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1.
J Orthop Surg Res ; 18(1): 12, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36604721

RESUMO

BACKGROUND: Increasing evidences have been indicated that FGF23 is associated with the biological behavior of malignant tumors, but its role in osteosarcoma and the specific mechanism need to be elucidated. The purpose of this study is to investigate the effects of FGF23 on the proliferation, migration and invasion of osteosarcoma cells, and the possible molecular mechanisms. METHODS: Western blot was used to detect differences in FGF23 expression in osteosarcoma cells MG-63 and U2-OS and osteoblasts hFOB1.19. FGF23-overexpressing adenoviruses and FGF-silencing plasmids were transfected into osteosarcoma cells, and transfection efficiency was verified using Western blot. MTT and colony formation assays were performed to detect osteosarcoma cell proliferation. Cell cycle was measured by flow cytometry. Scratch assay, holographic imaging cell analyzer Holomonitor ® M4 and transwell were applied to detect cell migration and invasion. Dual-luciferase reporter assay was performed to validate the interaction between FGF23 and miR-340-5p. Changes in miR-340-5p mRNA levels were measured by QRT-PCR. RESULTS: FGF23 is highly expressed in osteosarcoma cells compared to hFOB1.19. Overexpression of FGF23 significantly promoted the proliferation, migration and invasion of MG-63 and U2-OS cells. MiR-340-5p is a target of FGF23. Transfection of miR-340-5p mimics reversed the promoting effects of FGF23 on proliferation, migration and invasion of MG-63 and U2-OS cells. CONCLUSION: FGF23 promotes osteosarcoma cell proliferation, migration and invasion by targeting miR-340-5p gene expression.


Assuntos
Neoplasias Ósseas , Fator de Crescimento de Fibroblastos 23 , MicroRNAs , Osteossarcoma , Humanos , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Osteossarcoma/patologia , Fator de Crescimento de Fibroblastos 23/genética , Fator de Crescimento de Fibroblastos 23/metabolismo
2.
Int J Mol Sci ; 24(1)2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36614241

RESUMO

Improving the prognosis and cure rate of HGOSs (high-grade osteosarcomas) is an absolute need. Immune-based treatment approaches have been increasingly taken into consideration, in particular for metastatic, relapsed and refractory HGOS patients, to ameliorate the clinical results currently achieved. This review is intended to give an overview on the immunotherapeutic treatments targeting, counteracting or exploiting the different immune cell compartments that are present in the HGOS tumor microenvironment. The principle at the basis of these strategies and the possible mechanisms that HGOS cells may use to escape these treatments are presented and discussed. Finally, a list of the currently ongoing immune-based trials in HGOS is provided, together with the results that have been obtained in recently completed clinical studies. The different strategies that are presently under investigation, which are generally aimed at abrogating the immune evasion of HGOS cells, will hopefully help to indicate new treatment protocols, leading to an improvement in the prognosis of patients with this tumor.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Neoplasias Ósseas/patologia , Osteossarcoma/patologia , Microambiente Tumoral
3.
Indian J Pathol Microbiol ; 66(1): 184-187, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36656238

RESUMO

Phyllodes tumors (PTs) are uncommon biphasic breast neoplasms constituting 0.5 to 1.0% of all breast tumors. Malignant PTs form a very small proportion of these and may metastasize, especially to the lungs and bones. Aggression and metastatic potential are accentuated in tumors exhibiting heterologous differentiation. Metastases to the gastrointestinal tract (GIT) have seldom been reported and are often confined to a segment of the digestive tract. In the absence of relevant clinical history, such patients presenting with gastrointestinal symptoms can lead to diagnostic perplexities. We report a unique case of a malignant PT with extensive osteosarcomatous differentiation and widespread metastases to the GIT.


Assuntos
Neoplasias Ósseas , Neoplasias da Mama , Obstrução Intestinal , Osteossarcoma , Tumor Filoide , Humanos , Feminino , Tumor Filoide/diagnóstico , Tumor Filoide/patologia , Osteossarcoma/diagnóstico , Osteossarcoma/patologia , Obstrução Intestinal/diagnóstico , Obstrução Intestinal/etiologia , Neoplasias Ósseas/diagnóstico , Neoplasias da Mama/complicações , Neoplasias da Mama/diagnóstico
4.
Int J Mol Sci ; 24(2)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36674874

