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1.
J Cell Mol Med ; 28(8): e18269, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38568056

RESUMO

Circular RNAs (circRNAs) play an important role in the progression of osteosarcoma. However, the precise function of circPVT1 in osteosarcoma remains elusive. This study aims to explore the molecular mechanism underlying the involvement of circPVT1 in osteosarcoma cells. We quantified circPVT1 expression using qRT-PCR in both control and osteosarcoma cell lines. To investigate the roles of circPVT1, miR-490-5p and HAVCR2 in vitro, we separately conducted overexpression and inhibition experiments for circPVT1, miR-490-5p and HAVCR2 in HOS and U2OS cells. Cell migration was assessed through wound healing and transwell migration assays, and invasion was measured via the Matrigel invasion assay. To elucidate the regulatory mechanism of circPVT1 in osteosarcoma, a comprehensive approach was employed, including fluorescence in situ hybridization, qRT-PCR, Western blot, bioinformatics, dual-luciferase reporter assay and rescue assay. CircPVT1 expression in osteosarcoma cell lines surpassed that in control cells. The depletion of circPVT1 resulted in a notable reduction in the in vitro migration and invasion of osteosarcoma cells. Mechanism experiments revealed that circPVT1 functioned as a miR-490-5p sequester, and directly targeted HAVCR2. Overexpression of miR-490-5p led to a significant attenuation of migration and invasion of osteosarcoma cells, whereas HAVCR2 overexpression had the opposite effect, promoting these abilities. Additionally, circPVT1 upregulated HAVCR2 expression via sequestering miR-490-5p, thereby orchestrating the migration and invasion in osteosarcoma cells. CircPVT1 orchestrates osteosarcoma migration and invasion by regulating the miR-490-5p/HAVCR2 axis, underscoring its potential as a promising therapeutic target for osteosarcoma.


Assuntos
Neoplasias Ósseas , MicroRNAs , Osteossarcoma , Humanos , Hibridização in Situ Fluorescente , Movimento Celular/genética , Osteossarcoma/genética , Neoplasias Ósseas/genética , MicroRNAs/genética , Receptor Celular 2 do Vírus da Hepatite A
2.
Medicine (Baltimore) ; 103(14): e37642, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38579086

RESUMO

Pyroptosis is a programmed cell death, which has garnered increasing attention because it relates to the immune and therapy response. However, few studies focus on the application of pyroptosis-related genes (PRGs) in predicting osteosarcoma (OS) patients' prognoses. In this study, the gene expression and clinical information of OS patients were downloaded from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. Based on these PRGs and unsupervised clustering analysis, all OS samples can be classified into 2 clusters. The 8 key differential expressions for PRGs (LAG3, ITGAM, CCL2, TLR4, IL2RA, PTPRC, FCGR2B, and CD5) were established through the univariate Cox regression and utilized to calculate the risk score of all samples. According to the 8-gene signature, OS samples can be divided into high and low-risk groups and correlation analysis can be performed using immune cell infiltration and immune checkpoints. Finally, we developed a nomogram to improve the PRG-predictive model in clinical application. We verified the predictive performance using receiver operating characteristic (ROC) and calibration curves. There were significant differences in survival, immune cell infiltration and immune checkpoints between the low and high-risk groups. A nomogram was developed with clinical indicators and the risk scores were effective in predicting the prognosis of patients with OS. In this study, a prognostic model was constructed based on 8 PRGs were proved to be independent prognostic factors of OS and associated with tumor immune microenvironment. These 8 prognostic genes were involved in OS development and may serve as new targets for developing therapeutic drugs.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Prognóstico , Piroptose , Nomogramas , Osteossarcoma/genética , Neoplasias Ósseas/genética , Microambiente Tumoral
3.
Biol Direct ; 19(1): 25, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570856

