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1.
BMC Cancer ; 24(1): 703, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849717

RESUMO

Immunodeficient murine models are usually used as the preclinical models of osteosarcoma. Such models do not effectively simulate the process of tumorigenesis and metastasis. Establishing a suitable animal model for understanding the mechanism of osteosarcoma and the clinical translation is indispensable. The UMR-106 cell suspension was injected into the marrow cavity of Balb/C nude mice. Tumor masses were harvested from nude mice and sectioned. The tumor fragments were transplanted into the marrow cavities of SD rats immunosuppressed with cyclosporine A. Through muti-rounds selection in SD rats, we constructed orthotopic osteosarcoma animal models using rats with intact immune systems. The primary tumor cells were cultured in-vitro to obtain the immune-tolerant cell line. VX2 tumor fragments were transplanted into the distal femur and parosteal radius of New Zealand white rabbit to construct orthotopic osteosarcoma animal models in rabbits. The rate of tumor formation in SD rats (P1 generation) was 30%. After four rounds of selection and six rounds of acclimatization in SD rats with intact immune systems, we obtained immune-tolerant cell lines and established the orthotopic osteosarcoma model of the distal femur in SD rats. Micro-CT images confirmed tumor-driven osteolysis and the bone destruction process. Moreover, the orthotopic model was also established in New Zealand white rabbits by implanting VX2 tumor fragments into rabbit radii and femurs. We constructed orthotopic osteosarcoma animal models in rats with intact immune systems through muti-rounds in-vivo selection and the rabbit osteosarcoma model.


Assuntos
Neoplasias Ósseas , Modelos Animais de Doenças , Osteossarcoma , Animais , Osteossarcoma/patologia , Osteossarcoma/imunologia , Coelhos , Ratos , Neoplasias Ósseas/patologia , Neoplasias Ósseas/imunologia , Linhagem Celular Tumoral , Camundongos , Camundongos Nus , Ratos Sprague-Dawley , Microtomografia por Raio-X , Camundongos Endogâmicos BALB C , Imunocompetência , Humanos , Transplante de Neoplasias , Fêmur/patologia , Fêmur/diagnóstico por imagem , Masculino
2.
BMC Pediatr ; 24(1): 382, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38831258

RESUMO

BACKGROUND: Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Lungs are the most frequent and often the only site of metastatic disease. The presence of pulmonary metastases is a significant unfavourable prognostic factor. Thoracotomy is strongly recommended in these patients, while computed tomography (CT) remains the gold imaging standard. The purpose of our study was to create tools for the CT-based qualification for thoracotomy in osteosarcoma patients in order to reduce the rate of useless thoracotomies. METHODS: Sixty-four osteosarcoma paediatric patients suspected of lung metastases on CT and their first-time thoracotomies (n = 100) were included in this retrospective analysis. All CT scans were analysed using a compartmental evaluation method based on the number and size of nodules. Calcification and location of lung lesions were also analysed. Inter-observer reliability between two experienced radiologists was assessed. The CT findings were then correlated with the histopathological results of thoracotomies. Various multivariate predictive models (logistic regression, classification tree and random forest) were built and predictors of lung metastases were identified. RESULTS: All applied models proved that calcified nodules on the preoperative CT scan best predict the presence of pulmonary metastases. The rating of the operated lung on the preoperative CT scan, dependent on the number and size of nodules, and the total number of nodules on this scan were also found to be important predictors. All three models achieved a relatively high sensitivity (72-92%), positive predictive value (81-90%) and accuracy (74-79%). The positive predictive value of each model was higher than of the qualification for thoracotomy performed at the time of treatment. Inter-observer reliability was at least substantial for qualitative variables and excellent for quantitative variables. CONCLUSIONS: The multivariate models built and tested in our study may be useful in the qualification of osteosarcoma patients for metastasectomy through thoracotomy and may contribute to reducing the rate of unnecessary invasive procedures in the future.


Assuntos
Neoplasias Ósseas , Neoplasias Pulmonares , Osteossarcoma , Toracotomia , Tomografia Computadorizada por Raios X , Humanos , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/cirurgia , Osteossarcoma/secundário , Osteossarcoma/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/patologia , Adolescente , Criança , Estudos Retrospectivos , Masculino , Feminino , Neoplasias Ósseas/secundário , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/cirurgia
3.
Sci Rep ; 14(1): 12934, 2024 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-38839983

