-
Experimental Biology and Medicine... Dec 2023Curcumin, an antitumor agent, has been shown to inhibit cell growth and metastasis in osteosarcoma. However, there is no evidence of curcumin and its regulation of cell...
Curcumin, an antitumor agent, has been shown to inhibit cell growth and metastasis in osteosarcoma. However, there is no evidence of curcumin and its regulation of cell ferroptosis and nuclear factor E2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathways in osteosarcoma. This study aimed to investigate the effects of curcumin on osteosarcoma both and . To explore the effects and mechanisms of curcumin on osteosarcoma, cells (MNNG/HOS and MG-63) and xenograft mice models were established. Cell viability, cell apoptosis rate, cycle distribution, cell migration, cell invasion, reactive oxygen species, malonaldehyde and glutathione abilities, and protein levels were detected by cell counting kit-8, flow cytometry, wound healing, transwell assay, respectively. Nrf2 and GPX4 expressions were detected using an immunofluorescence assay. Nrf2/GPX4-related protein levels were detected using western blotting. The results showed that curcumin effectively decreased cell viability and increased apoptosis rate. Meanwhile, curcumin inhibited tumor volume in the xenograft model, and Nrf2/GPX4-related protein levels were also altered. Interestingly, the effects of curcumin were reversed by liproxstatin-1 (an effective inhibitor of ferroptosis) and bardoxolone-methyl (an effective activator of Nrf2). Our results indicate that curcumin has therapeutic effects on osteosarcoma cells and a xenograft model by regulating the expression of the Nrf2/GPX4 signaling pathway.
Topics: Humans; Animals; Mice; Curcumin; Ferroptosis; NF-E2-Related Factor 2; Osteosarcoma; Signal Transduction; Apoptosis; Disease Models, Animal; Bone Neoplasms
PubMed: 38166505
DOI: 10.1177/15353702231220670 -
Clinical and Translational Medicine May 2024Treatment for osteosarcoma, a paediatric bone cancer with no therapeutic advances in over three decades, is limited by a lack of targeted therapies. Osteosarcoma...
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.
Topics: Osteosarcoma; Humans; Drug Resistance, Neoplasm; Wnt Proteins; Animals; Mice; Bone Neoplasms; Neoplasm Metastasis; Neoplastic Stem Cells; Cell Line, Tumor
PubMed: 38689429
DOI: 10.1002/ctm2.1670 -
PloS One 2023Patients with osteosarcoma and synchronous lung metastasis (SLM) have poor survival. This study aimed to explore the epidemiology data and construct a predictive... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with osteosarcoma and synchronous lung metastasis (SLM) have poor survival. This study aimed to explore the epidemiology data and construct a predictive nomogram to identify cases at risk of SLM occurrence among pediatric and young adulthood osteosarcoma patients.
METHODS
All data were extracted from Surveillance, Epidemiology, and End Results 17 registries. The age-standardized incidence rate (ASIR) and annual percentage change was evaluated, and reported for the overall population and by age, gender, race, and primary site. Univariate and multivariate logistic regression analyses were used to identify risk factors associated with SLM occurrence, then significant factors were used to develop the nomogram. The area under the receiver operating characteristic curve (AUC) and calibration curve were used to evaluated the predictive power of the nomogram. Survival analysis was assessed by the Kaplan-Meier method and the log-rank test. Multivariate Cox analysis was used to determine the prognostic factors.
RESULTS
A total of 278 out of 1965 patients (14.1%) presented with SLM at diagnosis. The ASIR increased significant from 0.46 to 0.66 per 1,000,000 person-years from year 2010 to 2019, with an annual percentage change of 3.5, mainly in patients with age 10-19 years, male and appendicular location. All patients were randomly assigned into train cohort and validation cohort with a spilt of 7:3. In the train cohort, higher tumor grade, bigger tumor size, positive lymph nodes and other site-specific metastases (SSM) were identified as significant risk factors associated with SLM occurrence. Then a nomogram was developed based on the four factors. The AUC and calibration curve in both train and validation cohorts demonstrated that the nomogram had moderate predictive power. The median cancer-specific survival was 25 months. Patients with age 20-39 years, male, positive lymph nodes, other SSM were adverse prognostic factors, while surgery was protective factor.
CONCLUSIONS
This study performed a comprehensive analysis regarding pediatric and young adulthood osteosarcoma patients had SLM. A visual, clinically operable, and easy-to-interpret nomogram model was developed for predicting the risk of SLM, which could be used in clinic and help clinicians make better decisions.