RESUMO

Circular RNAs (circRNAs) are a class of highly multifunctional single-stranded RNAs that play crucial roles in cancer progression, including osteosarcoma (OS). Circ_0002669, generated from the dedicator of cytokinesis (DOCK) gene, was highly expressed in OS tissues, and negatively correlated with OS patient survival. Elevated circ_0002669 promoted OS cell growth and invasion in vivo and in vitro. By biotin pulldown and mass spectroscopy, we found that circ_0002669 directly bound to MYCBP, a positive regulator of c-myc, to prevent MYCBP from ubiquitin-mediated proteasome degradation. In addition, circ_0002669 interacted with miR-889-3p and served as a miRNA sponge to increase the expression of MYCBP, as determined by luciferase assays and RNA immunoprecipitation. Functional rescue experiments indicated MYCBP acted as a key factor for circ_0002669- and miR-889-3p-regulated OS cell proliferation and migration. Increased expression of c-myc-associated genes, such as CCND1, c-Jun and CDK4, were found in circ_0002669- and MYCBP-overexpressing OS cells. Our data thus provide evidence that circ_0002669 promotes OS malignancy by protecting MYCBP from protein ubiquitination and degradation and blocking miR-889-3p-mediated inhibition of MYCBP expression.


Assuntos
Neoplasias Ósseas , MicroRNAs , Osteossarcoma , Humanos , Neoplasias Ósseas/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células , Proteínas de Ligação a DNA , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Osteossarcoma/genética , Fatores de Transcrição
4.
J Nanobiotechnology ; 22(1): 151, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38575943

RESUMO

BACKGROUND: As the lethal bone tumor, osteosarcoma often frequently occurs in children and adolescents with locally destructive and high metastasis. Distinctive kinds of nanoplatform with high therapeutical effect and precise diagnosis for osteosarcoma are urgently required. Multimodal optical imaging and programmed treatment, including synergistic photothermal-chemodynamic therapy (PTT-CDT) elicits immunogenetic cell death (ICD) is a promising strategy that possesses high bio-imaging sensitivity for accurate osteosarcoma delineating as well as appreciable therapeutic efficacy with ignorable side-effects. METHODS AND RESULTS: In this study, mesoporous Cu and Ce based oxide nanoplatform with Arg-Gly-Asp (RGD) anchoring is designed and successfully constructed. After loading with indocyanine green, this nanoplatform can be utilized for precisely targeting and efficaciously ablating against osteosarcoma via PTT boosted CDT and the closely following ICD stimulation both in vitro and in vivo. Besides, it provides off-peak fluorescence bio-imaging in the second window of near-infrared region (NIR II, 1000-1700 nm) and Magnetic resonance signal, serves as the dual-mode contrast agents for osteosarcoma tissue discrimination. CONCLUSION: Tumor targeted Cu&Ce based mesoporous nanoplatform permits efficient osteosarcoma suppression and dual-mode bio-imaging that opens new possibility for effectively diagnosing and inhibiting the clinical malignant osteosarcoma.


Assuntos
Neoplasias Ósseas , Nanopartículas , Neoplasias , Osteossarcoma , Criança , Humanos , Adolescente , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/terapia , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/tratamento farmacológico , Imunoterapia , Linhagem Celular Tumoral , Fototerapia
5.
Oncol Res ; 32(4): 691-702, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38560565

RESUMO

Osteosarcoma is a malignant tumor originating from bone tissue that progresses rapidly and has a poor patient prognosis. Immunotherapy has shown great potential in the treatment of osteosarcoma. However, the immunosuppressive microenvironment severely limits the efficacy of osteosarcoma treatment. The dual pH-sensitive nanocarrier has emerged as an effective antitumor drug delivery system that can selectively release drugs into the acidic tumor microenvironment. Here, we prepared a dual pH-sensitive nanocarrier, loaded with the photosensitizer Chlorin e6 (Ce6) and CD47 monoclonal antibodies (aCD47), to deliver synergistic photodynamic and immunotherapy of osteosarcoma. On laser irradiation, Ce6 can generate reactive oxygen species (ROS) to kill cancer cells directly and induces immunogenic tumor cell death (ICD), which further facilitates the dendritic cell maturation induced by blockade of CD47 by aCD47. Moreover, both calreticulin released during ICD and CD47 blockade can accelerate phagocytosis of tumor cells by macrophages, promote antigen presentation, and eventually induce T lymphocyte-mediated antitumor immunity. Overall, the dual pH-sensitive nanodrug loaded with Ce6 and aCD47 showed excellent immune-activating and anti-tumor effects in osteosarcoma, which may lay the theoretical foundation for a novel combination model of osteosarcoma treatment.