RESUMO

This review provides an overview of histopathology, clinical presentation, molecular pathways, and potential new systemic treatments of high-grade chondrosarcomas (CS), including grade 2-3 conventional, dedifferentiated, and mesenchymal CS. The diagnosis of CS combines radiological and histological data in conjunction with patient clinical presentations. Conventional CS is the most frequent subtype of CS (85%) and represents about 25% of primary bone tumors in adults; they can be categorized according to their bone location into central, peripheral, and periosteal chondrosarcomas. Central and peripheral CS differ at the molecular level with either IDH1/2 mutations or EXT1/2 mutations, respectively. CDKN2A/B deletions are also frequent in conventional CS, as well as COL2A1 mutations. Dedifferentiated CS develops when low-grade conventional CS transforms into a high-grade sarcoma and most frequently exhibits features of osteosarcoma, fibrosarcoma, or undifferentiated pleomorphic sarcoma. Their molecular characteristics are similar to conventional CS. Mesenchymal CS is a totally different pathological entity exhibiting recurrent translocations. Their clinical presentation and management are different too. The standard treatment of CSs is wide en-bloc resection. CS are relatively radiotherapy resistant; therefore, doses >60 Gy are needed in an attempt to achieve local control in unresectable tumors. Chemotherapy is possibly effective in mesenchymal chondrosarcoma and is of uncertain value in dedifferentiated chondrosarcoma. Due to resistance to standard anticancer agents, the prognosis is poor in patients with metastatic or unresectable chondrosarcomas. Recently, the refined characterization of the molecular profile, as well as the development of new treatments, allow new therapeutic options for these rare tumors. The efficiency of IDH1 inhibitors in other malignancies suggests that these inhibitors will be part of IDH1/2 mutated conventional CS management soon. Other treatment approaches, such as PIK3-AKT-mTOR inhibitors, cell cycle inhibitors, and epigenetic or immune modulators based on improving our understanding of CS molecular biology, are emerging.


Assuntos
Neoplasias Ósseas , Condrossarcoma , Osteossarcoma , Adulto , Humanos , Condrossarcoma/diagnóstico , Condrossarcoma/genética , Condrossarcoma/terapia , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Radiografia , Osteossarcoma/patologia , Biologia
5.
Gen Physiol Biophys ; 42(1): 1-12, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36705300

RESUMO

This study aimed to identify immune-based prognostic biomarkers associated with metastasis of osteosarcoma. Based on the GEO and TCGA databases, 437 differentially expressed genes were screened between primary and metastatic osteosarcoma. Weighted gene co-expression network analysis (WGCNA) revealed 496 genes in turquoise module which had the highest correlation with osteosarcoma metastasis. Within these two group genes, 122 common genes involved in osteosarcoma metastasis were identified. These genes were enriched in chemokine activity, chemokine receptor binding, TNF signaling pathway, etc. Survival analysis revealed 8 prognostic genes (ANK3, EGR1, FBP1, FOS, KIFC3, MAOB, ISLR and MFAP4) from the 122 genes. RT-qPCR showed that all of these eight genes were differentially expressed between 143B and MNNG/HOS Cl cells. Various infiltrating immune cells showed significant differences between primary and metastatic osteosarcoma. Expression of all the 8 prognostic genes was correlated with infiltration abundance of multiple immune cells, such as follicular helper T cells, activated dendritic cells. In addition, 10 microRNAs and 7 transcription factors that targeted these prognostic genes were predicted. In conclusion, 8 immune-based prognostic genes associated with osteosarcoma metastasis were identified.


Assuntos
MicroRNAs , Osteossarcoma , Humanos , Prognóstico , MicroRNAs/metabolismo , Biomarcadores , Perfilação da Expressão Gênica , Osteossarcoma/genética , Osteossarcoma/patologia , Proteínas de Transporte/genética , Glicoproteínas/genética , Glicoproteínas/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Cinesinas/genética , Cinesinas/metabolismo
6.
J Transl Med ; 21(1): 7, 2023 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-36611209