RESUMO

Osteosarcoma is a primary malignant tumor that commonly affects children and adolescents, with a poor prognosis. The existence of tumor heterogeneity leads to different molecular subtypes and survival outcomes. Recently, lipid metabolism has been identified as a critical characteristic of cancer. Therefore, our study aims to identify osteosarcoma's lipid metabolism molecular subtype and develop a signature for survival outcome prediction. Four multicenter cohorts-TARGET-OS, GSE21257, GSE39058, and GSE16091-were amalgamated into a unified Meta-Cohort. Through consensus clustering, novel molecular subtypes within Meta-Cohort patients were delineated. Subsequent feature selection processes, encompassing analyses of differentially expressed genes between subtypes, univariate Cox analysis, and StepAIC, were employed to pinpoint biomarkers related to lipid metabolism in TARGET-OS. We selected the most effective algorithm for constructing a Lipid Metabolism-Related Signature (LMRS) by utilizing four machine-learning algorithms reconfigured into ten unique combinations. This selection was based on achieving the highest concordance index (C-index) in the test cohort of GSE21257, GSE39058, and GSE16091. We identified two distinct lipid metabolism molecular subtypes in osteosarcoma patients, C1 and C2, with significantly different survival rates. C1 is characterized by increased cholesterol, fatty acid synthesis, and ketone metabolism. In contrast, C2 focuses on steroid hormone biosynthesis, arachidonic acid, and glycerolipid and linoleic acid metabolism. Feature selection in the TARGET-OS identified 12 lipid metabolism genes, leading to a model predicting osteosarcoma patient survival. The LMRS, based on the 12 identified genes, consistently accurately predicted prognosis across TARGET-OS, testing cohorts, and Meta-Cohort. Incorporating 12 published signatures, LMRS showed robust and significantly superior predictive capability. Our results offer a promising tool to enhance the clinical management of osteosarcoma, potentially leading to improved clinical outcomes.


Assuntos
Neoplasias Ósseas , Metabolismo dos Lipídeos , Aprendizado de Máquina , Osteossarcoma , Osteossarcoma/genética , Osteossarcoma/mortalidade , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Humanos , Metabolismo dos Lipídeos/genética , Prognóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Masculino , Regulação Neoplásica da Expressão Gênica , Adolescente , Perfilação da Expressão Gênica/métodos , Criança
4.
J Cell Mol Med ; 28(11): e18462, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38847478

RESUMO

Osteosarcoma (OS) is the most common primary malignant bone tumour in children and young adults. Account for 80% of all OS cases, conventional OS are characterized by the presence of osteoblastic, chondroblastic and fibroblastic cell types. Despite this heterogeneity, therapeutic treatment and prognosis of OS are essentially the same for all OS subtypes. Here, we report that DEC2, a transcriptional repressor, is expressed at higher levels in chondroblastic OS compared with osteoblastic OS. This difference suggests that DEC2 is disproportionately involved in the progression of chondroblastic OS, and thus, DEC2 may represent a possible molecular target for treating this type of OS. In the human chondroblastic-like OS cell line MNNG/HOS, we found that overexpression of DEC2 affects the proliferation of the cells by activating the VEGFC/VEGFR2 signalling pathway. Enhanced expression of DEC2 increased VEGFR2 expression, as well as increased the phosphorylation levels at sites Y951 and Y1175 of VEGFR2. On the one hand, activation of VEGFR2Y1175 enhanced cell proliferation through VEGFR2Y1175-PLCγ1-PKC-SPHK-MEK-ERK signalling. On the other hand, activation of VEGFR2Y951 decreased mitochondria-dependent apoptosis rate through VEGFR2Y951-VARP-PI3K-AKT signalling. Activation of these two signalling pathways resulted in enhanced progression of chondroblastic OS. In conclusion, DEC2 plays a pivotal role in cell proliferation and apoptosis-resistance in chondroblastic OS via the VEGFC/VEGFR2 signalling pathway. These findings lay the groundwork for developing focused treatments that target specific types of OS.


Assuntos
Neoplasias Ósseas , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Osteossarcoma , Transdução de Sinais , Fator C de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Osteossarcoma/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Linhagem Celular Tumoral , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Neoplasias Ósseas/genética , Fator C de Crescimento do Endotélio Vascular/metabolismo , Fator C de Crescimento do Endotélio Vascular/genética , Animais , Apoptose/genética , Fosforilação
5.
Medicine (Baltimore) ; 103(23): e38470, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38847690

RESUMO

Osteosarcoma (OS) is the most common primary malignant bone tumor occurring in children and adolescents. Improvements in our understanding of the OS pathogenesis and metastatic mechanism on the molecular level might lead to notable advances in the treatment and prognosis of OS. Biomarkers related to OS metastasis and prognosis were analyzed and identified, and a prognostic model was established through the integration of bioinformatics tools and datasets in multiple databases. 2 OS datasets were downloaded from the Gene Expression Omnibus database for data consolidation, standardization, batch effect correction, and identification of differentially expressed genes (DEGs); following that, gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the DEGs; the STRING database was subsequently used for protein-protein interaction (PPI) network construction and identification of hub genes; hub gene expression was validated, and survival analysis was conducted through the employment of the TARGET database; finally, a prognostic model was established and evaluated subsequent to the screening of survival-related genes. A total of 701 DEGs were identified; by gene ontology and KEGG pathway enrichment analyses, the overlapping DEGs were enriched for 249 biological process terms, 13 cellular component terms, 35 molecular function terms, and 4 KEGG pathways; 13 hub genes were selected from the PPI network; 6 survival-related genes were identified by the survival analysis; the prognostic model suggested that 4 genes were strongly associated with the prognosis of OS. DEGs related to OS metastasis and survival were identified through bioinformatics analysis, and hub genes were further selected to establish an ideal prognostic model for OS patients. On this basis, 4 protective genes including TPM1, TPM2, TPM3, and TPM4 were yielded by the prognostic model.