Assuntos
Neoplasias Ósseas , Clorofilídeos , Nanopartículas , Neoplasias , Osteossarcoma , Fotoquimioterapia , Humanos , Antígeno CD47 , Linhagem Celular Tumoral , Osteossarcoma/tratamento farmacológico , Imunoterapia , Neoplasias Ósseas/tratamento farmacológico , Concentração de Íons de Hidrogênio , Microambiente Tumoral
6.
Nat Commun ; 15(1): 2810, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561347

RESUMO

Osteosarcoma is the most common primary malignant bone tumor with a strong tendency to metastasize, limiting the prognosis of affected patients. Genomic, epigenomic and transcriptomic analyses have demonstrated the exquisite molecular complexity of this tumor, but have not sufficiently defined the underlying mechanisms or identified promising therapeutic targets. To systematically explore RNA-protein interactions relevant to OS, we define the RNA interactomes together with the full proteome and the transcriptome of cells from five malignant bone tumors (four osteosarcomata and one malignant giant cell tumor of the bone) and from normal mesenchymal stem cells and osteoblasts. These analyses uncover both systematic changes of the RNA-binding activities of defined RNA-binding proteins common to all osteosarcomata and individual alterations that are observed in only a subset of tumors. Functional analyses reveal a particular vulnerability of these tumors to translation inhibition and a positive feedback loop involving the RBP IGF2BP3 and the transcription factor Myc which affects cellular translation and OS cell viability. Our results thus provide insight into potentially clinically relevant RNA-binding protein-dependent mechanisms of osteosarcoma.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Proliferação de Células/genética , Linhagem Celular Tumoral , Osteossarcoma/metabolismo , Neoplasias Ósseas/metabolismo , RNA , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Regulação Neoplásica da Expressão Gênica
7.
J Nanobiotechnology ; 22(1): 141, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561739

RESUMO

Osteosarcoma (OS) is an aggressive bone tumor with strong invasiveness, rapid metastasis, and dreadful mortality. Chemotherapy is a commonly used approach for OS treatment but is limited by the development of drug resistance and long-term adverse effects. To date, OS still lacks the curative treatment. Herein, we fabricated pyrite-based nanoparticles (FeS2@CP NPs) as synergetic therapeutic platform by integrating photothermal therapy (PTT) and chemo-dynamic therapy (CDT) into one system. The synthetic FeS2@CP NPs showed superior Fenton reaction catalytic activity. FeS2@CP NPs-based CDT efficaciously eradicated the tumor cells by initiating dual-effect of killing of apoptosis and ferroptosis. Furthermore, the generated heat from FeS2@CP under near-infrared region II (NIR-II) laser irradiation could not only inhibit tumor's growth, but also promote tumor cell apoptosis and ferroptosis by accelerating •OH production and GSH depletion. Finally, the photothermal/NIR II-enhanced CDT synergistic therapy showed excellent osteosarcoma treatment effects both in vitro and in vivo with negligible side effects. Overall, this work provided a high-performance and multifunctional Fenton catalyst for osteosarcoma synergistic therapy, which provided a pathway for the clinical application of PTT augmented CDT.


