xinzhan Mao
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Haiqin Song
- Department of General Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 20025, China
| | - Kun Shang
- Department of Nuclear Medicine, Peking University People's Hospital, Beijing 100044, China
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14
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Zheng J, Zhuo S, Huang L, Wang J, Huang G. Mg-ZIF nanozymes disrupt the level of ROS for osteosarcoma killing via POD activity. Front Pharmacol 2024; 15:1407989. [PMID: 38769996 PMCID: PMC11102994 DOI: 10.3389/fphar.2024.1407989] [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: 03/27/2024] [Accepted: 04/23/2024] [Indexed: 05/22/2024] Open
Abstract
Osteosarcoma (OS) is notorious for its high malignancy, and conventional chemotherapy drugs, while killing tumor cells, often inflict significant harm on the patient's body. The tumor microenvironment of OS is characterized by high levels of hydrogen peroxide (H2O2). Leveraging this feature, we have developed Mg-ZIF nanoparticles, which incorporate magnesium (Mg) to confer robust peroxidase (POD)-like enzymatic activity. These Mg-ZIF nanozymes can generate highly lethal superoxide anions within tumor cells in a responsive manner, thereby achieving effective tumor destruction. Both in vitro and in situ OS models have corroborated the anti-tumor efficacy of Mg-ZIF nanozymes, while also validating their biosafety. The design of Mg-ZIF nanozymes opens a new avenue for the treatment of OS, offering a promising therapeutic strategy.
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Affiliation(s)
| | | | | | | | - Gaofeng Huang
- Department of Orthopedics, Shanghai Sixth People’s Hospital Fujian, Luoshan Section, Quanzhou, China
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15
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Liu B, Liu XY, Wang GP, Chen YX. The immune cell infiltration-associated molecular subtypes and gene signature predict prognosis for osteosarcoma patients. Sci Rep 2024; 14:5184. [PMID: 38431660 PMCID: PMC10908810 DOI: 10.1038/s41598-024-55890-0] [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: 05/26/2023] [Accepted: 02/28/2024] [Indexed: 03/05/2024] Open
Abstract
Host immune dysregulation involves in the initiation and development of osteosarcoma (OS). However, the exact role of immune cells in OS remains unknown. We aimed to distinguish the molecular subtypes and establish a prognostic model in OS patients based on immunocyte infiltration. The gene expression profile and corresponding clinical feature of OS patients were obtained from TARGET and GSE21257 datasets. MCP-counter and univariate Cox regression analyses were applied to identify immune cell infiltration-related molecular subgroups. Functional enrichment analysis and immunocyte infiltration analysis were performed between two subgroups. Furthermore, Cox regression and LASSO analyses were performed to establish the prognostic model for the prediction of prognosis and metastasis in OS patients. The subgroup with low infiltration of monocytic lineage (ML) was related to bad prognosis in OS patients. 435 DEGs were screened between the two subgroups. Functional enrichment analysis revealed these DEGs were involved in immune- and inflammation-related pathways. Three important genes (including TERT, CCDC26, and IL2RA) were identified to establish the prognostic model. The risk model had good prognostic performance for the prediction of metastasis and overall survival in OS patients. A novel stratification system was established based on ML-related signature. The risk model could predict the metastasis and prognosis in OS patients. Our findings offered a novel sight for the prognosis and development of OS.
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Affiliation(s)
- Bin Liu
- Department of Spine Surgery, Hunan Provincial People's Hospital (The First-Affiliated Hospital of Hunan Normal University), Changsha, 410005, Hunan, China
| | - Xiang-Yang Liu
- Department of Spine Surgery, Hunan Provincial People's Hospital (The First-Affiliated Hospital of Hunan Normal University), Changsha, 410005, Hunan, China
| | - Guo-Ping Wang
- Department of Spine Surgery, Hunan Provincial People's Hospital (The First-Affiliated Hospital of Hunan Normal University), Changsha, 410005, Hunan, China
| | - Yi-Xin Chen
- Department of Rehabilitation Medicine, Xiangya Hospital of Central South University, No. 87, Xiangya Road, Changsha, 410008, Hunan, China.
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16
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Su Q, Wang N, Wang B, Wang Y, Dai Z, Zhao X, Li X, Li Q, Yang G, Nie P. Ct-based intratumoral and peritumoral radiomics for predicting prognosis in osteosarcoma: A multicenter study. Eur J Radiol 2024; 172:111350. [PMID: 38309216 DOI: 10.1016/j.ejrad.2024.111350] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 01/09/2024] [Accepted: 01/25/2024] [Indexed: 02/05/2024]
Abstract
PURPOSE To evaluate the performance of CT-based intratumoral, peritumoral and combined radiomics signatures in predicting prognosis in patients with osteosarcoma. METHODS The data of 202 patients (training cohort:102, testing cohort:100) with osteosarcoma admitted to the two hospitals from August 2008 to February 2022 were retrospectively analyzed. Progression free survival (PFS) and overall survival (OS) were used as the end points. The radiomics features were extracted from CT images, three radiomics signatures（RSintratumoral, RSperitumoral, RScombined）were constructed based on intratumoral, peritumoral and combined radiomics features, respectively, and the radiomics score (Rad-score) were calculated. Kaplan-Meier survival analysis was used to evaluate the relationship between the Rad-score with PFS and OS, the Harrell's concordance index (C-index) was used to evaluate the predictive performance of the radiomics signatures. RESULTS Finally, 8, 6, and 21 features were selected for the establishment of RSintratumoral, RSperitumoral, and RScombined, respectively. Kaplan-Meier survival analysis confirmed that the Rad-scores of the three RSs were significantly correlated with the PFS and OS of patients with osteosarcoma. Among the three radiomics signatures, RScombined had better predictive performance, the C-index of PSF prediction was 0.833 in the training cohort and 0.814 in the testing cohort, the C-index of OS prediction was 0.796 in the training cohort and 0.764 in the testing cohort. CONCLUSIONS CT-based intratumoral, peritumoral and combined radiomics signatures can predict the prognosis of patients with osteosarcoma, which may assist in individualized treatment and improving the prognosis of osteosarcoma patients.
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Affiliation(s)
- Qiushi Su
- Department of Radiology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Ning Wang
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Bingyan Wang
- Department of Ultrasound, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | | | - Zhengjun Dai
- Scientific Research Department, Huiying Medical Technology Co., Ltd, Beijing, China
| | - Xia Zhao
- Department of Radiology, the Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Xiaoli Li
- Department of Radiology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Qiyuan Li
- Department of Radiology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Guangjie Yang
- Department of Nuclear Medicine, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
| | - Pei Nie
- Department of Radiology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
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17
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Ding M, Ran X, Qian S, Zhang Y, Wang Z, Dong M, Yang Z, Wu S, Feng X, Zhang J, Zhu L, Niu S, Zhang X. Clinical and therapeutical significances of the cluster and signature based on oxidative stress for osteosarcoma. Aging (Albany NY) 2023; 15:15360-15381. [PMID: 38180104 PMCID: PMC10781490 DOI: 10.18632/aging.205354] [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: 08/01/2023] [Accepted: 11/13/2023] [Indexed: 01/06/2024]
Abstract
BACKGROUND It is of great clinical significance to find out the ideal tumor biomarkers and therapeutic targets to improve the prognosis of patients with osteosarcoma (OS). Oxidative stress (OXS) can directly target intracellular macromolecules and exhibit dual effects of tumor promotion and suppression. METHODS OXS-related genes (OXRGs) were extracted from public databases, including TARGET and GEO. Univariate Cox regression analysis, Random Survival Forest algorithm, and LASSO regression were performed to identify prognostic genes and establish the OXS-signature. The efficacy of the OXS-signature was further evaluated by Kaplan-Meier curves and timeROC package. Evaluation of immunological characteristics was achieved based on ESTIMATE algorithm and ssGSEA. Submap algorithm was used to explore the response to anti-PD1 and anti-CTLA4 therapy for OS. Drug response prediction was conducted by using pRRophetic package. The expression values of related genes in the OXS-signature were detected with PCR assays. RESULTS Two OXS-clusters were identified for OS, with remarkable differences of clusters presented in prognosis. Kyoto Encyclopedia of Genes Genomes (KEGG) analysis showed that differentially expressed genes (DEGs) between the OXS-clusters were significantly enriched in several immune-related pathways. Patients with lower OS-scores attained better clinical outcomes, and presented more sensitivity to ICB therapy. By contrast, OS patients with higher OS-scores revealed more sensitivity to certain drugs. Furthermore, critical genes, RHBDL2 and CGREF1 from the model, were significantly higher expressed in OS cell lines. CONCLUSIONS Our study identified the clusters and signature based on OXS, which would lay the foundation for molecular experimental research, disease prevention and treatment of OS.
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Affiliation(s)
- Mengjie Ding
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xianting Ran
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Siyu Qian
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yue Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zeyuan Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Meng Dong
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhenzhen Yang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Shaoxuan Wu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xiaoyan Feng
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jieming Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Linan Zhu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Songtao Niu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xudong Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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18
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Kim C, Davis LE, Albert CM, Samuels B, Roberts JL, Wagner MJ. Osteosarcoma in Pediatric and Adult Populations: Are Adults Just Big Kids? Cancers (Basel) 2023; 15:5044. [PMID: 37894411 PMCID: PMC10604996 DOI: 10.3390/cancers15205044] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/16/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023] Open
Abstract
Malignant bone tumors are commonly classified as pediatric or adolescent malignancies, and clinical trials for these diseases have generally focused on these populations. Of primary bone cancers, osteosarcoma is among the most common. Osteosarcoma has a bimodal age distribution, with the first peak occurring in patients from 10 to 14 years old, and the second peak occurring in patients older than 65, with about 25% of cases occurring in adults between 20 and 59 years old. Notably, adult osteosarcoma patients have worse outcomes than their pediatric counterparts. It remains unclear whether age itself is a poor prognostic factor, or if inherent differences in tumor biology exist between age groups. Despite these unknowns, current treatment strategies for adults are largely extrapolated from pediatric studies since the majority of clinical trials for osteosarcoma treatments are based on younger patient populations. In light of the different prognoses observed in pediatric and adult osteosarcoma, we summarize the current understanding of the molecular etiology of osteosarcoma and how it may differ between age groups, hypothesizing why adult patients have worse outcomes compared to children.
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Affiliation(s)
- Caleb Kim
- Division of Hematology and Oncology, University of Washington, Spokane, WA 99202, USA;
| | - Lara E. Davis
- Division of Hematology/Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Catherine M. Albert
- Division of Pediatric Hematology, Oncology, Bone Marrow Transplant and Cellular Therapy, Seattle Children’s Hospital, Seattle, WA 98105, USA
| | | | - Jesse L. Roberts
- Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA 98109, USA
| | - Michael J. Wagner
- Division of Hematology and Oncology, University of Washington, Seattle, WA 98109, USA
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
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Liu Y, Zhang X, Ren X, Sun J, Wen Y, Guo Z, Ma Q. Tandem mass tag (TMT) quantitative protein analysis-based proteomics and parallel reaction monitoring (PRM) validation revealed that MST4 accelerates osteosarcoma proliferation by increasing MRC2 activity. Mol Carcinog 2023; 62:1338-1354. [PMID: 37378424 DOI: 10.1002/mc.23567] [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: 08/25/2022] [Revised: 02/14/2023] [Accepted: 03/14/2023] [Indexed: 06/29/2023]
Abstract
Osteosarcoma is one of the most common orthopedic malignancies and is characterized by rapid disease progression and a poor prognosis. Currently, research on methods to inhibit osteosarcoma proliferation is still limited. In this study, we found that MST4 levels were significantly increased in osteosarcoma cell lines and tumor tissues compared to normal controls and demonstrated that MST4 is an influential factor in promoting osteosarcoma proliferation both in vivo and in vitro. Proteomic analysis was performed on osteosarcoma cells in the MST4 overexpression and vector expression groups, and 545 significantly differentially expressed proteins were identified and quantified. The candidate differentially expressed protein MRC2 was then identified using parallel reaction monitoring validation. Subsequently, MRC2 expression was silenced with small interfering RNA (siRNA), and we were surprised to find that this alteration affected the cell cycle of MST4-overexpressing osteosarcoma cells, promoted apoptosis and impaired the positive regulation of osteosarcoma growth by MST4. In conclusion, this study identified a novel approach for suppressing osteosarcoma proliferation. Reduction of MRC2 activity inhibits osteosarcoma proliferation in patients with high MST4 expression by altering the cell cycle, which may be valuable for treating osteosarcoma and improving patient prognosis.