Assuntos
Neoplasias Ósseas , Biologia Computacional , Osteossarcoma , Mapas de Interação de Proteínas , Osteossarcoma/genética , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Humanos , Biologia Computacional/métodos , Prognóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Mapas de Interação de Proteínas/genética , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Bases de Dados Genéticas , Análise de Sobrevida , Metástase Neoplásica/genética
6.
Cancer J ; 30(3): 133-139, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38753746

RESUMO

PURPOSE: In this study, we used a series of immunohistochemical measurements of 2 cell cycle regulators, p16 and p21, to evaluate their prognostic value, separately and in combination, for the disease outcomes. METHOD: A total of 101 patients with high-grade osteosarcoma were included in this study. Clinicopathologic data were collected, and immunohistochemistry for p16 and p21 was performed and interpreted by 3 independent pathologists. Statistical analysis was performed to assess the strength of each of these markers relative to disease outcome. RESULTS: Our results indicate that more than 90% expression (high) of p16 by immunohistochemistry on the initial biopsy has a strong predictive value for good histologic response to chemotherapy. The patients are also more likely to survive the past 5 years and less likely to develop metastasis than patients with less than 90% p16 (low) expression. The results for p21, on the other hand, show a unique pattern of relationship to the clinicopathologic outcomes of the disease. Patients with less than 1% (low) or more than 50% (high) expression of p21 by immunohistochemistry show a higher chance of metastasis, poor necrotic response to chemotherapy, and an overall decreased survival rate when compared with p21 expression between 1% and 50% (moderate). Our results also showed that the expression of p16 and combined p16 and p21 demonstrates a stronger predictive relationship to 5-year survival than tumor histologic necrosis and p21 alone. DISCUSSION: The results of this study, once proven to be reproducible by a larger number of patients, will be valuable in the initial assessment and risk stratification of the patients for treatment and possibly the clinical trials.


Assuntos
Biomarcadores Tumorais , Neoplasias Ósseas , Inibidor p16 de Quinase Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p21 , Osteossarcoma , Humanos , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Osteossarcoma/metabolismo , Osteossarcoma/tratamento farmacológico , Osteossarcoma/diagnóstico , Osteossarcoma/terapia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Masculino , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Adulto , Prognóstico , Adolescente , Neoplasias Ósseas/patologia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/metabolismo , Criança , Biomarcadores Tumorais/metabolismo , Adulto Jovem , Pessoa de Meia-Idade , Imuno-Histoquímica , Gradação de Tumores , Pontos de Checagem do Ciclo Celular , Idoso
7.
J Vis Exp ; (207)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38767376

RESUMO

Understanding the relationship between the cells and their location within each tissue is critical to uncover the biological processes associated with normal development and disease pathology. Spatial transcriptomics is a powerful method that enables the analysis of the whole transcriptome within tissue samples, thus providing information about the cellular gene expression and the histological context in which the cells reside. While this method has been extensively utilized for many soft tissues, its application for the analyses of hard tissues such as bone has been challenging. The major challenge resides in the inability to preserve good quality RNA and tissue morphology while processing the hard tissue samples for sectioning. Therefore, a method is described here to process freshly obtained bone tissue samples to effectively generate spatial transcriptomics data. The method allows for the decalcification of the samples, granting successful tissue sections with preserved morphological details while avoiding RNA degradation. In addition, detailed guidelines are provided for samples that were previously paraffin-embedded, without demineralization, such as samples collected from tissue banks. Using these guidelines, high-quality spatial transcriptomics data generated from tissue bank samples of primary tumor and lung metastasis of bone osteosarcoma are shown.