RESUMO

BACKGROUND: Osteosarcoma (OS) is the most frequent cancer derived from bone, and the prognosis of OS is poor. Metabolic alterations have been previously reported to contribute to the development of OS, and arsenic compounds have been suggested to exhibit strong anti-OS effects. However, few studies have described the therapeutic efficiency of arsenic compounds by targeting metabolism in OS. METHODS: Here, we presented a novel organo-arsenic compound, Aa-Z2, and its antitumour efficacy against OS both in vitro and in vivo. RESULTS: Aa-Z2 induced OS cell apoptosis, G2/M phase arrest, and autophagy through the accumulation of reactive oxygen species (ROS). Elevated ROS functioned by promoting the mitochondrial-dependent caspase cascade and attenuating the PI3K/Akt/mTOR signalling pathway. N-acetylcysteine (NAC), a kind of ROS scavenger, could reverse the effects of Aa-Z2 treatment on 143B and HOS cells. Specifically, by targeting pyruvate dehydrogenase kinase 1 (PDK-1), Aa-Z2 induced changes in mitochondrial membrane potential and alterations in glucose metabolism to accumulate ROS. Overexpression of PDK-1 could partially desensitize OS cells to Aa-Z2 treatment. Importantly, Aa-Z2 suppressed tumour growth in our xenograft osteosarcoma model. CONCLUSION: The study provides new insights into the mechanism of Aa-Z2-related metabolic alterations in OS inhibition, as well as pharmacologic evidence supporting the development of metabolism-targeting therapeutics.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Apoptose , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo
7.
Int J Biol Sci ; 19(2): 412-425, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36632453

RESUMO

Osteosarcoma is a highly mortal bone tumor, with a high metastatic potential, promoted in part by the enzyme procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2). Increasing level of PLOD2 in osteosarcoma tissue correlates with lymphatic and distant metastasis. The adipokine apelin (APLN) is also found in different cancers and APLN upregulation promotes angiogenesis and metastasis, but its effects on osteosarcoma metastasis are uncertain. We explored APLN functioning in metastatic osteosarcoma. An analysis of records from the Gene Expression Omnibus (GEO) database showed higher levels of APLN expression in osteosarcoma tissue than in normal tissue. Similarly, levels of APLN and PLOD2 mRNA synthesis were upregulated in osteosarcoma tissue. Levels of APLN and PLOD2 protein correlated positively with osteosarcoma clinical stages. APLN increased PLOD2 expression in human osteosarcoma cell lines and cell migration via the mammalian Sterile 20-like kinase 1 (MST1), monopolar spindle-one-binder protein (MOB)1, and YAP cascades, and through hsa_circ_0000004 functioning as a sponge of miR-1303. We also found that knockdown of APLN antagonized lung metastasis in mice with osteosarcoma. APLN may be a therapeutic target in osteosarcoma metastasis.


Assuntos
Neoplasias Ósseas , MicroRNAs , Osteossarcoma , Humanos , Animais , Camundongos , Via de Sinalização Hippo , Apelina/genética , Apelina/metabolismo , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/genética , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/metabolismo , Linhagem Celular Tumoral , MicroRNAs/genética , Osteossarcoma/genética , Osteossarcoma/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Proliferação de Células , Regulação Neoplásica da Expressão Gênica/genética , Mamíferos/metabolismo
8.
Int J Biol Sci ; 19(2): 537-551, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36632464

RESUMO

Numerous studies have confirmed that in addition to interfering with the tumor inflammatory environment, anti-inflammatory agents can directly increase apoptosis and sensitivity to conventional therapies and decrease invasion and metastasis, making them useful candidates for cancer therapy. Here, we first used high-throughput screening and had screened one compound candidate, ebastine (a H1-histamine receptor antagonist), for osteosarcoma therapy. Cell viability assays, colony formation assays, wound healing assays, and Transwell assays demonstrated that ebastine elicited antitumor effects in osteosarcoma cells. In addition, ebastine treatment exerted obvious effects on cell cycle arrest, metastasis inhibition, apoptosis and autophagy induction both in vitro and in vivo. Mechanistically, we observed that ebastine treatment triggered proapoptotic autophagy by activating AMPK/ULK1 signaling in osteosarcoma cells. Treatment with the AMPK inhibitor dorsomorphin reversed ebastine-induced apoptosis and autophagy. More importantly, we found that IPMK interacted with AMPK and functioned as a positive regulator of AMPK protein in osteosarcoma cells. A rescue study showed that the induction of autophagy and activation of the AMPK/ULK1 signaling pathway by ebastine treatment were reversed by IPMK knockdown, indicating that the activity of ebastine was IPMK dependent. We provide experimental evidence demonstrating that ebastine has antitumor activity in osteosarcoma and promotes autophagy by activating the AMPK/ULK1 signaling pathway, which is IPMK dependent. Our results provide insight into the clinical application potential of ebastine, which may represent a new potential therapeutic candidate for the treatment of osteosarcoma.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Proteínas Quinases Ativadas por AMP/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Transdução de Sinais , Autofagia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Neoplasias Ósseas/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
9.
DNA Cell Biol ; 42(1): 53-64, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36580535