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Affiliation(s)
- Yunyan Liu
- Department of Orthopedic Surgery, Orthopedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Xiaoyu Zhang
- Department of Orthopedic Surgery, Orthopedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Xingguang Ren
- Department of Orthopedic Surgery, Orthopedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Jin Sun
- Department of Orthopedic Surgery, Orthopedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Yanhua Wen
- Department of Orthopedic Surgery, Orthopedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Zheng Guo
- Department of Orthopedic Surgery, Orthopedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Qiong Ma
- Department of Orthopedic Surgery, Orthopedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
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20
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Cao J, Du X, Zhao H, Zhu C, Li C, Zhang X, Wei L, Ke X. Sequentially degradable hydrogel-microsphere loaded with doxorubicin and pioglitazone synergistically inhibits cancer stemness of osteosarcoma. Biomed Pharmacother 2023; 165:115096. [PMID: 37421781 DOI: 10.1016/j.biopha.2023.115096] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/27/2023] [Accepted: 06/27/2023] [Indexed: 07/10/2023] Open
Abstract
Drug resistance represents one of the greatest challenges in cancer treatment. Cancer stem cells (CSCs) are thought to be the major cause of failure in cancer therapy due to their considerable resistance to most chemotherapeutic agents, resulting in tumor recurrence and eventually metastasis. Here, we report a treatment strategy for osteosarcoma using hydrogel-microspheres (Gel-Mps) complex mainly composed of collagenase (Col) and PLGA microspheres (Mps) carrying Pioglitazone (Pio) and Doxorubicin (Dox). Col was encapsulated in the thermosensitive gel to preferentially degrade tumor extracellular matrix (ECM), ensuring subsequent drug penetration, while Mps with Pio and Dox were co-delivered to synergistically inhibit tumor growth and metastasis. Our results showed that the Gel-Mps dyad functions as a highly biodegradable, extremely efficient, and low-toxic reservoir for sustained drug release, displaying potent inhibition of tumor proliferation and subsequent lung metastasis. Selective PPARγ agonist Pio reversed drug resistance to Dox by significantly down-regulating the expression of stemness markers and P-glycoprotein (P-gp) in osteosarcoma cells. The Gel@Col-Mps@Dox/Pio exhibited advanced therapeutic efficacy in vivo, demonstrating its great potential to serve a novel osteosarcoma therapy, which not only inhibits the growth of, but also attenuates the stemness of osteosarcoma. The dual effects reinforce the sensitivity and efficacy of chemotherapy.
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Affiliation(s)
- Jie Cao
- Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, Jiangsu Province, China
| | - Xiaoxuan Du
- Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, Jiangsu Province, China
| | - Hui Zhao
- Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, Jiangsu Province, China
| | - Chenhong Zhu
- Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, Jiangsu Province, China
| | - Chenchen Li
- Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, Jiangsu Province, China
| | - Xin Zhang
- School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, Jiangsu Province, China
| | - Libin Wei
- School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, Jiangsu Province, China.
| | - Xue Ke
- Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, Jiangsu Province, China.
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21
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Xu Y, Du L, Han B, Wang Y, Fei J, Xia K, Zhai Y, Yu Z. Black phosphorus quantum dots camouflaged with platelet-osteosarcoma hybrid membrane and doxorubicin for combined therapy of osteosarcoma. J Nanobiotechnology 2023; 21:243. [PMID: 37507707 PMCID: PMC10386629 DOI: 10.1186/s12951-023-02016-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 07/21/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Osteosarcoma (OS) is the most prevalent primary malignant bone tumor. However, single-agent chemotherapy exhibits limited efficacy against OS and often encounters tumor resistance. Therefore, we designed and constructed an integrated treatment strategy of photothermal therapy (PTT) combined with chemotherapy and used a surface-encapsulated platelet-osteosarcoma hybrid membrane (OPM) that enhances circulation time and enables OS-specific targeting. RESULTS The OPM functions as a shell structure, encapsulating multiple drug-loaded nanocores (BPQDs-DOX) and controlling the release rate of doxorubicin (DOX). Moreover, near-infrared light irradiation accelerates the release of DOX, thereby extending circulation time and enabling photostimulation-responsive release. The OPM encapsulation system improves the stability of BPQDs, enhances their photothermal conversion efficiency, and augments PTT efficacy. In vitro and ex vivo experiments demonstrate that BPQDs-DOX@OPM effectively delivers drugs to tumor sites with prolonged circulation time and specific targeting, resulting in superior anti-tumor activity compared to single-agent chemotherapy. Furthermore, these experiments confirm the favorable biosafety profile of BPQDs-DOX@OPM. CONCLUSIONS Compared to single-agent chemotherapy, the combined therapy using BPQDs-DOX@OPM offers prolonged circulation time, targeted drug delivery, enhanced anti-tumor activity, and high biosafety, thereby introducing a novel approach for the clinical treatment of OS.
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Affiliation(s)
- Yanlong Xu
- Department of Orthopedics, Jinshan Hospital, Fudan University, Longhang Road 1508#, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Longhai Du
- Department of Orthopedics, Jinshan Hospital, Fudan University, Longhang Road 1508#, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Binxu Han
- Department of Orthopedics, Jinshan Hospital, Fudan University, Longhang Road 1508#, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Yu Wang
- Department of Orthopedics, Jinshan Hospital, Fudan University, Longhang Road 1508#, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Jichang Fei
- Department of Orthopedics, Nanping First Hospital of Fujian Medical University, Fujian, People's Republic of China
| | - Kuo Xia
- Department of Orthopedics, Jinshan Hospital, Fudan University, Longhang Road 1508#, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Yonghua Zhai
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China
| | - Zuochong Yu
- Department of Orthopedics, Jinshan Hospital, Fudan University, Longhang Road 1508#, Jinshan District, Shanghai, 201508, People's Republic of China.
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22
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Markowitz MI, Donato Z, Constantinescu DS, Al-Hardan W, Baron M, Crawford B. Orthopedic approaches for bone sarcoma: A bibliometric review of the 50 most cited papers. J Orthop 2023; 38:53-61. [PMID: 37008450 PMCID: PMC10051026 DOI: 10.1016/j.jor.2023.03.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/26/2023] [Accepted: 03/08/2023] [Indexed: 04/04/2023] Open
Abstract
Background Curative treatment of bone sarcoma is primarily based on operative management. The Orthopedic Oncology approach towards this disease has evolved greatly to the breakthrough in systemic treatment options as well as unique implant designs favoring limb salvage over amputations. The purpose of this study was to perform a bibliometric analysis of the top 50 most cited papers related to the orthopedic the approach to bone sarcomas. Methods We queried the ISI Web of Knowledge database in July 2022. Keywords utilized were: ""Bone Sarcoma" OR "Osteosarcoma" OR "Ewing Sarcoma" OR "Chondrosarcoma" OR "Chordoma". The top 50 articles pertaining to the orthopedic approach to bone sarcoma were included for analysis and included manuscript title, authors, citation count, journal and publication year. Results The mean number of citations are 187.06 (Range 125-400; SD 67.83). The average citations per year is 10.03 (Range 47.86-3.43; SD 8.05). Many articles were published from 2000 to 2009 (n = 20) and 1990-1999 (n = 13). The majority of the articles were published by institutions within the United States (n = 32). The most common level of evidence was level IV (n = 37). Majority of the articles focused on treatment outcome (n = 22). Conclusion This study offers a comprehensive review of the most cited literature regarding orthopedic approaches to bony sarcomas. Modern treatment approaches for bone sarcoma has resulted in an increased focus within the literature on achieving disease free survival wide tissue margins. Understanding the trends of available studies allows for physicians and researchers to target and innovate future areas of study.
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Affiliation(s)
- Moses I. Markowitz
- University of Miami Miller School of Medicine, 1120 NW 14th St, Miami, FL, 33136, USA
| | - Zachary Donato
- University of Miami Miller School of Medicine, 1120 NW 14th St, Miami, FL, 33136, USA
| | - David S. Constantinescu
- University of Miami Miller School of Medicine, Department of Orthopaedic Surgery, 1611 NW 12th Ave #303, Miami, FL, 33136, USA
| | - Waleed Al-Hardan
- University of Miami Miller School of Medicine, Department of Orthopaedic Surgery, 1611 NW 12th Ave #303, Miami, FL, 33136, USA
| | - Max Baron
- University of Miami Miller School of Medicine, 1120 NW 14th St, Miami, FL, 33136, USA
| | - Brooke Crawford
- University of Miami Miller School of Medicine, Department of Orthopaedic Surgery, 1611 NW 12th Ave #303, Miami, FL, 33136, USA
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23
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Gong M, Huang Y, Feng H, Lin J, Huang A, Hu J, Tang Q, Zhu X, Han S, Lu J, Wang J. A nanodrug combining CD47 and sonodynamic therapy efficiently inhibits osteosarcoma deterioration. J Control Release 2023; 355:68-84. [PMID: 36682726 DOI: 10.1016/j.jconrel.2023.01.038] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 01/03/2023] [Accepted: 01/14/2023] [Indexed: 01/24/2023]
Abstract
Treatments for osteosarcoma (OS) with pulmonary metastases reach a bottleneck with a survival rate of 10-20%. The suppressive tumor associated macrophages(TAMs) and CD47 over-expression greatly lead to the treatment failure. Sonodynamic therapy (SDT) can generate ROS with deep tumor penetration to induce tumor cell apoptosis, which is reported to further induce M1 macrophage polarization. CD47 inhibition combined with SDT to synergistically modulate TAMs may induce superior effects for OS treatment. In this work, for the first time, a biomimetic nanodrug named MPIRx was deveploped by loading IR780 (a sonosensitizer) and RRx-001 (a CD47 inhibitor) in PEG-PCL nanomicelles and then coating with OS cell membranes. After ultrasound activation, the nanodrug significantly inhibited OS proliferation and migration, induced apoptosis and immunogenic cell death in OS cells. Furthermore, MPIRx could guide macrophage migrating towards tumor cells and promote M1-type polarization while increasing the phagocytosis activity of macrophages on OS cells. Ultimately, MPIRx showed good tumor accumulation in vivo and successfully inhibited subcutaneous OS and orthotopic tumor with deterioration of pulmonary metastasis. Overall, by creating a local oxidative microenvironment and modulating the TAMs/CD47 in tumor tissue, the MPIRx nanodrug presents a novel strategy for macrophage-related immunotherapy to successfully eliminate OS and inhibit the intractable pulmonary metastasis.
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Affiliation(s)
- Ming Gong
- Department of Musculoskeletal Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, PR China
| | - Yufeng Huang
- Department of Musculoskeletal Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, PR China
| | - Huixiong Feng
- Department of Musculoskeletal Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, PR China
| | - Jiaming Lin
- Department of Musculoskeletal Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, PR China
| | - Anfei Huang
- Department of Musculoskeletal Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, PR China
| | - Jinxin Hu
- Department of Musculoskeletal Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, PR China
| | - Qinglian Tang
- Department of Musculoskeletal Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, PR China
| | - Xiaojun Zhu
- Department of Musculoskeletal Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, PR China
| | - Shisong Han
- Zhuhai Institute of Translational Medicine, Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai 519000, PR China.
| | - Jinchang Lu
- Department of Musculoskeletal Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, PR China.
| | - Jin Wang
- Department of Musculoskeletal Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, PR China.