Assuntos
Neoplasias Ósseas , Osso e Ossos , Transcriptoma , Humanos , Transcriptoma/genética , Osso e Ossos/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , Osteossarcoma/metabolismo , Perfilação da Expressão Gênica/métodos , Inclusão em Parafina/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo
8.
Folia Neuropathol ; 62(1): 96-101, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38741436

RESUMO

Gliosarcoma (GS) is a rare variant of IDH-wildtype glioblastoma. It is classified as grade 4 in the latest WHO CNS classification of both glial and mesenchymal components. Gliosarcoma may arise de novo or secondary from glioblastoma. It occurs in up to 2% of patients diagnosed with glioblastoma. We present a case report of a 51-year-old patient who was initially diagnosed with glioblastoma multiforme, which transformed into secondary gliosarcoma with an osteosarcoma component 16 months after the initial diagnosis. We believe that increasing reporting of secondary gliosarcoma (sGS) will be helpful in understanding, diagnosing and providing more effective treatment for this cancer.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Gliossarcoma , Isocitrato Desidrogenase , Osteossarcoma , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Gliossarcoma/genética , Gliossarcoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Osteossarcoma/genética , Osteossarcoma/patologia , Pessoa de Meia-Idade , Isocitrato Desidrogenase/genética , Masculino
9.
BMC Cancer ; 24(1): 580, 2024 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-38735973

RESUMO

BACKGROUND: SRSF1, a member of Serine/Arginine-Rich Splicing Factors (SRSFs), has been observed to significantly influence cancer progression. However, the precise role of SRSF1 in osteosarcoma (OS) remains unclear. This study aims to investigate the functions of SRSF1 and its underlying mechanism in OS. METHODS: SRSF1 expression level in OS was evaluated on the TCGA dataset, TAGET-OS database. qRT-PCR and Western blotting were employed to assess SRSF1 expression in human OS cell lines as well as the interfered ectopic expression states. The effect of SRSF1 on cell migration, invasion, proliferation, and apoptosis of OS cells were measured by transwell assay and flow cytometry. RNA sequence and bioinformatic analyses were conducted to elucidate the targeted genes, relevant biological pathways, and alternative splicing (AS) events regulated by SRSF1. RESULTS: SRSF1 expression was consistently upregulated in both OS samples and OS cell lines. Diminishing SRSF1 resulted in reduced proliferation, migration, and invasion and increased apoptosis in OS cells while overexpressing SRSF1 led to enhanced growth, migration, invasion, and decreased apoptosis. Mechanistically, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and Gene Set Enrichment Analysis (GSEA) revealed that the biological functions of SRSF1 were closely associated with the dysregulation of the protein targeting processes, location of the cytosolic ribosome, extracellular matrix (ECM), and proteinaceous extracellular matrix, along with the PI3K-AKT pathway, Wnt pathway, and HIPPO pathway. Transcriptome analysis identified AS events modulated by SRSF1, especially (Skipped Exon) SE events and (Mutually exclusive Exons) MXE events, revealing potential roles of targeted molecules in mRNA surveillance, RNA degradation, and RNA transport during OS development. qRT-PCR confirmed that SRSF1 knockdown resulted in the occurrence of alternative splicing of SRRM2, DMKN, and SCAT1 in OS. CONCLUSIONS: Our results highlight the oncogenic role of high SRSF1 expression in promoting OS progression, and further explore the potential mechanisms of action. The significant involvement of SRSF1 in OS development suggests its potential utility as a therapeutic target in OS.


Assuntos
Apoptose , Neoplasias Ósseas , Movimento Celular , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Osteossarcoma , Fatores de Processamento de Serina-Arginina , Humanos , Fatores de Processamento de Serina-Arginina/genética , Fatores de Processamento de Serina-Arginina/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , Osteossarcoma/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/metabolismo , Proliferação de Células/genética , Linhagem Celular Tumoral , Apoptose/genética , Movimento Celular/genética , Regulação para Cima , Processamento Alternativo
10.
Dalton Trans ; 53(20): 8633-8641, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38695060

RESUMO

Poor cellular permeability greatly hampers the utilization of anionic Ir(III) complexes, though efficiently emissive and remarkably stable, in cell-based diagnosis. To overcome this barrier, we present the development of an alkaline phosphatase (ALP)-responsive, anionic, and aggregation-induced emission (AIE)-active Ir(III) complex (Ir1) for specific recognition of osteosarcoma cells. Containing phosphate moieties, Ir1 exhibits a net -1 charge, enabling charge repulsion from the cell membrane and resulting in low cellular uptake and good biocompatibility in normal osteoblast cells. Upon ALP-mediated hydrolysis of phosphate groups, the resulting dephosphorylated product, Ir2, demonstrates a positive charge and increased lipophilicity, promoting cellular uptake and activating its AIE properties for specific recognition of osteosarcoma cells that express elevated levels of ALP. This study elucidates the role of ALP as an ideal trigger for enhancing the cellular permeability of phosphate ester-containing Ir(III) complexes, thus expanding the potential of anionic Ir(III) complexes for biomedical applications.