RESUMO

Circular RNA (circRNA) is involved in the occurrence and development of various cancers. To this day, the expression and mechanism of circRNA in osteosarcoma (OS) remain unclear. We previously found that circ_0001060 was highly expressed in OS tumor tissues. In this work, we identified that high level expression of circ_0001060 was significantly associated with late clinical stage, larger tumor volume, higher frequency of metastasis, and poor prognosis in OS patients. Furthermore, we confirmed that silencing circ_0001060 inhibited the proliferation and migration of OS cell. Using bioinformatics analysis, we built three circRNA-miRNA-mRNA regulatory modules (circ_0001060-miR-203a-5p-TRIM21, circ_0001060-miR-208b-5p-MAP3K5, and circ_0001060-miR-203a-5p-PRKX), suggesting that these signaling axes may be involved in the inhibitory effect of circ_0001060 on OS. To sum up, circ_0001060 is a novel tumor biomarker for OS as well as a potential therapeutic target.


Assuntos
Neoplasias Ósseas , MicroRNAs , Osteossarcoma , Humanos , RNA Circular/genética , RNA Circular/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proliferação de Células/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia
10.
J Orthop Traumatol ; 23(1): 59, 2022 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-36571630

RESUMO

BACKGROUND: Improved patient and limb survival rates have led to an increased interest in the functional outcome and return to sports of patients undergoing megaprosthetic reconstruction in musculoskeletal oncology. This study evaluates the functional outcome and postoperatively performed level of sports in patients undergoing proximal humeral replacement (PHR) following resection of a primary bone sarcoma and identifies potential beneficial and limiting factors. PATIENTS AND METHODS: Between 2007 and 2020, a total of 606 patients underwent resection of a primary bone sarcoma and reconstruction with a single-design modular implant. For 112 (18%) patients, the location of the tumour was the proximal humerus. Exclusion criteria were death (n = 65), patients living overseas (n = 8), and subsequent amputation (n = 1), leaving 38 patients for evaluation, of whom 32 were available for the study (13 women, median age 42 years). Clinical data regarding oncological and surgical treatment as well as subsequent complications were obtained from the patients' electronic medical records. Functional outcome was determined using the Musculoskeletal Tumor Society Score (MSTS) and Toronto Extremity Salvage Score (TESS) as well as the Subjective Shoulder Value (SSV). Return to sports was assessed using the Tegner Activity Score (TS) and the modified Weighted Activity Score (WAS). RESULTS: At the last follow-up after a median of 30 months (IQR 22-58), median MSTS was 18 (IQR 12-24), median TESS was 80% (IQR 69-87), median SSV was 35% (IQR 10-58), median TS was 5 (IQR 4-6) and median WAS was 5 (IQR 0-10). Preservation of the axillary nerve, a reverse shoulder reconstruction and a WAS of > 10 prior to surgery were associated with better functional outcome and return to sports activity scores. CONCLUSION: Following PHR, good to excellent functional outcomes are possible, and patients regularly return to participate in sports activities-most commonly in low-impact types of sports, but some individuals are even able to participate in high-impact sports activities. LEVEL OF EVIDENCE: IV.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Sarcoma , Humanos , Feminino , Adulto , Ombro/patologia , Volta ao Esporte , Resultado do Tratamento , Sarcoma/cirurgia , Sarcoma/patologia , Osteossarcoma/patologia , Neoplasias Ósseas/cirurgia , Neoplasias Ósseas/patologia , Úmero/cirurgia , Estudos Retrospectivos
11.
J Orthop Surg Res ; 17(1): 557, 2022 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-36544170