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24
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Hou S, Ni X, Wang J, Ding R, Liu T. Study on the effect of artificial joint replacement for osteosarcoma. Medicine (Baltimore) 2023; 102:e32896. [PMID: 36827028 PMCID: PMC11309729 DOI: 10.1097/md.0000000000032896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/16/2023] [Accepted: 01/18/2023] [Indexed: 02/25/2023] Open
Abstract
Osteosarcoma is one of the most prevalent primary malignant bone tumors that affects teenagers more than adults. In recent years, artificial femoral replacement has become more and more common. The use of artificial total femoral replacement surgery prevents the need for amputating the damaged limb, preserves the patient's ability to move and bear weight on the leg, lessens the severity of the psychological trauma, and significantly raises the patient's quality of life. To explore the treatment methods and therapeutic effects of artificial femoral replacement in the treatment of femoral osteosarcoma. The clinical data of 11 patients with femoral malignant tumors who underwent artificial femoral replacement from January 2019 to March 2022 were retrospectively analyzed. Among them, 7 males and 4 females, 11 to 40 years old, average 19.36 ± 9.44 years old. The disease duration is 2 to 7 months, with an average of 4.7 months. Before and 3 months after operation, the patients who had tumors were given a score on the visual analog scale, and their quality of life was also measured. At the most recent follow-up, both the Musculoskeletal Tumor Society score and the Harris hip score were analyzed. Eleven patients were followed up for 6 to 58 months, and an average of 21 months. Complications such as wound infection, joint dislocation, and nerve damage did not occur. In 1 patient, popliteal vein thrombus formation, and in 2 patients with osteosarcoma died from tumor progression. Visual analog scale score at 3 months after surgery and the quality-of-life scores were 3.68 ± 1.39 and 40.04 ± 4.31, respectively, which were significantly improved compared to before surgery (5.94 ± 1.19 and 22.42 ± 3.63, respectively, P < .05). At the last interview, Musculoskeletal Tumor Society score is scored from 18 to 29 points, average 22.5 ± 5.9 points, and Harris hip score is scored from 42 to 90 points, with an average score of 69.0 ± 14.7. Artificial total femoral replacement is an effective limb salvage operation in the treatment of osteosarcoma.
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Affiliation(s)
- Shuming Hou
- Department of Orthopaedic Oncology, Changzheng Hospital of the Navy Medical University, Shanghai, China
| | - Xiangzhi Ni
- Department of Orthopaedic Oncology, Changzheng Hospital of the Navy Medical University, Shanghai, China
| | - Jing Wang
- Department of Orthopaedic Oncology, Changzheng Hospital of the Navy Medical University, Shanghai, China
| | - Rumeng Ding
- Department of Orthopaedic Oncology, Changzheng Hospital of the Navy Medical University, Shanghai, China
| | - Tielong Liu
- Department of Orthopaedic Oncology, Changzheng Hospital of the Navy Medical University, Shanghai, China
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Dai Z, Liu Z, Yang R, Cao W, Ji T. EVI2B Is a Prognostic Biomarker and Is Correlated with Monocyte and Macrophage Infiltration in Osteosarcoma Based on an Integrative Analysis. Biomolecules 2023; 13:327. [PMID: 36830696 PMCID: PMC9953216 DOI: 10.3390/biom13020327] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 01/25/2023] [Accepted: 02/03/2023] [Indexed: 02/11/2023] Open
Abstract
Osteosarcoma (OS) is the most common malignant bone tumor. However, treatment strategies have not changed over the past 30 years. The relationship between OS and the immune microenvironment may provide a basis for the establishment of novel therapeutic targets. In this study, a large-scale gene expression dataset (GSE42352) was used to identify key genes in OS. A Target-OS dataset from the Cancer Genome Atlas was used as a validation set. Ecotropic viral integration site 2B (EVI2B) was significantly upregulated in OS tumor samples. Differentially expressed genes (DEGs) were identified between samples with high and low EVI2B expression in both the test and validation cohorts. The top three functions of DEGs determined by a gene set enrichment analysis (GSEA) were chemokine signaling, cytokine-cytokine receptor interaction, and Human T-cell leukemia virus 1 infection. A prognostic prediction model including EVI2B, DOCK2, and CD33 was constructed by a Cox regression analysis. This model indicated that EVI2B is an independent protective prognostic marker in OS. An analysis of immune infiltration further showed that high EVI2B expression levels were correlated with high levels of macrophage infiltration. Protein expression data derived from the Human Protein Atlas suggested EVI2B to be highly expressed in monocytes. Finally, we validated the elevated expression of EVI2B in OS cell lines and OS tissue samples; these results were consistent with those of the analyses of the GSE42352 and Target-OS datasets. Our integrative bioinformatics analysis and experimental results provide clear evidence for the prognostic value of EVI2B in OS and its close relationship with monocyte and macrophage infiltration.
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Affiliation(s)
- Zhenlin Dai
- Department of Oral and Maxillofacial & Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai 200011, China
| | - Zheqi Liu
- Department of Oral and Maxillofacial & Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai 200011, China
| | - Rong Yang
- Department of Oral and Maxillofacial & Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai 200011, China
| | - Wei Cao
- Department of Oral and Maxillofacial & Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai 200011, China
| | - Tong Ji
- Department of Oral and Maxillofacial & Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai 200011, China
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26
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Zhong W, Luo W, Lin Z, Wu Z, Yuan Y, He Y. Prognostic analysis of telangiectatic osteosarcoma of the extremities. Front Oncol 2023; 12:1105054. [PMID: 36815074 PMCID: PMC9939512 DOI: 10.3389/fonc.2022.1105054] [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: 11/22/2022] [Accepted: 12/19/2022] [Indexed: 02/09/2023] Open
Abstract
Background and objectives Telangiectatic osteosarcoma (TOS) is a rare but highly malignant subtype of osteosarcoma. Although surgical treatment is the primary treatment modality for osteosarcoma, evidence on the benefits of different surgical methods in patients with TOS is lacking. This study aimed to compare the effects of different surgical and adjuvant treatments on overall survival of TOS, and the association of patient demographics, oncological characteristics, and socioeconomic status on treatment outcomes. Method This retrospective study selected the most common TOS cases of the extremities registered in the Surveillance, Epidemiology, and End Results (SEER) database from 1989 to 2019. Univariate and multivariate Cox regression models were used to analyze all prognostic factors, and Kaplan-Meier analyses were performed for disease-specific treatment factors of survival. Result A total of 127 patients were included in the analysis. The average age at initial diagnosis was 20.09 years. In univariate analyses, the absence of metastasis at initial diagnosis, limb-salvage surgery, adjuvant chemotherapy, and no regional lymph node dissection were associated with a lower risk of death. Multivariate analysis further showed that the presence or absence of distant metastasis and regional lymph node dissection, implementation of adjuvant chemotherapy, and choice of surgical method were independent predictors of prognosis. Conclusion Distant metastasis and regional lymph node dissection are associated with poorer outcomes in TOS, and amputation has no better prognosis than limb salvage surgery. Compared with conventional chemotherapy, neoadjuvant chemotherapy did not significantly improve the prognosis of TOS.
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Affiliation(s)
- Wei Zhong
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
| | - Wei Luo
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Changsha, China,*Correspondence: Wei Luo,
| | - Zili Lin
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
| | - Ziyi Wu
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
| | - Yuhao Yuan
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
| | - Yizhe He
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
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27
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Zeng C, Zhong L, Liu W, Zhang Y, Yu X, Wang X, Zhang R, Kang T, Liao D. Targeting the Lysosomal Degradation of Rab22a-NeoF1 Fusion Protein for Osteosarcoma Lung Metastasis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2205483. [PMID: 36529692 PMCID: PMC9929137 DOI: 10.1002/advs.202205483] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 11/03/2022] [Indexed: 06/17/2023]
Abstract
Rab22a-NeoF fusion protein has recently been reported as a promising target for osteosarcoma lung metastasis. However, how this fusion protein is regulated in cells remains unknown. Here, using multiple screenings, it is reported that Rab22a-NeoF1 fusion protein is degraded by an E3 ligase STUB1 via the autophagy receptor NDP52-mediated lysosome pathway, which is facilitated by PINK1 kinase. Mechanistically, STUB1 catalyzes the K63-linked ubiquitin chains on lysine112 of Rab22a-NeoF1, which is responsible for the binding of Rab22a-NeoF1 to NDP52, resulting in lysosomal degradation of Rab22a-NeoF1. PINK1 is able to phosphorylate Rab22a-NeoF1 at serine120, which promotes ubiquitination and degradation of Rab22a-NeoF1. Consistently, by upregulating PINK1, Sorafenib and Regorafenib can inhibit osteosarcoma lung metastasis induced by Rab22a-NeoF1. These findings reveal that the lysosomal degradation of Rab22a-NeoF1 fusion protein is targetable for osteosarcoma lung metastasis, proposing that Sorafenib and Regorafenib may benefit cancer patients who are positive for the RAB22A-NeoF1 fusion gene.
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Affiliation(s)
- Cuiling Zeng
- State Key Laboratory of Oncology in South ChinaSun Yat‐sen University Cancer CenterCollaborative Innovation Center for Cancer MedicineGuangzhou510060China
| | - Li Zhong
- Center of Digestive DiseasesThe Seventh Affiliated Hospital, Sun Yat‐sen UniversityShenzhen518107China
- Scientific Research CenterThe Seventh Affiliated Hospital, Sun Yat‐sen UniversityShenzhenChina
| | - Wenqiang Liu
- State Key Laboratory of Oncology in South ChinaSun Yat‐sen University Cancer CenterCollaborative Innovation Center for Cancer MedicineGuangzhou510060China
- Department of OncologyThe Fifth Affiliated Hospital, Sun Yat‐sen UniversityZhuhai519000China
| | - Yu Zhang
- State Key Laboratory of Oncology in South ChinaSun Yat‐sen University Cancer CenterCollaborative Innovation Center for Cancer MedicineGuangzhou510060China
| | - Xinhao Yu
- State Key Laboratory of Oncology in South ChinaSun Yat‐sen University Cancer CenterCollaborative Innovation Center for Cancer MedicineGuangzhou510060China
| | - Xin Wang
- State Key Laboratory of Oncology in South ChinaSun Yat‐sen University Cancer CenterCollaborative Innovation Center for Cancer MedicineGuangzhou510060China
| | - Ruhua Zhang
- State Key Laboratory of Oncology in South ChinaSun Yat‐sen University Cancer CenterCollaborative Innovation Center for Cancer MedicineGuangzhou510060China
| | - Tiebang Kang
- State Key Laboratory of Oncology in South ChinaSun Yat‐sen University Cancer CenterCollaborative Innovation Center for Cancer MedicineGuangzhou510060China
| | - Dan Liao
- State Key Laboratory of Oncology in South ChinaSun Yat‐sen University Cancer CenterCollaborative Innovation Center for Cancer MedicineGuangzhou510060China
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28
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Xie L, Yin W, Tang F, He M. Pan-Cancer analysis of TERT and Validation in Osteosarcoma Cell Lines. Biochem Biophys Res Commun 2023; 639:106-116. [PMID: 36476950 DOI: 10.1016/j.bbrc.2022.11.068] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 11/22/2022] [Accepted: 11/23/2022] [Indexed: 11/27/2022]
Abstract
PURPOSE To investigate the possible functions of TERT in pan-cancer and OS. METHODS First, differential TERT gene expression analysis was conducted using multi-omics data integrative analyses, including differential expression, prognosis, the correlation between infiltrating inflammatory immune cells, and mutation in pan-cancer. Furthermore, differential TERT gene expression analysis was conducted using mRNA expression profiles related to OS based on the GEO Datasets. Various differentially expressed genes were chosen based on a fitness threshold for further investigations. Finally, the function of the TERT gene was assessed in OS cells, including cellular proliferation, migration, and metastasis. RESULTS Pan-cancer research demonstrated that variable expression of TERT was not only associated with numerous types of human cancer but was also intimately linked to DNA methylation. Bioinformatic investigation revealed a link between the differential expression of TERT with immune cell infiltration in the tumor microenvironment (TME). In vitro studies indicated that inhibition of TERT decreased OS cell proliferation, motility, and metastasis. CONCLUSION TERT may serve as a useful genomic biomarker for the diagnosis and prediction of pan-cancer and as a prospective therapeutic target for the treatment of OS.
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Affiliation(s)
- Long Xie
- Division of Spinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China; Trauma Department of Orthopaedics, The Affiliated Yuebei People's Hospital of Shantou University Medical College, Shaoguan, Guangdong Province, China
| | - Wenhua Yin
- Trauma Department of Orthopaedics, The Affiliated Yuebei People's Hospital of Shantou University Medical College, Shaoguan, Guangdong Province, China
| | - Fuxing Tang
- Division of Spinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Maolin He
- Division of Spinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.