Assuntos
Neoplasias Ósseas , Nanopartículas , Neoplasias , Osteossarcoma , Sulfetos , Humanos , Terapia Fototérmica , Osteossarcoma/tratamento farmacológico , Ferro , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Peróxido de Hidrogênio
8.
J Exp Clin Cancer Res ; 43(1): 97, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561833

RESUMO

BACKGROUND: CAR T cell therapy is a promising approach to improve outcomes and decrease toxicities for patients with cancer. While extraordinary success has been achieved using CAR T cells to treat patients with CD19-positive malignancies, multiple obstacles have so far limited the benefit of CAR T cell therapy for patients with solid tumors. Novel manufacturing and engineering approaches show great promise to enhance CAR T cell function against solid tumors. However, similar to single agent chemotherapy approaches, CAR T cell monotherapy may be unable to achieve high cure rates for patients with difficult to treat solid tumors. Thus, combinatorial drug plus CAR T cell approaches are likely required to achieve widespread clinical success. METHODS: We developed a novel, confocal microscopy based, high-content screen to evaluate 1114 FDA approved drugs for the potential to increase expression of the solid tumor antigen B7-H3 on the surface of osteosarcoma cells. Western blot, RT-qPCR, siRNA knockdown and flow cytometry assays were used to validate screening results and identify mechanisms of drug-induced B7-H3 upregulation. Cytokine and cytotoxicity assays were used to determine if drug pre-treatment enhanced B7-H3-CAR T cell effector function. RESULTS: Fifty-five drugs were identified to increase B7-H3 expression on the surface of LM7 osteosarcoma cells using a novel high-content, high-throughput screen. One drug, ingenol-3-angelate (I3A), increased B7-H3 expression by up to 100%, and was evaluated in downstream experiments. Validation assays confirmed I3A increased B7-H3 expression in a biphasic dose response and cell dependent fashion. Mechanistic studies demonstrated that I3A increased B7-H3 (CD276) mRNA, total protein, and cell surface expression via protein kinase C alpha activation. Functionally, I3A induced B7-H3 expression enhanced B7-H3-CAR T cell function in cytokine production and cytotoxicity assays. CONCLUSIONS: This study demonstrates a novel high-content and high-throughput screen can identify drugs to enhance CAR T cell activity. This and other high-content technologies will pave the way to develop clinical trials implementing rational drug plus CAR T cell combinatorial therapies. Importantly, the technique could also be repurposed for an array of basic and translational research applications where drugs are needed to modulate cell surface protein expression.


Assuntos
Neoplasias Ósseas , Diterpenos , Osteossarcoma , Humanos , Proteína Quinase C-alfa/metabolismo , Antígenos B7/genética , Antígenos B7/metabolismo , Osteossarcoma/metabolismo , Neoplasias Ósseas/patologia , Linfócitos T , Citocinas/metabolismo , Linhagem Celular Tumoral
9.
J Vis Exp ; (205)2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38587398

RESUMO

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. Despite the development of new treatment plans in recent years, the prognosis for osteosarcoma patients has not significantly improved. Therefore, it is crucial to establish a robust preclinical model with high fidelity. The patient-derived xenograft (PDX) model faithfully preserves the genetic, epigenetic, and heterogeneous characteristics of human malignancies for each patient. Consequently, PDX models are considered authentic in vivo models for studying various cancers in transformation studies. This article presents a comprehensive protocol for creating and maintaining a PDX mouse model that accurately mirrors the morphological features of human osteosarcoma. This involves the immediate transplantation of freshly resected human osteosarcoma tissue into immunocompromised mice, followed by successive passaging. The described model serves as a platform for studying the growth, drug resistance, relapse, and metastasis of osteosarcoma. Additionally, it aids in screening the target therapeutics and establishing personalized treatment schemes.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Adolescente , Criança , Humanos , Animais , Camundongos , Xenoenxertos , Ensaios Antitumorais Modelo de Xenoenxerto , Recidiva Local de Neoplasia , Osteossarcoma/genética , Osteossarcoma/patologia , Modelos Animais de Doenças , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia
10.
ACS Biomater Sci Eng ; 10(4): 2200-2211, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38447138