Assuntos
Fosfatase Alcalina , Ânions , Complexos de Coordenação , Irídio , Osteossarcoma , Irídio/química , Humanos , Osteossarcoma/patologia , Osteossarcoma/metabolismo , Fosfatase Alcalina/metabolismo , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Ânions/química , Linhagem Celular Tumoral
11.
Clin Transl Med ; 14(5): e1670, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38689429

RESUMO

BACKGROUND: Treatment for osteosarcoma, a paediatric bone cancer with no therapeutic advances in over three decades, is limited by a lack of targeted therapies. Osteosarcoma frequently metastasises to the lungs, and only 20% of patients survive 5 years after the diagnosis of metastatic disease. We found that WNT5B is the most abundant WNT expressed in osteosarcoma tumours and its expression correlates with metastasis, histologic subtype and reduced survival. METHODS: Using tumor-spheroids to model cancer stem-like cells, we performed qPCR, immunoblotting, and immunofluorescence to monitor changes in gene and protein expression. Additionally, we measured sphere size, migration and forming efficiency to monitor phenotypic changes. Therefore, we characterised WNT5B's relevance to cancer stem-like cells, metastasis, and chemoresistance and evaluated its potential as a therapeutic target. RESULTS: In osteosarcoma cell lines and patient-derived spheres, WNT5B is enriched in stem cells and induces the expression of the stemness gene SOX2. WNT5B promotes sphere size, sphere-forming efficiency, and cell proliferation, migration, and chemoresistance to methotrexate (but not cisplatin or doxorubicin) in spheres formed from conventional cell lines and patient-derived xenografts. In vivo, WNT5B increased osteosarcoma lung and liver metastasis and inhibited the glycosaminoglycan hyaluronic acid via upregulation of hyaluronidase 1 (HYAL1), leading to changes in the tumour microenvironment. Further, we identified that WNT5B mRNA and protein correlate with the receptor ROR1 in primary tumours. Targeting WNT5B through inhibition of WNT/ROR1 signalling with an antibody to ROR1 reduced stemness properties, including chemoresistance, sphere size and SOX2 expression. CONCLUSIONS: Together, these data define WNT5B's role in driving osteosarcoma cancer stem cell expansion and methotrexate resistance and provide evidence that the WNT5B pathway is a promising candidate for treating osteosarcoma patients. KEY POINTS: WNT5B expression is high in osteosarcoma stem cells leading to increased stem cell proliferation and migration through SOX2. WNT5B expression in stem cells increases rates of osteosarcoma metastasis to the lungs and liver in vivo. The hyaluronic acid degradation enzyme HYAL1 is regulated by WNT5B in osteosarcoma contributing to metastasis. Inhibition of WNT5B with a ROR1 antibody decreases osteosarcoma stemness.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Osteossarcoma , Proteínas Wnt , Osteossarcoma/patologia , Osteossarcoma/metabolismo , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Wnt/metabolismo , Proteínas Wnt/genética , Animais , Camundongos , Neoplasias Ósseas/patologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/tratamento farmacológico , Metástase Neoplásica/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Linhagem Celular Tumoral
12.
Sci Transl Med ; 16(749): eadg9814, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38809963

RESUMO

T cell-based cancer immunotherapy has typically relied on membrane-bound cytotoxicity enhancers such as chimeric antigen receptors expressed in autologous αß T cells. These approaches are limited by tonic signaling of synthetic constructs and costs associated with manufacturing. γδ T cells are an emerging alternative for cellular therapy, having innate antitumor activity, potent antibody-dependent cellular cytotoxicity, and minimal alloreactivity. We present an immunotherapeutic platform technology built around the innate properties of the Vγ9Vδ2 T cell, harnessing specific characteristics of this cell type and offering an allocompatible cellular therapy that recruits bystander immunity. We engineered γδ T cells to secrete synthetic tumor-targeting opsonins in the form of an scFv-Fc fusion protein and a mitogenic IL-15Rα-IL-15 fusion protein (stIL15). Using GD2 as a model antigen, we show that GD2-specific opsonin-secreting Vγ9Vδ2 T cells (stIL15-OPS-γδ T cells) have enhanced cytotoxicity and promote bystander activity of other lymphoid and myeloid cells. Secretion of stIL-15 abrogated the need for exogenous cytokine supplementation and further mediated activation of bystander natural killer cells. Compared with unmodified γδ T cells, stIL15-OPS-γδ T cells exhibited superior in vivo control of subcutaneous tumors and persistence in the blood. Moreover, stIL15-OPS-γδ T cells were efficacious against patient-derived osteosarcomas in animal models and in vitro, where efficacy could be boosted with the addition of zoledronic acid. Together, the data identify stIL15-OPS-γδ T cells as a candidate allogeneic cell therapy platform combining direct cytolysis with bystander activation to promote tumor control.