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Du L, Zhu G, Xu Y, Han B, Wang Y, Zhu M, Meng Y, Chen H, Yu Z. Integrated radiochemotherapy study of ZIF-8 coated with osteosarcoma-platelet hybrid membranes for the delivery of Dbait and Adriamycin. Front Bioeng Biotechnol 2023; 11:1147064. [PMID: 36873373 PMCID: PMC9981937 DOI: 10.3389/fbioe.2023.1147064] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 02/09/2023] [Indexed: 02/19/2023] Open
Abstract
Introduction: The toxic side effects of systemic high-dose chemotherapy and poor sensitivity to radiotherapy hinder the survival rate of patients with osteosarcoma (OS). Nanotechnology offers new solutions for OS treatment; however, conventional nanocarriers suffer from inadequate targeting of tumors and short in vivo circulation time. Methods: Here, we designed a novel drug delivery system, [Dbait-ADM@ZIF-8]OPM, which uses OS-platelet hybrid membranes to encapsulate nanocarriers, to enhance the targeting and circulation time of nanocarriers, thereby enabling high enrichment of the nanocarriers in OS sites. Results: In the tumor microenvironment, the pH-sensitive nanocarrier, which is the metal-organic framework ZIF-8, dissociates to release radiosensitizer Dbait and the classical chemotherapeutic agent Adriamycin for the integrated treatment of OS via radiotherapy and chemotherapy. Benefiting from the excellent targeting ability of the hybrid membrane and the outstanding drug loading capacity of the nanocarrier, [Dbait-ADM@ZIF-8]OPM showed potent anti-tumor effects in tumor-bearing mice with almost no significant biotoxicity. Conclusion: Overall, this project is a successful exploration of the combination of radiotherapy and chemotherapy of OS treatment. Our findings solve the problems of the insensitivity of OS to radiotherapy and the toxic side effects of chemotherapy. Furthermore, this study is an expansion of the research of OS nanocarriers and provides new potential treatments for OS.
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Affiliation(s)
- Longhai Du
- Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai, China
| | - Guanghao Zhu
- Department of Otolaryngology, Head and Neck Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Yanlong Xu
- Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai, China
| | - Binxu Han
- Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai, China
| | - Yu Wang
- Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai, China
| | - Minhui Zhu
- Department of Otolaryngology, Head and Neck Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Yingdi Meng
- Department of Otolaryngology, Head and Neck Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Huaiwen Chen
- Department of Otolaryngology, Head and Neck Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Zuochong Yu
- Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai, China
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Li Z, Xu B, Cai J, Zha Z. Cancer-Specific Survival after Limb Salvage versus Amputation in Children and Adolescents with Osteosarcoma: A Population-Based Analysis with Propensity Score Matching. JOURNAL OF ONCOLOGY 2023; 2023:8635829. [PMID: 37089259 PMCID: PMC10118882 DOI: 10.1155/2023/8635829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 07/20/2022] [Indexed: 04/25/2023]
Abstract
Background The study aims to identify whether osteosarcoma patients of children and young adults will benefit from a survival profit from the choice of the operation method. Methods The National Cancer Institute SEER database from 2000 to 2018 was selected for a retrospective analysis of 1630 children and young adults with a primary diagnosis of osteosarcoma, 1222 who underwent limb-preserving surgery, and 408 who underwent amputation. Confounders were controlled for by propensity score matching (PSM), cancer-specific survival (CSS) was analyzed using the Kaplan-Meier method, and univariate and multivariate Cox regression was used to analyze the factors influencing the prognosis of children and young osteosarcoma patients after surgery. A nomogram plot predicted 1-, 3-, and 5- survival rate in osteosarcoma. The model's accuracy was validated by the area under the ROC and calibration curves. Results After PSM, multifactor Cox regression analysis found AJCC Stage III-IV (CSS : HR = 5.26, 95% CI 1.95-14.18, p=0. 001; HR = 5.54, 95% CI 2.56-12.01, p < 0. 001. Limb salvage surgery (CSS : HR = 0.58, 95% CI 0.44-0.77, p < 0. 001) has independent impact factors for CSS prognosis. The survival curve before and after PSM showed that patients with osteosarcoma of children and young adults who underwent limb salvage surgery had a survival benefit compared with those who underwent amputation surgery. Gender, chemotherapy, histology, primary tumor site, stage, and surgical modality were modeled in a total of six variables in the nomogram. The model exhibited good predictive performance. The AUC were 0.823, 0.74, and 0.757 for training set at 1, 3, and 5 years, respectively. The AUC of validation set 0.666, 0.722, and 0.699 at 1, 3, and 5 years, respectively. The model also predicted CSS with good fidelity for both datasets. This model was significantly superior to the 8th edition of the AJCC TNM staging system, with a better net benefit in predicting CSS in children and young adults with osteosarcoma. Conclusion Limb salvage surgery is an option for children and young adults with osteosarcoma and cancer-specific survival rates can be improved by receiving limb salvage surgery.
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Affiliation(s)
- Zhenwei Li
- Center for Bone, Joint and Sports Medicine, The First Hospital of Jinan University, Jinan University, Guangzhou, China
- Department of Orthopedics, The Second Affiliated Hospital of Bengbu Medical College, Anhui Province, China
| | - Bo Xu
- Department of Orthopedic, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Jingjing Cai
- School of Clinical Medicine, Bengbu Medical College, Anhui Province, China
| | - Zhengang Zha
- Center for Bone, Joint and Sports Medicine, The First Hospital of Jinan University, Jinan University, Guangzhou, China
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Cheng G, An F, Cao Z, Zheng M, Zhao Z, Wu H. DPY30 promotes the growth and survival of osteosarcoma cell by regulating the PI3K/AKT signal pathway. Eur J Histochem 2022; 67:3413. [PMID: 36546421 PMCID: PMC9827427 DOI: 10.4081/ejh.2023.3413] [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: 03/27/2022] [Accepted: 09/11/2022] [Indexed: 12/24/2022] Open
Abstract
Osteosarcoma (OS) is characterized by aggressive features including invasiveness and high incidence of metastasis. OS patients with metastases are difficult to treat and suffer from a poor prognosis. DPY30 (protein dpy-30 homolog) is a key component of SET1/MLL family of H3K4 methyltransferases, which is implicated in the progression of multiple cancers. However, the potential functional engagement of DPY30 in OS remains to be unveiled. The objective of this study is to investigate the potential roles of DPY30 in the regulation of malignant phenotypes of OS cells. We examined DPY30 expression from a published dataset (GSE28424) as well as in OS tissues and adjacent normal tissues from OS patients. The association of DPY30 expression level and clinicopathologic parameters was assessed by Chi-square test. The role of DPY30 in regulating the malignant phenotype of OS cells and tumorigenesis was examined by in vitro functional assays and xenograft mouse model. We reported an upregulation of DPY30 in OS tumor tissues in both published dataset and clinical samples. A high level of DPY30 expression was associated with larger tumor size and more metastasis in OS patients, as well as poor overall survival. DPY30 knockdown in OS cells significantly impairs proliferation, migration and invasion, but induced cellular apoptosis. We further demonstrated that the agonist of PI3K/AKT pathway can rescue the inhibitory effects of DPY30 knockdown in OS cells. Together, our data indicate that DPY30 functions as an oncogene to promote the malignancy of OS cells possibly through PI3K/AKT pathway. The dependency of OS cells on DPY30 overexpression is a targetable vulnerability in OS cells.
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Affiliation(s)
- Gong Cheng
- Department of Orthopedics, Yantaishan Hospital, Yantai City, Shandong Province,*Gong Cheng and Fengmin An are co-first authors
| | - Fengmin An
- Department of Sports Medicine, Yantai Affiliated Hospital of Binzhou Medical University, Yantai City, Shandong Province, China,*Gong Cheng and Fengmin An are co-first authors
| | - Zhilin Cao
- Department of Orthopedics, Yantaishan Hospital, Yantai City, Shandong Province
| | - Mingdi Zheng
- Department of Orthopedics, Yantaishan Hospital, Yantai City, Shandong Province
| | - Zhongyuan Zhao
- Department of Orthopedics, Yantaishan Hospital, Yantai City, Shandong Province
| | - Hao Wu
- Department of Orthopedics, Yantaishan Hospital, Yantai City, Shandong Province,Correspondence: Hao Wu, Department of Orthopedics, Yantaishan Hospital, No. 10087 Science and Technology Avenue, Laishan District, Yantai City 246003, Shandong Province, China. Tel. +86.0535.6863159.
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Sun H, Zhou X, Zhang Y, Zhang L, Yu X, Ye Z, Laurencin CT. Bone Implants (Bone Regeneration and Bone Cancer Treatments). BIOFABRICATION FOR ORTHOPEDICS 2022:265-321. [DOI: 10.1002/9783527831371.ch10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Niu J, Yan T, Guo W, Wang W, Ren T, Huang Y, Zhao Z, Yu Y, Chen C, Huang Q, Lou J, Guo L. The COPS3-FOXO3 positive feedback loop regulates autophagy to promote cisplatin resistance in osteosarcoma. Autophagy 2022:1-18. [DOI: 10.1080/15548627.2022.2150003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Affiliation(s)
- Jianfang Niu
- Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Taiqiang Yan
- Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Wei Guo
- Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Wei Wang
- Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Tingting Ren
- Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Yi Huang
- Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Zhiqing Zhao
- Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Yiyang Yu
- Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Chenglong Chen
- Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Qingshan Huang
- Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Jingbing Lou
- Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Lei Guo
- Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
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Todosenko N, Yurova K, Khaziakhmatova O, Malashchenko V, Khlusov I, Litvinova L. Heparin and Heparin-Based Drug Delivery Systems: Pleiotropic Molecular Effects at Multiple Drug Resistance of Osteosarcoma and Immune Cells. Pharmaceutics 2022; 14:pharmaceutics14102181. [PMID: 36297616 PMCID: PMC9612132 DOI: 10.3390/pharmaceutics14102181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/29/2022] [Accepted: 10/10/2022] [Indexed: 11/23/2022] Open
Abstract
One of the main problems of modern health care is the growing number of oncological diseases both in the elderly and young population. Inadequately effective chemotherapy, which remains the main method of cancer control, is largely associated with the emergence of multidrug resistance in tumor cells. The search for new solutions to overcome the resistance of malignant cells to pharmacological agents is being actively pursued. Another serious problem is immunosuppression caused both by the tumor cells themselves and by antitumor drugs. Of great interest in this context is heparin, a biomolecule belonging to the class of glycosaminoglycans and possessing a broad spectrum of biological activity, including immunomodulatory and antitumor properties. In the context of the rapid development of the new field of “osteoimmunology,” which focuses on the collaboration of bone and immune cells, heparin and delivery systems based on it may be of intriguing importance for the oncotherapy of malignant bone tumors. Osteosarcoma is a rare but highly aggressive, chemoresistant malignant tumor that affects young adults and is characterized by constant recurrence and metastasis. This review describes the direct and immune-mediated regulatory effects of heparin and drug delivery systems based on it on the molecular mechanisms of (multiple) drug resistance in (onco) pathological conditions of bone tissue, especially osteosarcoma.