RESUMO

BACKGROUND: Osteosarcoma is highly malignant. The migration, invasion, and chemoresistance contribute to poor prognosis of osteosarcoma. Research reported that endogenous bornavirus-like nucleoprotein 3 pseudogene (EBLN3P) promotes the progression of osteosarcoma. METHODS: In this study, the expression of EBLN3P in osteosarcoma tissue with different methotrexate (MTX) treatment responses was measured. Osteosarcoma cell lines with MTX resistance were constructed, and bioinformatic analysis was performed to explore the potential involved targets and pathways. RESULTS: Higher EBLN3P was associated with MTX resistance. Downregulation of LncEBLN3P decreased the MTX resistance of osteosarcoma cells by sponging miR-200a-3p, an important microRNA that affects epithelial-mesenchymal transition (EMT). The decreased miR-200a-3p resulted in the upregulation of its target gene O-GlcNAc transferase (OGT), which in turn promoted the EMT process of osteosarcoma cells. Further analysis confirmed that the loss of OGT and over-expression of miR-200a-3p could partly abolish the MTX resistance induced by LncEBLN3P. CONCLUSION: LncEBLN3P is upregulated in osteosarcoma and increases the MTX resistance in osteosarcoma cells through downregulating miR-200a-3p, which in turn promoted the EMT process of osteosarcoma cells by increasing the OGT.


Assuntos
Neoplasias Ósseas , Resistencia a Medicamentos Antineoplásicos , Metotrexato , MicroRNAs , Osteossarcoma , RNA Longo não Codificante , Humanos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Metotrexato/farmacologia , MicroRNAs/genética , MicroRNAs/metabolismo , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Osteossarcoma/patologia , Pseudogenes , RNA Longo não Codificante/genética , Resistencia a Medicamentos Antineoplásicos/genética
12.
Expert Rev Mol Diagn ; 22(12): 1099-1106, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36510847

RESUMO

BACKGROUND: Osteosarcoma, the most prevalent primary bone cancer, tends to relapse or metastasize quickly. Hypoxia-inducible factor-1 alpha (HIF-1α) affects tumor metabolism, differentiation, angiogenesis, proliferation, and metastasis. Many studies have investigated the possible inconsistent prognostic value of HIF-1 α. This study evaluated the correlation between HIF-1 α expression and prognosis in osteosarcoma patients. METHODS: : A total of 978 patients from 12 studies were followed up. A meta-analysis was conducted on articles investigating HIF-1 α prognostic value in osteosarcoma patients. The authors excluded articles with overlapping data, duplicate data, reviews, case reports, and letters that did not provide original data. Calculation of the hazard ratios (HR) and pooled risk ratios (RR) with corresponding 95% confidence intervals were used to determine the association degree (CIs). RESULTS: It was determined that HIF-1 α in osteosarcoma patients had a prognostic value based on the RRs and HRs. The results showed that high HIF-1 α expression was associated with a worse prognosis when compared to low or undetectable HIF-1 α expression. CONCLUSION: HIF-1 α overexpression was found to predict poor outcomes in osteosarcomas. The present study suggests that HIF-1α is a useful prognostic biomarker to predict OS in patients with osteosarcoma.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Fator 1 Induzível por Hipóxia , Prognóstico , Recidiva Local de Neoplasia , Osteossarcoma/patologia , Neoplasias Ósseas/patologia , Biomarcadores , Subunidade alfa do Fator 1 Induzível por Hipóxia
13.
BMC Cancer ; 22(1): 1370, 2022 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-36585638

RESUMO

BACKGROUND: The purpose of this study was to investigate the significance of preoperative C-reactive protein-to-albumin ratio (CAR), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in predicting overall survival (OS) of osteosarcoma, to establish a nomogram of an individualized prognostic prediction model for osteosarcoma. METHODS: Two hundred thirty-five patients with osteosarcoma from multiple centers were included in this study. Receiver operating characteristic (ROC) and Youden index were used to determine the optimal cutoff values ​​for CAR, NLR, and PLR. Univariate analysis using COX proportional hazards model to identify factors associated with OS in osteosarcoma, and multivariate analysis of these factors to identify independent prognostic factors. R software (4.1.3-win) rms package was used to build a nomogram, and the concordance index (C-index) and calibration curve were used to assess model accuracy and discriminability. RESULTS: Univariate analysis revealed that the OS of osteosarcoma is significantly correlated (P < 0.05) with CAR, NLR, PLR, Enneking stage, tumor size, age, neoadjuvant chemotherapy (NACT), and high alkaline phosphatase. Multivariate analysis confirmed that CAR, NLR, Enneking stage, NACT and tumor size are independent prognostic factors for OS of osteosarcoma. The calibration curve shows that the nomogram constructed from these factors has acceptable consistency and calibration capability. CONCLUSION: Preoperative CAR and NLR were independent predictors of osteosarcoma prognosis, and the combination of nomogram model can realize individualized prognosis prediction and guide medical practice.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Estudos Retrospectivos , Linfócitos/patologia , Prognóstico , Neutrófilos/patologia , Osteossarcoma/cirurgia , Osteossarcoma/patologia , Neoplasias Ósseas/cirurgia
14.
Int J Mol Sci ; 23(24)2022 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-36555795