Assuntos
Osteossarcoma , Receptores de Antígenos de Linfócitos T gama-delta , Animais , Osteossarcoma/terapia , Osteossarcoma/imunologia , Osteossarcoma/patologia , Humanos , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Camundongos , Linfócitos T/imunologia , Ácido Zoledrônico/farmacologia , Efeito Espectador , Interleucina-15 , Engenharia Celular
13.
Asian Pac J Cancer Prev ; 25(5): 1497-1505, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38809621

RESUMO

BACKGROUND: Several studies of multi-drug regimens for osteosarcoma have shown different efficacies and are still controversial. Meanwhile, chemotherapy options have remained largely unchanged over a couple of decades. This study is designed to ascertain the outcome and safety of Methotrexate, Doxorubicin, and Cisplatin regimen for chemotherapy in osteosarcoma patients through the utilization of meta-analysis. METHODS: We interrogated trials that compared the MAP regimen with other regimens as chemotherapy for osteosarcoma from several databases encompassing PubMed, Science Direct, and grey literature (Google Scholar) until December 2022. The analyzed outcomes including Event-Free Survival (EFS), Overall Survival (OS), Tumor Necrosis (TN) rate, and Adverse Event (AE) were then analyzed using RevMan 5.4 software in fixed or random effect models. RESULTS: Our meta-analysis comprised 8 prospective articles that evaluated a cumulative number of 2920 OS patients. The analysis results indicated no meaningful difference in 5-year EFS (OR=0.99, 95% CI=0.77-1.27, [P = 0.91]) and neoadjuvant chemotherapy response (TN) (OR=0.76, 95% CI=0.49-1.17, [P = 0.22]) between the MAP and control groups. Furthermore, 5-year OS analysis revealed a significant association in the control group (OR=0.82, 95% CI=0.68-0.99, [P = 0.04]). However, the control group was associated with statistically meaningful AE compared to the MAP group, particularly in thrombocytopenia (OR=0.46, 95% CI=0.23-0.90, [P = 0.02]) and fever (OR=0.34, 95% CI=0.26-0.46, [P < 0.00001]). CONCLUSION: The present meta-analysis showed that the MAP regimen remains preferable in treating osteosarcoma patients despite no significant outcome compared to the other regimens considering the less frequent AE in the MAP regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ósseas , Cisplatino , Doxorrubicina , Metotrexato , Osteossarcoma , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Osteossarcoma/mortalidade , Humanos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Doxorrubicina/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/administração & dosagem , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Segurança do Paciente , Prognóstico , Taxa de Sobrevida , Resultado do Tratamento
14.
Aging (Albany NY) ; 16(10): 9188-9203, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38819212

RESUMO

AIM: Pseudouridylation has demonstrated the potential to control the development of numerous malignancies. PUS7(Pseudouridine Synthase 7) is one of the pseudouridine synthases, but the literature on this enzyme is limited to several cancer types. Currently, no investigation has been performed on the systematic pan-cancer analysis concerning PUS7 role in cancer diagnosis and prognosis. METHODS: Employing public databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), Human Protein Atlas (HPA), UALCAN and Tumor Immune Single-cell Hub (TISCH), this work investigated the PUS7 carcinogenesis in pan-cancer. Differential expression analysis, prognostic survival analysis and biological function were systematically performed. Furthermore, PUS7 potential as an osteosarcoma biomarker for diagnosis and prognosis was assessed in this study. RESULTS: The findings indicated that PUS7 was overexpressed in the majority of malignancies. High PUS7 expression contributed to the poor prognosis among 11 cancer types, including Adrenocortical Cancer (ACC), Bladder Cancer (BLCA), Liver Cancer (LIHC), Kidney Papillary Cell Carcinoma (KIRP), Mesothelioma (MESO), Lower Grade Glioma (LGG), Kidney Chromophobe (KICH), Sarcoma (SARC), osteosarcoma (OS), Pancreatic Cancer (PAAD), and Thyroid Cancer (THCA). In addition, elevated PUS7 expression was linked to advanced TNM across multiple malignancies, including ACC, BLCA, KIRP, LIHC and PAAD. The function enrichment analysis revealed that PUS7 participates in E2F targets, G2M checkpoint, ribosome biogenesis, and rRNA metabolic process. Moreover, PUS7 is also a reliable biomarker and a potential therapeutic target for osteosarcoma. CONCLUSIONS: In summary, PUS7 is a putative pan-cancer biomarker that reliably forecasts cancer patients' prognosis. In addition, this enzyme regulates the cell cycle, ribosome biogenesis, and rRNA metabolism. Most importantly, PUS7 possibly regulates osteosarcoma initiation and progression.


Assuntos
Biomarcadores Tumorais , Osteossarcoma , Humanos , Osteossarcoma/genética , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Osteossarcoma/metabolismo , Osteossarcoma/diagnóstico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Regulação Neoplásica da Expressão Gênica , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/diagnóstico , Neoplasias/genética , Neoplasias/diagnóstico , Neoplasias/mortalidade , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas de Membrana , Proteínas Adaptadoras de Transdução de Sinal
15.
Mol Cell Biol ; 44(5): 178-193, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38767243