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Affiliation(s)
- Natalia Todosenko
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, 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
| | - Vladimir Malashchenko
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
| | - Igor Khlusov
- Department of Morphology and General Pathology, Siberian State Medical University, 634050 Tomsk, Russia
| | - Larisa Litvinova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
- Correspondence:
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Liang J, Chen J, Hua S, Qin Z, Lu J, Lan C. Bioinformatics analysis of the key genes in osteosarcoma metastasis and immune invasion. Transl Pediatr 2022; 11:1656-1670. [PMID: 36345453 PMCID: PMC9636461 DOI: 10.21037/tp-22-402] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/08/2022] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND This study sought to identify potential key genes for osteosarcoma metastasis and analyze their immune infiltration patterns using bioinformatic methods. METHODS We obtained transcriptomic data related to osteosarcoma and osteosarcoma with metastasis from the Therapeutically Applicable Research to Generate Effective Treatment (TARGET) and The Gene Expression Omnibus (GEO) databases and identified the differentially expressed genes (DEGs). We also identified potential key genes for osteosarcoma metastasis by a protein-protein interaction network analysis, and we conducted a Gene Ontology (GO) functional annotation analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to identify the core genes for prognosis, immune cell infiltration, and drug sensitivity, and the risk prediction and prognosis models of metastasis were constructed. RESULTS By comparing the transcriptome data of osteosarcomas without metastasis and those with metastasis, a total of 19 core DEGs were identified, and the GO and KEGG analyses revealed an association between these DEGs and the regulation of cell division, secretory granule lumen, the Ras-associated protein 1 (Rap1) signaling pathway, and the mitogen-activated protein kinase (MAPK) signaling pathway. Compared with other immune cells, macrophage infiltration was predominant in osteosarcoma samples with metastatic osteosarcoma, and insulin-like growth factors-1 (IGF1) and myelocytomatosis protein 2 (MYC2) genes were predicted to more than 50 targeted therapeutic agents. A metastasis prediction model with 5 genes [i.e., ecotropic viral integration site 2B (EVI2B), CCAAT/enhancer binding protein (CEBPA), lymphocyte cytosolic protein 2 (LCP2), selectin L (SELL), and Niemann-Pick disease, type C2A (NPC2A)], and a prognostic model with 4 genes [i.e., insulin-like growth factors-2 (IGF2), cathepsin O (CTSO), Niemann-Pick disease, type C2 (NPC2), and amyloid beta (A4) precursor protein-binding, family B, member 1 interacting protein (APBB1IP)] were developed. CONCLUSIONS We constructed a metastasis prediction model with 5 genes (i.e., EVI2B, CEBPA, LCP2, SELL, and NPC2A), and a prognostic model with 4 genes (i.e., IGF2, CTSO, NPC2, and APBB1IP) that may be potential biomarkers for osteosarcoma metastasis. Macrophages are the predominant immune infiltrating cells in osteosarcoma metastasis and may provide a new direction for the treatment of osteosarcoma.
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Affiliation(s)
- Junqing Liang
- Department of Joint Surgery, The People's Hospital of Baise, Baise, China
| | - Jun Chen
- Department of Joint Surgery, The People's Hospital of Baise, Baise, China
| | - Shuliang Hua
- Department of Joint Surgery, The People's Hospital of Baise, Baise, China
| | - Zhuangguang Qin
- Department of Joint Surgery, The People's Hospital of Baise, Baise, China
| | - Jili Lu
- Department of Joint Surgery, The People's Hospital of Baise, Baise, China
| | - Changgong Lan
- Department of Joint Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
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Intercalary frozen autografts for reconstruction of bone defects following meta-/diaphyseal tumor resection at the extremities. BMC Musculoskelet Disord 2022; 23:890. [PMID: 36180843 PMCID: PMC9526247 DOI: 10.1186/s12891-022-05840-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 09/14/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
For patients with malignant limb tumors, salvage surgery can be achieved using endoprosthesis or biological reconstructions like allograft or autograft. In carefully selected patients, resected bone can be recycled after sterilization using methods like autoclaving, irradiation, pasteurization or freezing with liquid nitrogen. We evaluated the clinical outcome and complications of malignant limb tumors treated with intercalary resection and frozen autograft reconstruction.
Methods
We reviewed 33 patients whose malignant bone tumors were treated by wide resection and reconstruction with recycling liquid nitrogen-treated autografts between 2006 and 2017. Limb function, bone union at the osteotomy site and complications were evaluated. Functional outcome was assessed using the Musculoskeletal Tumor Society (MSTS) scoring system.
Results
The cohort comprised 16 males and 17 females, with a mean age of 35.4 years (14–76 years). The most common tumor was osteosarcoma (7 cases). Tumors were located in the humerus (5), ulna (1), femur (10) and tibia (17). The mean follow-up was 49.9 months (range 12–127 months). Of the 33 patients, 16 remained disease-free, and 3 were alive with disease. The mean size of the defect after tumor resection was 11.6 cm (range 6–25 cm). Bone union was achieved in 32 patients, with a mean union time of 8.8 months (range 4–18 months). Complications included 1 graft nonunion, 2 infections (1 superficial, 1 deep infection), 1 leg length discrepancy, 2 graft fractures and 3 local recurrences. The mean MSTS score was 87.2% (range 70–100%).
Conclusion
Liquid nitrogen-treated tumor-bearing autograft is an effective option for biological reconstruction after meta-/diaphyseal tumor resection of long bones. This method has excellent clinical outcomes and is especially recommended for patients with no severe osteolytic bone tumors.
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Wu Q, Yang C, Yan H, Wang Z, Zhang Z, Wang Q, Huang R, Hu X, Li B. Prognostic Nomogram of Osteocarcinoma after Surgical Treatment. JOURNAL OF ONCOLOGY 2022; 2022:9778555. [PMID: 37954859 PMCID: PMC10635754 DOI: 10.1155/2022/9778555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 07/11/2022] [Accepted: 07/19/2022] [Indexed: 11/14/2023]
Abstract
Purpose This study aimed to establish a valid prognostic nomogram for osteocarcinoma after surgical management. Methods Based on the SEER database, we retrieved the clinical variables of patients confirmed to have osteocarcinoma between 1975 and 2016. Then, we performed univariate and multivariate analyses and constructed a nomogram of overall survival. Results Multivariate analysis of the primary cohort revealed that the independent factors for survival were age, grade, pathologic stage, T stage, and surgery performed. All these factors were showed by the nomogram. The correction curve of survival probability showed that the prediction results of nomogram well agreed with the actual observation results. The C index of the nomogram used to predict survival was 0.82; the AUC of 1-year, 3-year, and 5-year survival rates in the training cohort were 0.9, 0.819, and 0.80631, respectively, indicating that the model was accurate and reliable; whether the operation was performed or not; T stage; grade; and age were the main factors affecting the survival of patients. The AUC of the validation cohort for 1 year, 3 years, and 5 years were 0.8, 0.831, and 0.80023, respectively. Conclusion The proposed nomogram can more accurately predict the prognosis of patients with osteocarcinoma after surgical management. This could be a potential method that services clinical work.
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Affiliation(s)
- Qiuli Wu
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Canchun Yang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China
| | - Haolin Yan
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China
| | - Zheyu Wang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China
| | - Zhilei Zhang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China
| | - Qiwei Wang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China
| | - Renyuan Huang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China
| | - Xumin Hu
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China
| | - Bo Li
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China
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Li HB, Huang G, Tu J, Lv DM, Jin QL, Chen JK, Zou YT, Lee DF, Shen JN, Xie XB. METTL14-mediated epitranscriptome modification of MN1 mRNA promote tumorigenicity and all-trans-retinoic acid resistance in osteosarcoma. EBioMedicine 2022; 82:104142. [PMID: 35810559 PMCID: PMC9272358 DOI: 10.1016/j.ebiom.2022.104142] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 06/15/2022] [Accepted: 06/21/2022] [Indexed: 11/29/2022] Open
Abstract
Background Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents. The molecular mechanism behind OS progression and metastasis remains poorly understood, which limits the effectiveness of current therapies. RNA N6-methyladenosine (m6A) modification plays a critical role in influencing RNA fate. However, the biological significance of m6A modification and its potential regulatory mechanisms in the development of OS remain unclear. Methods Liquid chromatography-tandem mass spectrometry (LC-MS/MS), dot blotting, and colorimetric ELISA were used to detect m6A levels. Western blotting, quantitative real-time PCR (RT-qPCR) and immunohistochemistry (IHC) were used to investigate METTL14 expression levels. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptomic RNA sequencing (RNA-seq) were used to screen the target genes of METTL14. RNA pull-down and RNA immunoprecipitation (RIP) assays were conducted to explore the specific binding of target genes and relevant m6A “readers”. RNA stability and polysome analysis assays were used to detect the half-lives and translation efficiencies of the downstream genes of METTL14. IHC and clinical data were applied to explore the clinical correlations of METTL14 and its downstream target genes with the prognosis of OS. Findings We observed the abundance of m6A modifications in OS and revealed that METTL14 plays an oncogenic role in facilitating OS progression. MeRIP-seq and RNA-seq revealed that MN1 is a downstream gene of METTL14. MN1 contributes to tumor progression and all-trans-retinoic acid (ATRA) chemotherapy resistance in OS. Mechanistically, MN1 is methylated by METTL14, specifically in the coding sequence (CDS) regions, and this modification is recognized by the specific m6A reader insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) to prevent MN1 mRNA degradation and promote it translation efficiency. IHC showed that MN1 expression was positively correlated with METTL14 and IGF2BP2 expression in OS tissues. The METTL14-IGF2BP2-MN1 panel demonstrated more promising prognostic value for OS patients than any of these molecules individually. Interpretation Our study revealed that METTL14 contributes to OS progression and ATRA resistance as an m6A RNA methylase by regulating the stability and translation efficiency of MN1 and thus provides both an underlying biomarker panel for prognosis prediction in OS patients. Funding This work was supported by the National Natural Science Foundation of China (Grants 81972510 and 81772864).
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Affiliation(s)
- Hong-Bo Li
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Gang Huang
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Jian Tu
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Dong-Ming Lv
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Qing-Lin Jin
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Jun-Kai Chen
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Yu-Tong Zou
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Dung-Fang Lee
- Department of Integrative Biology & Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX 77030-1501, US
| | - Jing-Nan Shen
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
| | - Xian-Biao Xie
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
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Luo A, Liu H, Huang C. KLF5-induced miR-487a augments the progression of osteosarcoma cells by targeting NKX3-1 in vitro. Oncol Lett 2022; 24:258. [PMID: 35765275 PMCID: PMC9219018 DOI: 10.3892/ol.2022.13378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 05/10/2022] [Indexed: 11/19/2022] Open
Abstract
MicroRNAs (miRNAs or miRs) are involved in the development and progression of numerous types of cancer however their role in osteosarcoma has not been fully clarified. The present study aimed to use high-throughput bioinformatics analysis as well as in vitro experiments to investigate the potential role of transcription factors, miRNAs and their targets in the progression of osteosarcoma. miRNA data and clinical information of osteosarcoma were obtained from Gene Expression Omnibus database to investigate differentially expressed miRNAs. The expression of miRNAs/mRNAs in osteosarcoma cell lines was detected via reverse transcription-quantitative (RT-qPCR). MTT and colony formation assay were used to determine cell proliferation ability and transwell assay was used to observe cell invasion and migration ability. A total of four prediction algorithms for miRNA-mRNA interactions were used to determine potential target genes of miR-487a. Predicted target genes were used to intersect with overlapped differentially expressed genes (DEGs) from GSE12865 and The Cancer Genome Atlas osteosarcoma datasets. Expression of NK3 homeobox 1 (NKX3-1) was analyzed by western blotting and RT-qPCR assay. Dual luciferase assay was conducted to verify whether NKX3-1 was a direct target of miR-487a. The regulatory association between Kruppel-like factor 5 (KLF5) and miR-487a was detected using chromatin immunoprecipitation assay. miR-487a was upregulated in osteosarcoma tissue (GSE65071 and GSE28423) and cell lines (HOS and MG63). miR-487a mimic promoted proliferation, migration and invasion of osteosarcoma cells. NKX3-1 was a direct target of miR-487a and transfection of NKX3-1 plasmid reversed the effect of miR-487a on proliferation, migration and invasion of osteosarcoma cells. KLF5 enhanced miR-487a expression by directly binding to its promoter region and miR-487a inhibitor reversed the effect of KLF5 on proliferation, migration and invasion of osteosarcoma cells. The present results indicated that KLF5/miR-487a signaling promoted invasion and metastasis of osteosarcoma cells via targeting NKX3-1.