RESUMO

In the clinic, inactivation of osteosarcoma using microwave ablation would damage the periosteum, resulting in frequent postoperative complications. Therefore, the development of an artificial periosteum is crucial for postoperative healing. In this study, we prepared an artificial periosteum using silk fibroin (SF) loaded with stromal cell-derived factor-1α (SDF-1α) and calcitonin gene-related peptide (CGRP) to accelerate bone remodeling after the microwave ablation of osteosarcoma. The prepared artificial periosteum showed a sustained release of SDF-1α and CGRP after 14 days of immersion. In vitro culture of rat periosteal stem cells (rPDSCs) demonstrated that the artificial periosteum is favorable for cell recruitment, the activity of alkaline phosphatase, and bone-related gene expression. Furthermore, the artificial periosteum improved the tube formation and angiogenesis-related gene expression of human umbilical vein endothelial cells (HUVECs). In an animal study, the periosteum in the femur of a rabbit was inactivated through microwave ablation and then removed. The damaged periosteum was replaced with the as-prepared artificial periosteum and favored bone regeneration. In all, the designed dual-factor-loaded artificial periosteum is a promising strategy to replace the damaged periosteum in the therapy of osteosarcoma for a better bone-rebuilding process.


Assuntos
Osteossarcoma , Periósteo , Ratos , Humanos , Animais , Coelhos , Quimiocina CXCL12/genética , Quimiocina CXCL12/farmacologia , Peptídeo Relacionado com Gene de Calcitonina , Células Endoteliais , Regeneração Óssea
11.
Zhonghua Bing Li Xue Za Zhi ; 53(3): 237-242, 2024 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-38433050

RESUMO

Objective: To investigate the diagnostic value of detecting MDM2 gene amplification by fluorescence in situ hybridization (FISH) in low-grade osteosarcoma (LGOS). Methods: Thirty cases of parosteal osteosarcoma (POS) and 14 cases of low-grade central osteosarcoma (LGCOS) from April 2009 to August 2022 at Beijing Jishuitan Hospital, Capital Medical University were analyzed for the presence of MDM2 gene amplification by FISH. Fifty-eight additional cases were used as negative controls (including 28 cases of fibrous dysplasia, 5 cases of giant cell tumor, 4 cases of conventional osteosarcoma, 2 cases each of periosteal osteosarcoma, reparative changes after fracture, pleomorphic undifferentiated sarcoma, low grade myofibroblastic sarcoma, fibrous dysplasia with malignant transformation, one case each of leiomyosarcoma, sclerosing epithelioid fibrosarcoma, malignant peripheral nerve sheath tumor, desmoplastic fibroma of bone, solitary fibrous tumor, aneurysmal bone cyst, clear cell chondrosarcoma, osteofibrous dysplasia, and 3 cases of unclassified spindle cell tumor). Results: Among the 30 patients with POS, 15 were male and 15 were female, ranging in age from 10 to 59 years (mean 35 years, median 30.5 years). Among the 14 patients with LGCOS, four were male and 10 were female, ranging in age from 15 to 56 years (mean 37 years, median 36 years). All except one case were successfully detected by FISH. MDM2 gene amplification was detected in 27 cases of POS (27/29,91.3%) and 8 cases of LGCOS (8/14). All the negative controls were negative for MDM2 gene amplification. The positive rate of MDM2 gene amplification was significantly different between the case group and the control group (P<0.05). The sensitivity and specificity of MDM2 gene amplification in diagnosing POS and LGCOS were 91.3% and 100.0%; and 57.1% and 100.0%, respectively. The sensitivity and specificity of MDM2 gene amplification in diagnosing LGOS (including POS and LGCOS) were 81.3% and 100.0%, respectively. In cases where MDM2 gene was amplified, the MDM2 amplified signal was clustered. Nine cases showed increased CEP12 signal different from polyploidy which was displayed as small and weak signal points or cloud flocculent and cluster signals. Conclusions: Detection of MDM2 gene amplification by FISH is a highly sensitive and specific marker for LGOS. The interpretation criteria for FISH detection of MDM2 amplification are currently not unified. The signal characteristics need more attention when interpreting.