RESUMO

Transcription factor 12 (TCF12) is a known oncogene in many cancers. However, whether TCF12 can regulate malignant phenotypes and angiogenesis in osteosarcoma is not elucidated. In this study, we demonstrated increased expression of TCF12 in osteosarcoma tissues and cell lines. High TCF12 expression was associated with metastasis and poor survival rate of osteosarcoma patients. Knockdown of TCF12 reduced the proliferation, migration, and invasion of osteosarcoma cells. TCF12 was found to bind to the promoter region of sphingosine kinase 1 (SPHK1) to induce transcriptional activation of SPHK1 expression and enhance the secretion of sphingosine-1-phosphate (S1P), which eventually resulted in the malignant phenotypes of osteosarcoma cells. In addition, S1P secreted by osteosarcoma cells promoted the angiogenesis of HUVECs by targeting S1PR4 on the cell membrane to activate the STAT3 signaling pathway. These findings suggest that TCF12 may induce transcriptional activation of SPHK1 to promote the synthesis and secretion of S1P. This process likely enhances the malignant phenotypes of osteosarcoma cells and induces angiogenesis via the S1PR4/STAT3 signaling pathway.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Lisofosfolipídeos , Neovascularização Patológica , Osteossarcoma , Fosfotransferases (Aceptor do Grupo Álcool) , Fator de Transcrição STAT3 , Transdução de Sinais , Esfingosina , Humanos , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Lisofosfolipídeos/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/genética , Linhagem Celular Tumoral , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Regulação Neoplásica da Expressão Gênica , Proliferação de Células/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Ativação Transcricional/genética , Receptores de Esfingosina-1-Fosfato/metabolismo , Receptores de Esfingosina-1-Fosfato/genética , Receptores de Lisoesfingolipídeo/metabolismo , Receptores de Lisoesfingolipídeo/genética , Movimento Celular/genética , Masculino , Animais , Feminino , Angiogênese
16.
J Cell Mol Med ; 28(10): e18400, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38780513

RESUMO

Osteosarcoma is the most common primary bone malignancy in children and adolescents. Overexpression of polo-like kinase 1 (PLK1) is frequent in osteosarcoma and drives disease progression and metastasis, making it a promising therapeutic target. In this study, we explored PLK1 knockdown in osteosarcoma cells using RNA interference mediated by high-fidelity Cas13d (hfCas13d). PLK1 was found to be significantly upregulated in osteosarcoma tumour tissues compared to normal bone. sgRNA-mediated PLK1 suppression via hfCas13d transfection inhibited osteosarcoma cell proliferation, induced G2/M cell cycle arrest, promoted apoptosis, reduced cell invasion and increased expression of the epithelial marker E-cadherin. Proximity labelling by TurboID coupled with co-immunoprecipitation identified novel PLK1 interactions with Smad3, a key intracellular transducer of TGF-ß signalling. PLK1 knockdown impaired Smad2/3 phosphorylation and modulated TGF-ß/Smad3 pathway inactivation. Finally, in vivo delivery of hfCas13d vectors targeting PLK1 substantially attenuated osteosarcoma xenograft growth in nude mice. Taken together, this study highlights PLK1 as a potential therapeutic target and driver of disease progression in osteosarcoma. It also demonstrates the utility of hfCas13d-mediated gene knockdown as a strategy for targeted therapy. Further optimization of PLK1 suppression approaches may ultimately improve clinical outcomes for osteosarcoma patients.


Assuntos
Apoptose , Proteínas de Ciclo Celular , Proliferação de Células , Camundongos Nus , Osteossarcoma , Quinase 1 Polo-Like , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas , Interferência de RNA , Transdução de Sinais , Proteína Smad3 , Fator de Crescimento Transformador beta , Osteossarcoma/patologia , Osteossarcoma/genética , Osteossarcoma/metabolismo , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Animais , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteína Smad3/metabolismo , Proteína Smad3/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Fator de Crescimento Transformador beta/metabolismo , Camundongos , Apoptose/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino
17.
Aging (Albany NY) ; 16(9): 8155-8170, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38747739

RESUMO

BACKGROUND: Osteosarcoma (OS) is a primary malignant bone tumor arising from mesenchymal cells. The standard clinical treatment for OS involves extensive tumor resection combined with neoadjuvant chemotherapy or radiotherapy. OS's invasiveness, lung metastasis, and drug resistance contribute to a low cure rate and poor prognosis with this treatment. Metallothionein 1G (MT1G), observed in various cancers, may serve as a potential therapeutic target for OS. METHODS: OS samples in GSE33382 and TARGET datasets were selected as the test cohorts. As the external validation cohort, 13 OS tissues and 13 adjacent cancerous tissues from The Second Affiliated Hospital of Nanchang University were collected. Patients with OS were divided into high and low MT1G mRNA-expression groups; differentially expressed genes (DEGs) were identified as MT1G-related genes. The biological function of MT1G was annotated using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) and gene set enrichment analysis (GSEA). Gene expression correlation analysis and competing endogenous RNA (ceRNA) regulatory network construction were used to determine potential biological regulatory relationships of DEGs. Survival analysis assessed the prognostic value of MT1G. RESULTS: MT1G expression increased in OS samples and presented higher in metastatic OS compared with non-metastatic OS. Functional analyses indicated that MT1G was mainly associated with spliceosome. A ceRNA network with DEGs was constructed. MT1G is an effective biomarker predicting survival and correlated with increased recurrence rates and poorer survival. CONCLUSIONS: This research identified MT1G as a potential biomarker for OS prognosis, highlighting its potential as a therapy target.