RESUMO

Osteosarcoma (OS) is a malignancy that is becoming increasingly common in adolescents. OS stem cells (OSCs) form a dynamic subset of OS cells that are responsible for malignant progression and chemoradiotherapy resistance. The unique properties of OSCs, including self-renewal, multilineage differentiation and metastatic potential, 149 depend closely on their tumor microenvironment. In recent years, the likelihood of its dynamic plasticity has been extensively studied. Importantly, the tumor microenvironment appears to act as the main regulatory component of OS cell plasticity. For these reasons aforementioned, novel strategies for OS treatment focusing on modulating OS cell plasticity and the possibility of modulating the composition of the tumor microenvironment are currently being explored. In this paper, we review recent studies describing the phenomenon of OSCs and factors known to influence phenotypic plasticity. The microenvironment, which can regulate OSC plasticity, has great potential for clinical exploitation and provides different perspectives for drug and treatment design for OS.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Adolescente , Humanos , Microambiente Tumoral , Linhagem Celular Tumoral , Neoplasias Ósseas/patologia , Osteossarcoma/patologia
15.
J Exp Clin Cancer Res ; 41(1): 354, 2022 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-36539799

RESUMO

BACKGROUND: Escaping from ER stress-induced apoptosis plays an important role in the progression of many tumours. However, its molecular mechanism in osteosarcoma remains incompletely understood. METHODS: The molecular mechanism was investigated using RNA sequencing, qRT-PCR and Western blot assays. The relationship between LINC00629 and KLF4 was investigated using RNA pulldown and ubiquitylation assays. The transcriptional regulation of laminin subunit alpha 4 (LAMA4) by KLF4 was identified using bioinformatic analysis, a luciferase assay, and a chromatin immunoprecipitation assay. RESULTS: Here, we demonstrated that LINC00629 was increased under ER stress treatment. Elevated LINC00629 inhibited ER stress-induced osteosarcoma cell apoptosis and promoted clonogenicity and migration in vitro and in vivo. Further mechanistic studies indicated that LINC00629 interacted with KLF4 and suppressed its degradation, which led to a KLF4 increase in osteosarcoma. In addition, we also found that KLF4 upregulated LAMA4 expression by directly binding to its promoter and that LINC00629 inhibited ER stress-induced apoptosis and facilitated osteosarcoma cell clonogenicity and metastasis by activating the KLF4-LAMA4 pathway. CONCLUSION: Collectively, our data indicate that LINC00629 is a critical long noncoding RNA (lncRNA) induced by ER stress and plays an oncogenic role in osteosarcoma cell by activating the KLF4-LAMA4 axis.


Assuntos
Neoplasias Ósseas , MicroRNAs , Osteossarcoma , RNA Longo não Codificante , Humanos , MicroRNAs/genética , Linhagem Celular Tumoral , Apoptose/genética , Osteossarcoma/patologia , Neoplasias Ósseas/patologia , Proliferação de Células , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica
16.
J Transl Med ; 20(1): 625, 2022 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-36575510