Assuntos
Neoplasias Ósseas , Fibrossarcoma , Osteossarcoma , Sarcoma , Humanos , Feminino , Masculino , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Amplificação de Genes , Hibridização in Situ Fluorescente , Osteossarcoma/diagnóstico , Osteossarcoma/genética , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/genética , Proteínas Proto-Oncogênicas c-mdm2/genética
12.
J Nanobiotechnology ; 22(1): 89, 2024 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-38433190

RESUMO

Despite advances in surgery and chemotherapy, the survival of patients with osteosarcoma (OS) has not been fundamentally improved over the last two decades. Microvesicles (MVs) have a high cargo-loading capacity and are emerging as a promising drug delivery nanoplatform. The aim of this study was to develop MVs as specifically designed vehicles to enable OS-specific targeting and efficient treatment of OS. Herein, we designed and constructed a nanoplatform (YSA-SPION-MV/MTX) consisting of methotrexate (MTX)-loaded MVs coated with surface-carboxyl Fe3O4 superparamagnetic nanoparticles (SPIONs) conjugated with ephrin alpha 2 (EphA2)-targeted peptides (YSAYPDSVPMMS, YSA). YSA-SPION-MV/MTX showed an effective targeting effect on OS cells, which was depended on the binding of the YSA peptide to EphA2. In the orthotopic OS mouse model, YSA-SPION-MV/MTX effectively delivered drugs to tumor sites with specific targeting, resulting in superior anti-tumor activity compared to MTX or MV/MTX. And YSA-SPION-MV/MTX also reduced the side effects of high-dose MTX. Taken together, this strategy opens up a new avenue for OS therapy. And we expect this MV-based therapy to serve as a promising platform for the next generation of precision cancer nanomedicines.


Assuntos
Neoplasias Ósseas , Micropartículas Derivadas de Células , Osteossarcoma , Animais , Humanos , Camundongos , Neoplasias Ósseas/tratamento farmacológico , Efrinas , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Osteossarcoma/tratamento farmacológico
13.
Drug Dev Res ; 85(2): e22167, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38444106

RESUMO

Osteosarcoma (OS) is a primary malignant bone tumor and is prevalent in children, adolescents, and elderly individuals. It has the characteristics of high invasion and metastasis. Neoadjuvant chemotherapy combined with surgical resection is the most commonly used treatment for OS. However, the efficacy of OS is considerably diminished by chemotherapy resistance. In recent years, noncoding RNAs (ncRNAs), including microRNAs, long noncoding RNAs, and circular RNAs, are hot topics in the field of chemotherapy resistance research. Several studies have demonstrated that ncRNAs are substantially associated with chemoresistance in OS. Thus, the present study overviews the abnormally expressed ncRNAs in OS and the molecular mechanisms involved in chemoresistance, with an emphasis on their function in promoting or inhibiting chemoresistance. ncRNAs are expected to become potential therapeutic targets for overcoming drug resistance and predictive biomarkers in OS, which are of great significance for enhancing the therapeutic effect and improving the prognosis.


Assuntos
Neoplasias Ósseas , MicroRNAs , Osteossarcoma , Adolescente , Criança , Idoso , Humanos , Resistencia a Medicamentos Antineoplásicos , MicroRNAs/genética , RNA não Traduzido/genética , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética
14.
Front Biosci (Landmark Ed) ; 29(3): 120, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38538251