Assuntos
Neoplasias Ósseas , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Células-Tronco Mesenquimais , Metalotioneína , Osteossarcoma , Feminino , Humanos , Masculino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/mortalidade , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Células-Tronco Mesenquimais/metabolismo , Metalotioneína/genética , Metalotioneína/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , Prognóstico
18.
Cancer Med ; 13(10): e7303, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38800967

RESUMO

Osteosarcoma (OS) is a prevalent bone solid malignancy that primarily affects adolescents, particularly boys aged 14-19. This aggressive form of cancer often leads to deadly lung cancer due to its high migration ability. Experimental evidence suggests that programmed cell death (PCD) plays a crucial role in the development of osteosarcoma. Various forms of PCD, including apoptosis, ferroptosis, autophagy, necroptosis, and pyroptosis, contribute significantly to the progression of osteosarcoma. Additionally, different signaling pathways such as STAT3/c-Myc signal pathway, JNK signl pathway, PI3k/AKT/mTOR signal pathway, WNT/ß-catenin signal pathway, and RhoA signal pathway can influence the development of osteosarcoma by regulating PCD in osteosarcoma cell. Therefore, targeting PCD and the associated signaling pathways could offer a promising therapeutic approach for treating osteosarcoma.


Assuntos
Apoptose , Neoplasias Ósseas , Osteossarcoma , Transdução de Sinais , Osteossarcoma/patologia , Osteossarcoma/terapia , Osteossarcoma/metabolismo , Humanos , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Neoplasias Ósseas/metabolismo , Autofagia , Ferroptose , Necroptose , Animais
19.
Folia Med (Plovdiv) ; 66(2): 196-202, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38690814

RESUMO

INTRODUCTION: Osteosarcoma (OS) and Ewing sarcoma (ES) represent the pediatric population's most common malignant bone tumors. 18-Fluorodeoxyglucose positron emission tomography has been shown to be effective in both the diagnostic and staging phases of cancer treatment. In recent years, some studies have also explored the possibility that FDG-PET could have a prognostic role.


Assuntos
Neoplasias Ósseas , Fluordesoxiglucose F18 , Osteossarcoma , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/diagnóstico por imagem , Sarcoma de Ewing/patologia , Sarcoma de Ewing/tratamento farmacológico , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/patologia , Osteossarcoma/tratamento farmacológico , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Necrose , Prognóstico
20.
BMC Med ; 22(1): 200, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38755647

RESUMO

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor and is highly prone to metastasis. OS can metastasize to the lymph node (LN) through the lymphatics, and the metastasis of tumor cells reestablishes the immune landscape of the LN, which is conducive to the growth of tumor cells. However, the mechanism of LN metastasis of osteosarcoma and remodeling of the metastatic lymph node (MLN) microenvironment is not clear. METHODS: Single-cell RNA sequencing of 18 samples from paracancerous, primary tumor, and lymph nodes was performed. Then, new signaling axes closely related to metastasis were identified using bioinformatics, in vitro experiments, and immunohistochemistry. The mechanism of remodeling of the LN microenvironment in tumor cells was investigated by integrating single-cell and spatial transcriptomics. RESULTS: From 18 single-cell sequencing samples, we obtained 117,964 cells. The pseudotime analysis revealed that osteoblast(OB) cells may follow a differentiation path from paracancerous tissue (PC) → primary tumor (PT) → MLN or from PC → PT, during the process of LN metastasis. Next, in combination of bioinformatics, in vitro and in vivo experiments, and immunohistochemistry, we determined that ETS2/IBSP, a new signal axis, might promote LN metastasis. Finally, single-cell and spatial dissection uncovered that OS cells could reshape the microenvironment of LN by interacting with various cell components, such as myeloid, cancer-associated fibroblasts (CAFs), and NK/T cells. CONCLUSIONS: Collectively, our research revealed a new molecular mechanism of LN metastasis and clarified how OS cells influenced the LN microenvironment, which might provide new insight for blocking LN metastasis.


Assuntos
Neoplasias Ósseas , Linfonodos , Metástase Linfática , Osteossarcoma , Análise de Célula Única , Transcriptoma , Microambiente Tumoral , Osteossarcoma/patologia , Osteossarcoma/genética , Humanos , Neoplasias Ósseas/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Linfonodos/patologia , Metástase Linfática/patologia , Animais , Camundongos , Linhagem Celular Tumoral , Perfilação da Expressão Gênica
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