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Affiliation(s)
- Anyu Luo
- Department of Orthopedics, Hanyang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430051, P.R. China
| | - Hanlin Liu
- Department of Orthopedics, Hanyang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430051, P.R. China
| | - Chen Huang
- Department of Orthopedics, Hanyang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430051, P.R. China
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Wu W, Zhang Z, Jing D, Huang X, Ren D, Shao Z, Zhang Z. SGLT2 inhibitor activates the STING/IRF3/IFN-β pathway and induces immune infiltration in osteosarcoma. Cell Death Dis 2022; 13:523. [PMID: 35662245 PMCID: PMC9166744 DOI: 10.1038/s41419-022-04980-w] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 05/23/2022] [Accepted: 05/26/2022] [Indexed: 02/07/2023]
Abstract
SGLT2 (sodium-glucose cotransporter 2) is an important mediator of epithelial glucose transport and has been reported that SGLT2, robustly and diffusely expressed in malignant cancer cells, was overexpressed in various tumors, and inhibiting the SGLT2 expression significantly inhibited tumor progression. By blocking the functional activity of SGLT2, SGLT2 inhibitors have shown anticancer effects in several malignant cancers, including breast cancer, cervical cancer, hepatocellular cancer, prostate cancer, and lung cancer. However, the anticancer effect of SGLT2 inhibitors in osteosarcoma and the specific mechanism are still unclear. In the present study, we found that SGLT2 was overexpressed at the protein level in osteosarcoma. Furthermore, our results showed that the SGLT2 inhibitor significantly inhibited osteosarcoma tumor growth and induced infiltration of immune cells in vivo by upregulating STING expression and activating the IRF3/IFN-β pathway, which could attribute to the suppression of AKT phosphorylation. In addition, the combined treatment with SGLT2 inhibitor and STING agonist 2'3'-cGAMP exerted synergistic antitumor effects in osteosarcoma. Furthermore, the overexpression of SGLT2 at the protein level was correlated with the degradation of SGLT2 induced by TRIM21. This result demonstrated that SGLT2 is a novel therapeutic target of osteosarcoma, and that the SGLT2 inhibitor, especially in combination with 2'3'-cGAMP, is a potential therapeutic drug.
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Affiliation(s)
- Wei Wu
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Zhenhao Zhang
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Doudou Jing
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Xin Huang
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Dianyun Ren
- grid.33199.310000 0004 0368 7223Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Zengwu Shao
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Zhicai Zhang
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
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Yang YH, Chen JX, Chen QY, Wang Y, Zhou YB, Wang HW, Yuan T, Sun HP, Xie L, Yao ZH, Yang ZZ. Total femur replacement with 18 years of follow-up: A case report. World J Clin Cases 2022; 10:4957-4963. [PMID: 35801021 PMCID: PMC9198875 DOI: 10.12998/wjcc.v10.i15.4957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 12/27/2021] [Accepted: 04/09/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Osteosarcoma is one of the most common primary malignant bone tumors and is more common in adolescents. The femur is the most common site of osteosarcoma, and many patients require total femur replacement. We reviewed the relevant literature and case findings, summarized and analyzed this case in combination with relevant literature, and in doing so improved the understanding of the technology. CASE SUMMARY The case we report was a 15-year-old patient who was admitted to the hospital 15 days after the discovery of a right thigh mass. The diagnosis was osteosarcoma of the right femoral shaft. After completion of neoadjuvant chemotherapy and preoperative preparation, total right femoral resection + artificial total femoral replacement was performed. Then, chemotherapy was continued after surgery. The patient recovered well after treatment, and the function of the affected limb was good. No recurrence, metastasis, prosthesis loosening, dislocation, fracture or other complications were found during 18 years of follow-up. At present, the patient can still work and lives normally. The results of the medium- and long-term follow-up were satisfactory. CONCLUSION Artificial total femur replacement is a feasible limb salvage operation for patients with femoral malignant tumors, and the results of medium- and long-term follow-up are satisfactory.
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Affiliation(s)
- Yi-Hao Yang
- Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Yunnan Cancer Center, Kunming 650118, Yunnan Province, China
| | - Jia-Xiang Chen
- Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Yunnan Cancer Center, Kunming 650118, Yunnan Province, China
| | - Qiu-Yun Chen
- Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Yunnan Cancer Center, Kunming 650118, Yunnan Province, China
| | - Yu Wang
- Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Yunnan Cancer Center, Kunming 650118, Yunnan Province, China
| | - Yao-Bin Zhou
- Department of Orthopaedics, The People’s Hospital of Fuyuan, Fuyuan County, Qujing 655500, Yunnan Province, China
| | - Hong-Wei Wang
- Department of Orthopaedics, The People’s Hospital of Fuyuan, Fuyuan County, Qujing 655500, Yunnan Province, China
| | - Tao Yuan
- Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Yunnan Cancer Center, Kunming 650118, Yunnan Province, China
| | - Hong-Pu Sun
- Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Yunnan Cancer Center, Kunming 650118, Yunnan Province, China
| | - Lin Xie
- Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Yunnan Cancer Center, Kunming 650118, Yunnan Province, China
| | - Zhi-Hong Yao
- Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Yunnan Cancer Center, Kunming 650118, Yunnan Province, China
| | - Zuo-Zhang Yang
- Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Yunnan Cancer Center, Kunming 650118, Yunnan Province, China
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Blay JY, Palmerini E, Bollard J, Aguiar S, Angel M, Araya B, Badilla R, Bernabeu D, Campos F, Chs CS, Carvajal Montoya A, Casavilca-Zambrano S, Castro-Oliden, Chacón M, Clara-Altamirano MA, Collini P, Correa Genoroso R, Costa FD, Cuellar M, Dei Tos AP, Dominguez Malagon HR, Donati DM, Dufresne A, Eriksson M, Farias-Loza M, Frezza AM, Frisoni T, Garcia-Ortega DY, Gerderblom H, Gouin F, Gómez-Mateo MC, Gronchi A, Haro J, Hindi N, Huanca L, Jimenez N, Karanian M, Kasper B, Lopes A, Lopes David BB, Lopez-Pousa A, Lutter G, Maki RG, Martinez-Said H, Martinez-Tlahuel JL, Mello CA, Morales Pérez JM, Moura DS, Nakagawa SA, Nascimento AG, Ortiz-Cruz EJ, Patel S, Pfluger Y, Provenzano S, Righi A, Rodriguez A, Santos TG, Scotlandi K, Mlg S, Soulé T, Stacchiotti S, Valverde CM, Waisberg F, Zamora Estrada E, Martin-Broto J. SELNET clinical practice guidelines for bone sarcoma. Crit Rev Oncol Hematol 2022; 174:103685. [PMID: 35460913 DOI: 10.1016/j.critrevonc.2022.103685] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/14/2022] [Accepted: 04/14/2022] [Indexed: 11/29/2022] Open
Abstract
Bone sarcoma are infrequent diseases, representing < 0.2% of all adult neoplasms. A multidisciplinary management within reference centers for sarcoma, with discussion of the diagnostic and therapeutic strategies within an expert multidisciplinary tumour board, is essential for these patients, given its heterogeneity and low frequency. This approach leads to an improvement in patient's outcome, as demonstrated in several studies. The Sarcoma European Latin-American Network (SELNET), aims to improve clinical outcome in sarcoma care, with a special focus in Latin-American countries. These Clinical Practice Guidelines (CPG) have been developed and agreed by a multidisciplinary expert group (including medical and radiation oncologist, surgical oncologist, orthopaedic surgeons, radiologist, pathologist, molecular biologist and representatives of patients advocacy groups) of the SELNET consortium, and are conceived to provide the standard approach to diagnosis, treatment and follow-up of bone sarcoma patients in the Latin-American context.
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Affiliation(s)
- J Y Blay
- Léon Bérard Center, 28 rue Laennec 69373 Lyon Cedex 08, France.
| | - E Palmerini
- IRCCS Istituto Ortopedico Rizzoli, University of Bologna, Via Pupilli, 1, 40136, Bologna, Italy
| | - J Bollard
- Léon Bérard Center, 28 rue Laennec 69373 Lyon Cedex 08, France
| | - S Aguiar
- A.C.Camargo Cancer Center, Rua prof Antonio Prudente, 211 - Liberdade, São Paulo 01509-010, Brazil
| | - M Angel
- Instituto Alexander Fleming, Av. Cramer 1180. CP, C1426ANZ Buenos Aires, Argentina
| | - B Araya
- Hospital Dr. R. A. Calderón Guardia, 7-9 Av, 15-17 St, Aranjuez, San José, Costa Rica
| | - R Badilla
- Hospital Dr. R. A. Calderón Guardia, 7-9 Av, 15-17 St, Aranjuez, San José, Costa Rica
| | - D Bernabeu
- Hospital Universitario La Paz, Paseo de la Castellana, 261, 28046 Madrid, Spain
| | - F Campos
- A.C.Camargo Cancer Center, Rua prof Antonio Prudente, 211 - Liberdade, São Paulo 01509-010, Brazil
| | - Caro-Sánchez Chs
- Instituto Nacional de Cancerologia, Torre Nueva de Hospitalización, primer piso. Av. San Fernando 86, Colonia Niño Jesus. CP, 14080 Tlalpan Mexico
| | - A Carvajal Montoya
- Hospital Dr. R. A. Calderón Guardia, 7-9 Av, 15-17 St, Aranjuez, San José, Costa Rica
| | - S Casavilca-Zambrano
- Instituto Nacional de Enfermedades Neoplásicas, Av. Angamos Este 2520, Lima, Peru
| | - Castro-Oliden
- Instituto Nacional de Enfermedades Neoplásicas, Av. Angamos Este 2520, Lima, Peru
| | - M Chacón
- Instituto Alexander Fleming, Av. Cramer 1180. CP, C1426ANZ Buenos Aires, Argentina
| | - M A Clara-Altamirano
- Instituto Nacional de Cancerologia, Torre Nueva de Hospitalización, primer piso. Av. San Fernando 86, Colonia Niño Jesus. CP, 14080 Tlalpan Mexico
| | - P Collini
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133 Milano, Italy
| | - R Correa Genoroso
- Hospital Clínico Universitario Virgen de la Victoria, Campus Universitario de Teatinos s/n, 29010, Malaga, Spain
| | - F D Costa
- A.C.Camargo Cancer Center, Rua prof Antonio Prudente, 211 - Liberdade, São Paulo 01509-010, Brazil
| | - M Cuellar
- Instituto Nacional de Cancerologia, Torre Nueva de Hospitalización, primer piso. Av. San Fernando 86, Colonia Niño Jesus. CP, 14080 Tlalpan Mexico
| | - A P Dei Tos
- Treviso General Hospital Treviso, University of Padua, Padova, Italy
| | - H R Dominguez Malagon
- Instituto Nacional de Cancerologia, Torre Nueva de Hospitalización, primer piso. Av. San Fernando 86, Colonia Niño Jesus. CP, 14080 Tlalpan Mexico
| | - D M Donati
- IRCCS Istituto Ortopedico Rizzoli, University of Bologna, Via Pupilli, 1, 40136, Bologna, Italy
| | - A Dufresne
- Léon Bérard Center, 28 rue Laennec 69373 Lyon Cedex 08, France
| | - M Eriksson
- Skane University Hospital and Lund University, Lund, Sweden
| | - M Farias-Loza
- Instituto Nacional de Enfermedades Neoplásicas, Av. Angamos Este 2520, Lima, Peru
| | - A M Frezza
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133 Milano, Italy
| | - T Frisoni
- IRCCS Istituto Ortopedico Rizzoli, University of Bologna, Via Pupilli, 1, 40136, Bologna, Italy
| | - D Y Garcia-Ortega
- Instituto Nacional de Cancerologia, Torre Nueva de Hospitalización, primer piso. Av. San Fernando 86, Colonia Niño Jesus. CP, 14080 Tlalpan Mexico
| | - H Gerderblom
- Leiden University Medical Center, Leiden, The Netherlands
| | - F Gouin
- Léon Bérard Center, 28 rue Laennec 69373 Lyon Cedex 08, France
| | - M C Gómez-Mateo
- Hospital Universitario Miguel Servet, Paseo Isabel la Católica, 1-3, 50009 Zaragoza, Spain
| | - A Gronchi
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133 Milano, Italy
| | - J Haro
- Instituto Nacional de Enfermedades Neoplásicas, Av. Angamos Este 2520, Lima, Peru
| | - N Hindi
- Research Health Institute Fundacion Jimenez Diaz (IIS/FJD), 28015 Madrid, Spain; Hospital Fundación Jimenez Diaz University Hospital, 28040 Madrid, Spain; General de Villalba University Hospital, 28400 Madrid, Spain
| | - L Huanca
- Instituto Nacional de Enfermedades Neoplásicas, Av. Angamos Este 2520, Lima, Peru
| | - N Jimenez