RESUMO

BACKGROUND: Osteosarcoma cells are prone to metastasis, and the mechanism of N6-methyladenosine (m6A) methylation modification in this process is still unclear. Methylation modification of m6A plays an important role in the development of osteosarcoma, which is mainly due to abnormal expression of enzymes related to methylation modification of m6A, which in turn leads to changes in the methylation level of downstream target genes messenger RNA (mRNA) leading to tumor development. METHODS: We analyzed the expression levels of m6A methylation modification-related enzyme genes in GSE12865 whole-genome sequencing data. And we used shRNA (short hairpin RNA) lentiviral interference to interfere with METTL3 (Methyltransferase 3) expression in osteosarcoma cells. We studied the cytological function of METTL3 by Cell Counting Kit-8 (CCK8), flow cytometry, migration and other experiments, and the molecular mechanism of METTL3 by RIP (RNA binding protein immunoprecipitation), Western blot and other experiments. RESULTS: We found that METTL3 is abnormally highly expressed in osteosarcoma and interferes with METTL3 expression in osteosarcoma cells to inhibit metastasis, proliferation, and apoptosis of osteosarcoma cells. We subsequently found that METTL3 binds to the mRNA of CBX4 (chromobox homolog 4), a very important regulatory protein in osteosarcoma metastasis, and METTL3 regulates the mRNA and protein expression of CBX4. Further studies revealed that METTL3 inhibited metastasis of osteosarcoma cells by regulating CBX4. METTL3 has been found to be involved in osteosarcoma cells metastasis by CBX4 affecting the protein expression of matrix metalloproteinase 2 (MMP2), MMP9, E-Cadherin and N-Cadherin associated with osteosarcoma cells metastasis. CONCLUSIONS: These results suggest that the combined action of METTL3 and CBX4 plays an important role in the regulation of metastasis of osteosarcoma, and therefore, the METTL3-CBX4 axis pathway may be a new potential therapeutic target for osteosarcoma.


Assuntos
Adenina , Neoplasias Ósseas , Metaloproteinase 2 da Matriz , Osteossarcoma , Humanos , Adenina/análogos & derivados , Epigênese Genética , Ligases/genética , Metaloproteinase 2 da Matriz/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , Osteossarcoma/genética , Osteossarcoma/secundário , Proteínas do Grupo Polycomb/genética , RNA Mensageiro/genética , RNA Interferente Pequeno , Neoplasias Ósseas/patologia
15.
J Immunother Cancer ; 12(3)2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38519053

RESUMO

BACKGROUND: The survival benefit observed in children with neuroblastoma (NB) and minimal residual disease who received treatment with anti-GD2 monoclonal antibodies prompted our investigation into the safety and potential clinical benefits of anti-CD3×anti-GD2 bispecific antibody (GD2Bi) armed T cells (GD2BATs). Preclinical studies demonstrated the high cytotoxicity of GD2BATs against GD2+cell lines, leading to the initiation of a phase I/II study in recurrent/refractory patients. METHODS: The 3+3 dose escalation phase I study (NCT02173093) encompassed nine evaluable patients with NB (n=5), osteosarcoma (n=3), and desmoplastic small round cell tumors (n=1). Patients received twice-weekly infusions of GD2BATs at 40, 80, or 160×106 GD2BATs/kg/infusion complemented by daily interleukin-2 (300,000 IU/m2) and twice-weekly granulocyte macrophage colony-stimulating factor (250 µg/m2). The phase II segment focused on patients with NB at the dose 3 level of 160×106 GD2BATs/kg/infusion. RESULTS: Of the 12 patients enrolled, 9 completed therapy in phase I with no dose-limiting toxicities. Mild and manageable cytokine release syndrome occurred in all patients, presenting as grade 2-3 fevers/chills, headaches, and occasional hypotension up to 72 hours after GD2BAT infusions. GD2-antibody-associated pain was minimal. Median overall survival (OS) for phase I and the limited phase II was 18.0 and 31.2 months, respectively, with a combined OS of 21.1 months. A phase I NB patient had a complete bone marrow response with overall stable disease. In phase II, 10 of 12 patients were evaluable: 1 achieved partial response, and 3 showed clinical benefit with prolonged stable disease. Over 50% of evaluable patients exhibited augmented immune responses to GD2+targets post-GD2BATs, as indicated by interferon-gamma (IFN-γ) EliSpots, Th1 cytokines, and/or chemokines. CONCLUSIONS: This study demonstrated the safety of GD2BATs up to 160×106 cells/kg/infusion. Coupled with evidence of post-treatment endogenous immune responses, our findings support further investigation of GD2BATs in larger phase II clinical trials.