RESUMO

BACKGROUND: Early prediction of response to neoadjuvant chemotherapy (NACT) is important to aid personalized treatment in osteosarcoma. Diffusion-weighted Intravoxel Incoherent Motion (IVIM) MRI was used to evaluate the predictive value for response to NACT and survival outcome in osteosarcoma. METHODS: Total fifty-five patients with biopsy-proven osteosarcoma were recruited prospectively, among them 35 patients were further analysed. Patients underwent 3 cycles of NACT (Cisplatin + Doxorubicin) followed by surgery and response adapted adjuvant chemotherapy. Treatment outcomes were histopathological response to NACT (good-response ≥ 50% necrosis and poor-response < 50% necrosis) and survival outcome (event-free survival (EFS) and overall survival (OS)). IVIM MRI was acquired at 1.5T at baseline (t0), after 1-cycle (t1) and after 3-cycles (t2) of NACT. Quantitative IVIM parameters (D, D*, f & D*.f) were estimated using advanced state-of-the-art spatial penalty based IVIM analysis method bi-exponential model with total-variation penalty function (BETV) at 3 time-points and histogram analysis was performed. RESULTS: Good-responders: Poor-responders ratio was 13 (37%):22 (63%). EFS and OS were 31% and 69% with 16.27 and 25.9 months of median duration respectively. For predicting poor-response to NACT, IVIM parameters showed AUC = 0.87, Sensitivity = 86%, Specificity = 77% at t0, and AUC = 0.96, Sensitivity = 86%, Specificity = 100% at t1. Multivariate Cox regression analysis showed smaller tumour volume (HR = 1.002, p = 0.001) higher ADC-25th-percentile (HR = 0.047, p = 0.005) & D-Mean (HR = 0.1, p = 0.023) and lower D*-Mean (HR = 1.052, p = 0.039) were independent predictors of longer EFS (log-rank p-values: 0.054, 0.0034, 0.0017, 0.0019 respectively) and non-metastatic disease (HR = 4.33, p < 10-3), smaller tumour-volume (HR = 1.001, p = 0.042), lower D*-Mean (HR = 1.045, p = 0.056) and higher D*.f-skewness (HR = 0.544, p = 0.048) were independent predictors of longer OS (log-rank p-values: < 10-3, 0.07, < 10-3, 0.019 respectively). CONCLUSION: IVIM parameters obtained with a 1.5T scanner along with novel BETV method and their histogram analysis indicating tumour heterogeneity were informative in characterizing NACT response and survival outcome in osteosarcoma.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Terapia Neoadjuvante , Imageamento por Ressonância Magnética/métodos , Imagem de Difusão por Ressonância Magnética/métodos , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Necrose , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/tratamento farmacológico
17.
Int J Mol Sci ; 23(22)2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36430263

RESUMO

Bone sarcomas are a heterogeneous group of rare tumors with a predominance in the young population. Few options of systemic treatment are available once they become unresectable and resistant to conventional chemotherapy. A better knowledge of the key role that tyrosine kinase receptors (VEGFR, RET, MET, AXL, PDGFR, KIT, FGFR, IGF-1R) may play in the pathogenesis of these tumors has led to the development of multi-target inhibitors (TKIs) that are progressively being incorporated into our therapeutic arsenal. Osteosarcoma (OS) is the most frequent primary bone tumor and several TKIs have demonstrated clinical benefit in phase II clinical trials (cabozantinib, regorafenib, apatinib, sorafenib, and lenvatinib). Although the development of TKIs for other primary bone tumors is less advanced, preclinical data and early trials have begun to show their potential benefit in advanced Ewing sarcoma (ES) and rarer bone tumors (chondrosarcoma, chordoma, giant cell tumor of bone, and undifferentiated pleomorphic sarcoma). Previous reviews have mainly provided information on TKIs for OS and ES. We aim to summarize the existing knowledge regarding the use of TKIs in all bone sarcomas including the most recent studies as well as the potential synergistic effects of their combination with other systemic therapies.


Assuntos
Antineoplásicos , Neoplasias Ósseas , Osteossarcoma , Sarcoma , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
18.
Front Immunol ; 13: 992266, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405691

RESUMO

Angiogenesis has been recognized as a pivotal contributor to tumorigenesis and progression. However, the role of angiogenesis-related genes (ARGs) in vessel state, immune infiltration, and prognosis remains unknown in osteosarcoma (OS). Bulk RNA sequencing data of osteosarcoma patients were obtained from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database, and patients were divided into two angiogenesis subgroups according to the expression of ARGs. We compared their vessel state and used two independent algorithms to evaluate the tumor microenvironment (TME) in the two subgroups. Furthermore, hub genes of differentially expressed genes (DEGs) in the two subgroups were selected to perform LASSO regression and multivariate Cox stepwise regression, and two prognostic hub genes were found. An ARG_score based on prognostic hub genes was calculated and proved to be reliable in the overall survival prediction in OS patients. Furthermore, the ARG_score was significantly associated with ARGs, immune infiltration, response to immunotherapy, and drug sensitivity. To make our prediction model perform well, clinical features were added and a highly accurate interactive nomogram was constructed. Immunohistochemistry and qRT-PCR were utilized to verify the expression of prognostic hub genes. GSE21257 from the Gene Expression Omnibus (GEO) database was used as a validation dataset to verify its robustness. In conclusion, our comprehensive analysis of angiogenesis subgroups in OS illustrated that angiogenesis may lead to different vessel states and further affect immune infiltration and prognosis of OS patients. Our findings may bring a novel perspective for the immunotherapy strategies for OS patients.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Osteossarcoma/genética , Osteossarcoma/patologia , Prognóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Microambiente Tumoral/genética
19.
Comput Math Methods Med ; 2022: 6314182, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36388161