- Hospital San Vicente de Paúl, Avenue 16, streets 10 and 14, Heredia, Costa Rica
| | - M Karanian
- Léon Bérard Center, 28 rue Laennec 69373 Lyon Cedex 08, France
| | - B Kasper
- University of Heidelberg, Mannheim Cancer Center, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
| | - A Lopes
- A.C.Camargo Cancer Center, Rua prof Antonio Prudente, 211 - Liberdade, São Paulo 01509-010, Brazil
| | - B B Lopes David
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133 Milano, Italy
| | - A Lopez-Pousa
- Hospital de la Santa Creu i Sant Pau, Carrer de Sant Quintí, 89, 08041 Barcelona, Spain
| | - G Lutter
- Instituto Alexander Fleming, Av. Cramer 1180. CP, C1426ANZ Buenos Aires, Argentina
| | - R G Maki
- University of Pennsylvania, Abramson Cancer Center, 3400 Civic Center Boulevard, Philadelphia, PA 19104 USA
| | - H Martinez-Said
- Centro Oncologico Integral, Hospital Medica Sur, Planta Baja Torre III - Cons. 305, Col. Toriello Guerra, Deleg. Tlalpan. C.P., 14050, Mexico, D.F
| | - J L Martinez-Tlahuel
- Instituto Nacional de Cancerologia, Torre Nueva de Hospitalización, primer piso. Av. San Fernando 86, Colonia Niño Jesus. CP, 14080 Tlalpan Mexico
| | - C A Mello
- A.C.Camargo Cancer Center, Rua prof Antonio Prudente, 211 - Liberdade, São Paulo 01509-010, Brazil
| | - J M Morales Pérez
- Centro Oncologico Integral, Hospital Medica Sur, Planta Baja Torre III - Cons. 305, Col. Toriello Guerra, Deleg. Tlalpan. C.P., 14050, Mexico, D.F
| | - D S Moura
- Hospital Universitario Virgen del Rocio, Av Manuel Siurot s/n, 41013 Sevilla, Spain
| | - S A Nakagawa
- A.C.Camargo Cancer Center, Rua prof Antonio Prudente, 211 - Liberdade, São Paulo 01509-010, Brazil
| | - A G Nascimento
- A.C.Camargo Cancer Center, Rua prof Antonio Prudente, 211 - Liberdade, São Paulo 01509-010, Brazil
| | - E J Ortiz-Cruz
- Hospital Universitario La Paz, MD Anderson Cancer Center, Calle de Arturo Soria, 270, 28033 Madrid, Spain
| | - S Patel
- UT MD Anderson Cancer Center, Houston, TX, USA
| | - Y Pfluger
- Instituto Alexander Fleming, Av. Cramer 1180. CP, C1426ANZ Buenos Aires, Argentina
| | - S Provenzano
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133 Milano, Italy
| | - A Righi
- IRCCS Istituto Ortopedico Rizzoli, University of Bologna, Via Pupilli, 1, 40136, Bologna, Italy
| | - A Rodriguez
- Instituto Alexander Fleming, Av. Cramer 1180. CP, C1426ANZ Buenos Aires, Argentina
| | - T G Santos
- A.C.Camargo Cancer Center, Rua prof Antonio Prudente, 211 - Liberdade, São Paulo 01509-010, Brazil
| | - K Scotlandi
- IRCCS Istituto Ortopedico Rizzoli, University of Bologna, Via Pupilli, 1, 40136, Bologna, Italy
| | - Silva Mlg
- A.C.Camargo Cancer Center, Rua prof Antonio Prudente, 211 - Liberdade, São Paulo 01509-010, Brazil
| | - T Soulé
- Instituto Alexander Fleming, Av. Cramer 1180. CP, C1426ANZ Buenos Aires, Argentina
| | - S Stacchiotti
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133 Milano, Italy
| | - C M Valverde
- Vall d´Hebrón University Hospital, Passeig de la Vall d'Hebron, 119, 08035 Barcelona, Spain
| | - F Waisberg
- Instituto Alexander Fleming, Av. Cramer 1180. CP, C1426ANZ Buenos Aires, Argentina
| | - E Zamora Estrada
- Hospital Dr. R. A. Calderón Guardia, 7-9 Av, 15-17 St, Aranjuez, San José, Costa Rica
| | - J Martin-Broto
- Research Health Institute Fundacion Jimenez Diaz (IIS/FJD), 28015 Madrid, Spain; Hospital Fundación Jimenez Diaz University Hospital, 28040 Madrid, Spain; General de Villalba University Hospital, 28400 Madrid, Spain
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Ye G, Huang M, Li Y, Ouyang J, Chen M, Wen Q, Li X, Zeng H, Long P, Fan Z, Yin J, Ye W, Zhang D. The FAP α -activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway. Acta Pharm Sin B 2022; 12:1288-1304. [PMID: 35530139 PMCID: PMC9072247 DOI: 10.1016/j.apsb.2021.08.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/27/2021] [Accepted: 07/30/2021] [Indexed: 01/02/2023] Open
Abstract
Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties, a high incidence of pulmonary metastasis and a poor prognosis. Chemotherapy is the mainstay of treatment for osteosarcoma. Currently, there are no molecular targeted drugs approved for osteosarcoma treatment, particularly effective drugs for osteosarcoma with pulmonary metastases. It has been reported that fibroblast activation protein alpha (FAPα) is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis, demonstrating that FAPα-targeted agents might be a promising therapeutic strategy for osteosarcoma. In the present study, we reported that the FAPα-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPα-positive osteosarcoma cells in vitro and in vivo. Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells. Importantly, it also decreased the migration and invasion capacities and reversed epithelial–mesenchymal transition (EMT) of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo. Mechanistically, Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway, leading to inhibition of the growth and metastatic spread of osteosarcoma cells. These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPα-positive osteosarcoma, particularly osteosarcoma with pulmonary metastases.
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Dana PM, Sadoughi F, Asemi Z, Yousefi B. Molecular signaling pathways as potential therapeutic targets in osteosarcoma. Curr Med Chem 2022; 29:4436-4444. [PMID: 35139778 DOI: 10.2174/0929867329666220209110009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/01/2022] [Accepted: 01/03/2022] [Indexed: 11/22/2022]
Abstract
Among primary bone malignancies, osteosarcoma (OS) is the most common form causing morbidity and mortality in both adults and children. The interesting point about this malignancy is that nearly 10-20% of its newly diagnosed cases have developed metastasis. This adds up to the fact that the survival rate of both metastatic and non-metastatic patients of osteosarcoma hasn't changed in the past 30 years and suggests that we need to revise our therapeutic options for OS. In recent years, diverse signaling pathways have drawn the attention of the scientific community since they can be great candidates for treating complicated diseases such as cancer. In this review, we have tried to explain the pathophysiology of osteosarcoma by the help of different signaling pathways taking part in its initiation/progression and investigate how this pathway can be targeted for providing more efficient methods.
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Affiliation(s)
- Parisa Maleki Dana
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, I.R. Iran
| | - Fatemeh Sadoughi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, I.R. Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, I.R. Iran
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Wang J, Tang J, Tan X, Zhanghuang C, Jin L, Li M, Zhang Z, Mi T, He D. Amputation Predisposes to Higher Cancer-Specific Mortality Than Limb Salvage Surgery in Pediatric Patients With Osteosarcoma of the Limbs: A Propensity Matching Analysis. Front Surg 2022; 9:817051. [PMID: 35223978 PMCID: PMC8863859 DOI: 10.3389/fsurg.2022.817051] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 01/17/2022] [Indexed: 11/13/2022] Open
Abstract
ObjectiveWith the development of osteosarcoma treatment, limb salvage surgery is gradually replacing amputation as the primary surgical option. Most pediatric osteosarcomas of the limbs undergo limb-salvage surgery. We aimed to use propensity score matching (PSM) analysis test the difference in cancer-specific mortality (CSM) between amputation and limb-salvage surgery in pediatric patients with Osteosarcoma of the limbs. PSM is a statistical method used to deal with data from an Observational Study. The PSM method is designed to reduce the influence of biases and confounding variables to make a more reasonable comparison between experimental and control groups.MethodsPatient information was downloaded from the SEER (surveillance, epidemiology, and End Results) database from 2004 to 2018. We included all primary pediatric osteosarcoma patients who underwent limb salvage or amputation. Multivariate logistic regression models were used to explore the factors influencing patient choice of amputation. Differences in CSM and other causes of mortality (OSM) between limb salvage and amputation were analyzed using cumulative incidence plots and competitive risk regression tests after 1:1 proportional propensity score matching.ResultsA total of 1,058 pediatric patients with limbs Osteosarcoma were included. Patients who underwent amputations were more likely to be male (OR 1.4, P = 0.024) and more likely to have distant metastasis (OR 2.1, P < 0.001). Before propensity matching, CSM was 1.4 times higher in patients undergoing amputation than in patients undergoing limb salvage (P = 0.017) and 3.4 times higher in OSM (P = 0.007). After adjustment for propensity matching, CSM was 1.5 times higher in patients undergoing amputation than in patients undergoing limb salvage (P = 0.028), but there was no significant difference in OSM (HR 3.2, P = 0.078).ConclusionsOur results suggested that amputation is associated with a 1.5-fold increase in CSM in pediatric patients with limbs Osteosarcoma. Therefore, in the surgical selection of pediatric patients with Osteosarcoma, limb salvage surgery should be the first choice in the absence of other contraindications.
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Affiliation(s)
- Jinkui Wang
- Department of Urology, Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Jie Tang
- Department of Epidemiology, Public Health School, Shenyang Medical College, Shenyang, China
| | - Xiaojun Tan
- Department of Urology, Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Chenghao Zhanghuang
- Department of Urology, Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Liming Jin
- Department of Urology, Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Mujie Li
- Department of Urology, Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Zhaoxia Zhang
- Department of Urology, Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Tao Mi
- Department of Urology, Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Dawei He
- Department of Urology, Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- *Correspondence: Dawei He
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Feng X, Zhao Z, Zhao Y, Song Z, Ma Y, Wang W. Development of Personalized Signature Based on the Immune Landscape to Predict the Prognosis of Osteosarcoma and the Response to Immunotherapy and Targeted Therapy. Front Mol Biosci 2022; 8:783915. [PMID: 35127816 PMCID: PMC8811188 DOI: 10.3389/fmolb.2021.783915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 12/30/2021] [Indexed: 11/13/2022] Open
Abstract
As a heterogeneous and aggressive disease, osteosarcoma (OS) faces great challenges to prognosis and individualized treatment. Hence, we explore the role of immune-related genes in predicting prognosis and responsiveness to immunotherapy and targeted therapies in patients with OS based on the immunological landscape of osteosarcoma. Based on the database of the Therapeutical Applicable Research to Generate Effective Treatments (TARGET), single-sample gene set enrichment analysis (ssGSEA) was used to obtain the enrichment scores of 29 immune characteristics. A series of bioinformatics methods were performed to construct the immune-related prognostic signature (IRPS). Gene set enrichment analysis and gene set variation analysis were used to explore the biological functions of IRPS. We also analyzed the relationship between IRPS and tumor microenvironment. Lastly, the reactivity of IRPS to immune checkpoint therapy and targeted drugs was explored. The ssGSEA algorithm was used to define two immune subtypes, namely Immunity_High and Immunity_Low. Immunity_High was associated with a good prognosis and was an independent prognostic factor of OS. The IRPS containing 7 genes was constructed by the least absolute shrinkage and selection operator Cox regression. The IRPS can divide patients into low- and high-risk patients. Compared with high-risk patients, low-risk patients had a better prognosis and were positively correlated with immune cell infiltration and immune function. Low-risk patients benefited more from immunotherapy, and the sensitivity of targeted drugs in high- and low-risk groups was determined. IRPS can be used to predict the prognosis of OS patients, and provide therapeutic responsiveness to immunotherapy and targeted therapy.