Assuntos
Antineoplásicos , Neuroblastoma , Osteossarcoma , Criança , Humanos , Linfócitos T/patologia , Neuroblastoma/patologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Osteossarcoma/tratamento farmacológico
17.
Mol Biol Rep ; 51(1): 467, 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38551765

RESUMO

BACKGROUND: Osteosarcoma (OS) stands out as the most common bone tumor, with approximately 20% of the patients receiving a diagnosis of metastatic OS at their initial assessment. A significant challenge lies in the frequent existence of undetected metastases during the initial diagnosis. Mesenchymal stem cells (MSCs) possess unique abilities that facilitate tumor growth, and their interaction with OS cells is crucial for metastatic spread. METHODS AND RESULTS: We demonstrated that, in vitro, MSCs exhibited a heightened migration response toward the secretome of non-metastatic OS cells. When challenged to a secretome derived from lungs preloaded with OS cells, MSCs exhibited greater migration toward lungs colonized with metastatic OS cells. Moreover, in vivo, MSCs displayed preferential migratory and homing behavior toward lungs colonized by metastatic OS cells. Metastatic OS cells, in turn, demonstrated an increased migratory response to the MSCs' secretome. This behavior was associated with heightened cathepsin D (CTSD) expression and the release of active metalloproteinase 2 (MMP2) by metastatic OS cells. CONCLUSIONS: Our assessment focused on two complementary tumor capabilities crucial to metastatic spread, emphasizing the significance of inherent cell features. The findings underscore the pivotal role of signaling integration within the niche, with a complex interplay of migratory responses among established OS cells in the lungs, prometastatic OS cells in the primary tumor, and circulating MSCs. Pulmonary metastases continue to be a significant factor contributing to OS mortality. Understanding these mechanisms and identifying differentially expressed genes is essential for pinpointing markers and targets to manage metastatic spread and improve outcomes for patients with OS.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Animais , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Proliferação de Células/genética , Pulmão/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , Células Estromais/patologia , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Microambiente Tumoral
18.
Medicine (Baltimore) ; 103(13): e37269, 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38552042

RESUMO

BACKGROUND: Bone malignancies (BM), including osteosarcoma, Ewing's sarcoma, chondrosarcoma, and chordoma, are characterized by high rates of recurrence and mortality, despite the availability of diverse treatment approaches. Immunotherapy has gained increasing importance in cancer treatment. However, there is a lack of comprehensive studies that utilize bibliometric analysis to explore immunotherapy for BM. METHODS: A literature search of English studies on BM and immunotherapy from 2010 to 2023 was conducted in the Web of Science Core Collection database. Bibliometric analysis tools such as VOSviewer, CiteSpace, and R Studio were utilized to examine global trends and research hotspots in this field. RESULTS: A total of 719 eligible articles, including 528 original research articles and 191 reviews, were analyzed. The number of publications has shown an increasing trend over the past 14 years, particularly in the last 5 years. The majority of the published articles on this topic originated from China (284 articles), followed by the United States and Japan. The institution with the highest number of publications and citations was the University of Texas MD Anderson Cancer Center (30 articles; 1638 citations). Dean A. Lee (12 articles) and Richard Gorlick (576 citations) were the authors with the highest contribution in terms of article count and citation count, respectively. Among these journals, Frontiers in Oncology had the highest number of articles (39 articles), while the Journal of Clinical Oncology had the highest number of citations (1878 citations). Additionally, there has been a shift in the keywords from "antitumor activity" and "NK cells" to popular topics such as "PD-L1," "open label," and "single arm." CONCLUSION: A better understanding of the current status and prospects of immunotherapy for BM is crucial for the rationale selection of appropriate BM patients for immunotherapy. This study is expected to help clinical physicians and researchers gain comprehensive insights into the developmental trends of BM immunotherapy, providing practical guidance for the application of immunotherapy in BM patients.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Sarcoma de Ewing , Humanos , Imunoterapia , Neoplasias Ósseas/terapia , Bibliometria
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