RESUMO

Background: Cuprotopsis is a type of programmed cell death discovered in recent years. Long noncoding RNAs (lncRNAs) play an important regulatory role in programmed cell death. The effect of cuproptosis-related lncRNAs on osteosarcoma is unknown. Our work, based on cuproptosis-related lncRNAs, proposes a gene signature to assess the prognosis of patients with osteosarcoma. Methods: Osteosarcoma gene expression data from The Cancer Genome Atlas (TCGA), clinical features of osteosarcoma and RNA sequencing data of normal adipose tissue were obtained from the UCSC Xena database. A cuproptosis-related lncRNA risk model was established to calculate the risk score. At the same time, cluster analysis, clinicopathological analysis, functional enrichment analysis, and prediction of compounds with potential therapeutic value were evaluated. We analyzed whether there was a correlation between the risk score and tumour immunity. RT-qPCR was used to verify the expression level of lncRNA. Results: Nine lncRNAs (AC124798.1, AC006033.2, AL450344.2, AL512625.2, LINC01060, LINC00837, AC004943.2, AC064836.3, and AC100821.2) were identified to create a risk model and indicate the prognosis of patients with osteosarcoma. The high-risk group had a worse prognosis than the low-risk group. Analysis of clinicopathological features, principal component analysis, receiver operating characteristic curve, c-index curve, and comparative analysis of models proved that the model is reliable. Functional enrichment analysis suggests that the risk score may correlate with cell energy metabolism and tumour-related biological function. Three potentially therapeutic compounds have been predicted. These analyses may be beneficial to the treatment of osteosarcoma in the future. RT-qPCR verified the expression level of three lncRNA (LINC01060, NKILA, and SNHG8). Conclusions: Cuproptosis-related lncRNAs have a strong relationship with osteosarcoma patients. Nine lncRNA models can effectively forecast the prognosis of osteosarcoma and may play a significant role in the individualized treatment of osteosarcoma patients in the future.


Assuntos
Neoplasias Ósseas , Osteossarcoma , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , Prognóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia
20.
Medicine (Baltimore) ; 101(45): e31212, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36397344

RESUMO

Osteosarcoma (OS) is one of the most prevalent malignant bone tumors. The proportion of limb OS is relatively high, and lung metastases (LM) are one of the most prevalent metastatic types. A total of 1694 new cases of limb OS were identified in the surveillance, epidemiology and end results (SEER) database from 2010 to 2018. Cox regression analyze was performed to identify prognostic factors for limb OS with LM, and univariate and multivariate logistic regression analyses were used to assess risk factors for LM. Kaplan-Meier analysis was performed to calculate overall survival for LM, and a log-rank test was used for comparison. A total of 287 patients (16.94%) were diagnosed with limb OS with LM. 25 to 59 years old (odds ratio, OR 0.68; 95% confidence interval, CI: 0.46-0.99), larger than 100 mm tumors (OR 3.65, 95% CI: 1.54-8.64), telangiectatic osteosarcoma type (OR 0.24, 95% CI: 0.07-0.81), central osteosarcoma type (OR 0.44, 95% CI: 0.19-0.99), T2 stage (OR 2.59, 95% CI: 1.18-5.69), N1 stage (OR 7.79, 95% CI: 3.90-15.56), presence of bone metastases (OR 4.58, 95% CI: 2.43-8.63) and surgical treatments of primary site (OR 0.22, 95% CI: 0.14-0.33) were significant correlations with lung metastases. Elderly age, black race and absence of surgery were harmful for survival. Age between 25 and 59 years, telangiectatic osteosarcoma and central osteosarcoma were identified as high-risk factors in limb OS patients with LM, and surgical treatment of the primary site significantly increased the survival rate of LM in these patients.


Assuntos
Neoplasias Ósseas , Neoplasias Pulmonares , Osteossarcoma , Humanos , Idoso , Adulto , Pessoa de Meia-Idade , Programa de SEER , Prognóstico , Osteossarcoma/patologia , Neoplasias Ósseas/epidemiologia
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