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Affiliation(s)
- Xiaofei Feng
- Department of Orthopedics, The First Clinical Medical College of Lanzhou University, Gansu, China
| | - Zhenrui Zhao
- Department of Orthopedics, The First Clinical Medical College of Lanzhou University, Gansu, China
| | - Yuhao Zhao
- Department of Orthopedics, The First Clinical Medical College of Lanzhou University, Gansu, China
| | - Zhengdong Song
- Department of Orthopedics, The First Clinical Medical College of Lanzhou University, Gansu, China
| | - Yao Ma
- Clinical Laboratory Center, Gansu Provincial Maternity and Child-Care Hospital, Gansu, China
| | - Wenji Wang
- Department of Orthopedics, Lanzhou University First Affiliated Hospital, Gansu, China
- *Correspondence: Wenji Wang,
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47
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Sosa BR, Wang Z, Healey JH, Hameed M, Greenblatt MB. A Subset of Osteosarcoma Bears Markers of
CXCL12
‐Abundant Reticular Cells. JBMR Plus 2022; 6:e10596. [PMID: 35309866 PMCID: PMC8914147 DOI: 10.1002/jbm4.10596] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/11/2021] [Accepted: 12/20/2021] [Indexed: 11/22/2022] Open
Abstract
Currently, the cell of origin for osteosarcoma or other primary skeletal tumors is largely unknown. Recent reports identifying specific cell types comprising bone now newly enable investigation of this topic. Specifically, CXC motif chemokine 12 (CXCL12)‐abundant reticular (CAR) cells are a specific skeletal stromal cell type that orchestrate the bone marrow microenvironment through cross‐talk with hematopoietic and endothelial cells and a likely candidate cell of origin for at least a subset of primary skeletal tumors. Here, we analyze osteosarcomas via immunohistochemistry for known markers of CAR cells such as leptin receptor (LEPR), B‐cell factor 3 (EBF3), CXCL12, and platelet‐derived growth factor receptor alpha (PDGFRA). A large proportion of high‐grade tumors expressed LEPR, PDGFRA, and EBF3 but not CXCL12. These data raise the hypothesis that CAR cells are the cell of origin of this osteoblastic osteosarcoma subset, a finding with implications for the cellular oncogenesis of primary osteosarcoma and the development of effective targeted therapies. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Branden R Sosa
- Department of Pathology and Laboratory Medicine Weill Cornell Medicine New York NY USA
| | - Ziqi Wang
- Department of Pathology and Laboratory Medicine Weill Cornell Medicine New York NY USA
| | - John H Healey
- Orthopaedic Service, Department of Surgery Memorial Sloan Kettering Cancer Center New York NY USA
| | - Meera Hameed
- Department of Pathology Memorial Sloan Kettering Cancer Center New York NY USA
| | - Matthew B Greenblatt
- Department of Pathology and Laboratory Medicine Weill Cornell Medicine New York NY USA
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Li HB, Chen JK, Su ZX, Jin QL, Deng LW, Huang G, Shen JN. Cordycepin augments the chemosensitivity of osteosarcoma to cisplatin by activating AMPK and suppressing the AKT signaling pathway. Cancer Cell Int 2021; 21:706. [PMID: 34953496 PMCID: PMC8709946 DOI: 10.1186/s12935-021-02411-y] [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: 09/02/2021] [Accepted: 12/15/2021] [Indexed: 11/18/2022] Open
Abstract
Background Osteosarcoma is the most common primary bone tumor in children and adolescents. However, some patients with osteosarcoma develop resistance to chemotherapy, leading to a poor clinical prognosis. Hence, effective therapeutic agents that can improve the response to chemotherapy drugs to improve the prognosis of patients with osteosarcoma are urgently needed. Cordycepin has recently emerged as a promising antitumor drug candidate. This study aims to explore the effect of cordycepin in suppressing osteosarcoma in vivo and in vitro and the synergistic effect of cordycepin combined with cisplatin and to demonstrate the underlying molecular mechanism. Methods CCK-8 assay was performed to investigate the inhibition effect of cordycepin combined with cisplatin in osteosarcoma cell lines. The colony formation and invasion abilities were measured by colony formation assay and Transwell assay. Osteosarcoma cells apoptosis was detected by flow cytometry. Western blot analysis were used to detect the expression of cell apoptosis-related proteins and AMPK and AKT/mTOR signaling pathway-related proteins. Finally, we performed the in vivo animal model to further explore whether cordycepin and cisplatin exert synergistic antitumor effects. Results Notably, we found that treatment with cordycepin inhibited cell proliferation, invasion, and induced apoptosis in osteosarcoma cells in vitro and in vivo. Moreover, the combination of cordycepin and cisplatin led to marked inhibition of osteosarcoma cell proliferation and invasion and promoted osteosarcoma cell apoptosis in vitro and in vivo. Mechanistically, we demonstrated that cordycepin enhanced the sensitivity of osteosarcoma cells to cisplatin by activating AMPK and inhibiting the AKT/mTOR signaling pathway. Conclusions In brief, this study provides comprehensive evidence that cordycepin inhibits osteosarcoma cell growth and invasion and induces osteosarcoma cell apoptosis by activating AMPK and inhibiting the AKT/mTOR signaling pathway and enhances the sensitivity of osteosarcoma cells to cisplatin, suggesting that cordycepin is a promising treatment for osteosarcoma.
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Affiliation(s)
- Hong-Bo Li
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Jun-Kai Chen
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Ze-Xin Su
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Qing-Lin Jin
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Li-Wen Deng
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Gang Huang
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. .,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
| | - Jing-Nan Shen
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. .,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
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49
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Liu R, Hu Y, Liu T, Wang Y. Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of osteosarcoma cancer. BMC Cancer 2021; 21:1345. [PMID: 34922489 PMCID: PMC8684084 DOI: 10.1186/s12885-021-09042-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 11/18/2021] [Indexed: 11/23/2022] Open
Abstract
Backgrounds Osteosarcomas are one of the most common primary malignant tumors of bone. It primarily occurs in children and adolescents, with the second highest incidence among people over 50 years old. Although there were immense improvements in the survival of patients with osteosarcoma in the past 30 years, targetable mutations and agents of osteosarcomas still have been generally not satisfactory. Therefore, it is of great importance to further explore the highly specialized immune environment of bone, genes related to macrophage infiltration and potential therapeutic biomarkers and targets. Methods The 11 expression data sets of OS tissues and the 11 data sets of adjacent non-tumorous tissues available in the GEO database GSE126209 were used to conduct immune infiltration analysis. Then, through WGCNA analysis, we acquired the co-expression modules related to Mast cells activated and performed the GO and KEGG enrichment analysis. Next, we did the survival prognosis analysis and plotted a survival curve. Finally, we analyzed the COX multivariate regression of gene expression on clinical parameters and drew forest maps for visualization by the forest plot package. Results OS disease-related immune cell populations, mainly Mast cells activated, have higher cell content (p = 0.006) than the normal group. Then, we identified co-expression modules related to Mast cells activated. In sum, a total of 822 genes from the top three strongest positive correlation module MEbrown4, MEdarkslateblue and MEnavajowhite2 and the strongest negative correlation module MEdarkturquoise. From that, we identified nine genes with different levels in immune cell infiltration related to osteosarcoma, eight of which including SORBS2, BAIAP2L2, ATAD2, CYGB, PAMR1, PSIP1, SNAPC3 and ZDHHC21 in their low abundance have higher disease-free survival probability than the group in their high abundances. Conclusion These results could assist clinicians to select targets for immunotherapies and individualize treatment strategies for patients with OS. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-09042-6.
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Affiliation(s)
- Ruixuan Liu
- Department of Spine Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China
| | - Yuhang Hu
- Department of Spine Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China
| | - Tianyi Liu
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China
| | - Yansong Wang
- Department of Spine Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China.
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50
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Testa S, Hu BD, Saadeh NL, Pribnow A, Spunt SL, Charville GW, Bui NQ, Ganjoo KN. A Retrospective Comparative Analysis of Outcomes and Prognostic Factors in Adult and Pediatric Patients with Osteosarcoma. Curr Oncol 2021; 28:5304-5317. [PMID: 34940082 PMCID: PMC8700626 DOI: 10.3390/curroncol28060443] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/22/2021] [Accepted: 12/09/2021] [Indexed: 11/21/2022] Open
Abstract
Osteosarcoma is the most common primary bone malignancy in both children and adults. Despite introduction of intensive multimodal treatment with chemotherapy and surgery, outcomes are still poor, especially for patients with metastatic disease and adults. Hence, there is an ongoing need for better prognostic markers and outcome data to inform management decisions in both the adult and pediatric setting. Here, we retrospectively analyzed 112 patients with bone osteosarcoma treated at two large adult and pediatric tertiary academic centers between 1989 and 2019. Patients were divided into an adult (≥18 years) and pediatric (<18 years) cohort for comparison. Our aim was to evaluate predictors of outcomes in pediatric and adult patients, with a specific focus on the role of methotrexate when added to a combination of doxorubicin-cisplatin; the prognostic value of tumor necrosis after neoadjuvant chemotherapy; and outlining any differences in outcomes between adults and pediatric patients that could inform clinical management. Adult patients treated with methotrexate-doxorubicin-cisplatin and those treated with doxorubicin-cisplatin had similar 5-year PFS (26%, 95%CI: 45.5%–10% vs. 50%, 95%CI: 69.6%–26.2%, p = 0.1) and 5-year OS (63%, 95%CI: 82%–34%, vs. 78%, 95%CI: 90.6%–52.6%, p = 0.5). In the adult cohort, there was no difference between patients with ≥90% necrosis and <90% necrosis in either 5-year PFS (42%, 95%CI: 71.1%–11.3% vs. 38%, 95%CI: 57.7%–18.2%, p = 0.4) or 5-year OS (85%, 95%CI: 97.8%–33.4% vs. 56%, 95%CI: 76.8%–27.6%, p = 0.4). In the pediatric cohort, compared to patients with <90% necrosis, those with ≥90% necrosis had significantly better 5-year PFS (30%, 95%CI: 49.3%–14.1% vs. 55%, 95%CI: 73.9%–38.5%, p = 0.003) and 5-year OS (64%, 95%CI: 80.8%–41.1% vs. 78%, 95%CI: 92%–60.9%, p = 0.04). Adult and pediatric patients had similar 5-year OS (69%, 95%CI: 83.2%–49.8% vs. 73%, 95%CI: 83.2%–59.3%, p = 0.8) and 5-year PFS (37%, 95%CI: 52.4%–22.9% vs. 43%, 95%CI: 56.2%–30.4% p = 0.3) even though the proportion of patients with ≥90% necrosis after neoadjuvant chemotherapy was higher for children compared to adults (60.3% vs. 30%, OR: 3.54, 95%CI: 1.38–8.46, p = 0.006). In conclusion, in adult patients, the addition of methotrexate to doxorubicin and cisplatin did not correlate with a significant survival benefit, questioning the therapeutic value of methotrexate overall. Our study confirms the prognostic utility of percent tumor necrosis after neoadjuvant chemotherapy in pediatric patients but not in adult patients. Lastly, this is one of the few reported studies where patients with osteosarcoma younger and older than 18 years had similar PFS and OS.
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Affiliation(s)
- Stefano Testa
- Department of Medicine, Stanford University, Stanford, CA 94304, USA
- Correspondence: (S.T.); (K.N.G.)
| | - Benjamin D. Hu
- Department of Pediatrics, School of Medicine, Stanford University, Stanford, CA 94304, USA; (B.D.H.); (A.P.); (S.L.S.)
| | - Natalie L. Saadeh
- Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94304, USA; (N.L.S.); (N.Q.B.)
| | - Allison Pribnow
- Department of Pediatrics, School of Medicine, Stanford University, Stanford, CA 94304, USA; (B.D.H.); (A.P.); (S.L.S.)
| | - Sheri L. Spunt
- Department of Pediatrics, School of Medicine, Stanford University, Stanford, CA 94304, USA; (B.D.H.); (A.P.); (S.L.S.)
| | | | - Nam Q. Bui
- Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94304, USA; (N.L.S.); (N.Q.B.)
| | - Kristen N. Ganjoo
- Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94304, USA; (N.L.S.); (N.Q.B.)
- Correspondence: (S.T.); (K.N.G.)
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