Topics: Humans; Child; Male; Young Adult; Adult; Adolescent; Nomograms; Osteosarcoma; Lung Neoplasms; Ambulatory Care Facilities; Bone Neoplasms
PubMed: 37437020
DOI: 10.1371/journal.pone.0288492 -
Scandinavian Journal of Surgery : SJS :... Sep 2023Primary sarcomas of bone are rare malignant mesenchymal tumors. The most common bone sarcomas are osteosarcoma, Ewing's sarcoma, and chondrosarcoma. The prognosis has... (Review)
Review
Primary sarcomas of bone are rare malignant mesenchymal tumors. The most common bone sarcomas are osteosarcoma, Ewing's sarcoma, and chondrosarcoma. The prognosis has improved over the years, but bone sarcomas are still life-threatening tumors that need a multidisciplinary approach for diagnosis and treatment. Bone sarcomas arising in the pelvis present a unique challenge to orthopedic oncologists due to the absence of natural anatomical barriers, the close proximity of vital neurovascular structures, and the high mechanical demands placed on any pelvic reconstruction following the excision of the tumor. While radiotherapy has an important role especially in Ewing's sarcoma and chemotherapy for both Ewing's sarcoma and osteosarcoma, surgery remains the main choice of treatment for all three entities. While external hemipelvectomy has remained one option, the main aim of surgery is limb salvage. After complete tumor resection, the bone defect needs to be reconstructed. Possibilities to reconstruct the defect include prosthetic or biological reconstruction. The method of reconstruction is dependent on the location of tumor and the surgery required for its removal. The aim of this article is to give an insight into pelvic bone sarcomas, their oncological and surgical outcomes, and the options for treatment based on the authors' experiences.
Topics: Humans; Sarcoma, Ewing; Bone Neoplasms; Prognosis; Sarcoma; Osteosarcoma; Pelvic Bones; Pelvis; Soft Tissue Neoplasms
PubMed: 37438963
DOI: 10.1177/14574969231181504 -
Oncogene Jan 2024Doxorubicin and platinum are widely used in the frontline treatment of osteosarcoma, but resistance to chemotherapy limits its curative effect. Here, we have identified...
Doxorubicin and platinum are widely used in the frontline treatment of osteosarcoma, but resistance to chemotherapy limits its curative effect. Here, we have identified that METTL1 mediated N-Methyladenosine (mG) low expressed in osteosarcoma tissues, plays a critical oncogenic role, and enhances osteosarcoma chemosensitivity in osteosarcoma. Mechanistically, AlkAniline-Seq data revealed that Ferritin heavy chain (FTH1), the main component of ferritin, which is crucial for iron homeostasis and the inhibition of lipid peroxidation, is one of the top 10 genes with the most significant change in mG methylation sites mediated by METTL1 in human osteosarcoma cells. Interestingly, METTL1 significantly increased the expression of FTH1 at the mRNA level but was remarkably suppressed at the protein level. We then identified primary (pri)-miR-26a and pri-miR-98 in the Top 20 mG-methylated pri-miRNAs with highly conserved species. Further results confirmed that METTL1 enhances cell ferroptosis by targeting FTH1 and primary (pri)-miR-26a, promoting their maturity by enhancing RNA stability dependent on mG methylation. The increase of mature miR-26a-5p that resulted from METTL1 overexpression could further target FTH1 mRNA and eliminate FTH1 translation efficiency. Moreover, the reduction of FTH1 translation dramatically increases cell ferroptosis and promotes the sensitivity of osteosarcoma cells to chemotherapy drugs. Collectively, our study demonstrates the METTL1/pri-miR-26a/FTH1 axis signaling in osteosarcoma and highlights the functional importance of METTL1 and mG methylation in the progression and chemotherapy resistance of osteosarcoma, suggesting that reprogramming RNA mG methylation as a potential and promising strategy for osteosarcoma treatment.
Topics: Humans; Ferroptosis; MicroRNAs; Osteosarcoma; Bone Neoplasms; RNA, Messenger; Ferritins; Oxidoreductases
PubMed: 38040806
DOI: 10.1038/s41388-023-02882-5 -
Frontiers in Immunology 2023As the most abundant infiltrating immune cells in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) are pivotal in tumor development and treatment....
As the most abundant infiltrating immune cells in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) are pivotal in tumor development and treatment. The present investigation endeavors to explore the potential of M1 macrophage-related genes (MRGs) as biomarkers for assessing risk in individuals with osteosarcoma. RNA-sequence data and clinical data were derived from TCGA and GEO databases. The CIBERSORT method was utilized to discern subtypes of tumor-infiltrating immune cells. Identification of MRGs was achieved through Pearson correlation analysis. A prognostic risk model for MRGs was developed using Cox and LASSO regression analyses. A tripartite gene signature comprising CD37, GABRD, and ARHGAP25 was an independent prognostic indicator and was employed to develop a risk score model. The internal and external validation cohort confirmed the results. The area under the ROC curve (AUC) was determined for survival periods of 1 year, three years, and five years, yielding values of 0.746, 0.839, and 0.850, respectively. The C-index of the risk score was found to be superior to clinicopathological factors. GO/KEGG enrichment showed that the differences between high- and low-risk groups were predominantly associated with immune response pathways. Immune-related analysis related to proportions of immune cells, immune function, and expression levels of immune checkpoint genes all showed differences between the high- and low-risk groups. The qRT-PCR and Western blotting results indicate that CD37 expression was markedly higher in MG63 and U2OS cell lines when compared to normal osteoblast hFOB1.19. In U2OS cell line, GABRD expression levels were significantly upregulated. ARHGAP25 expression levels were elevated in both 143B and U2OS cell lines. In summary, utilizing a macrophage genes signature demonstrates efficacy in predicting both the prognosis and therapy response of OS. Additionally, immune analysis confirms a correlation between the risk score and the tumor microenvironment. Our findings, therefore, provide a cogent account for the disparate prognoses observed among patients and furnish a justification for further inquiry into biomarkers and anti-tumor treatment strategies.
Topics: Humans; Prognosis; Osteosarcoma; Macrophages; Osteoblasts; Bone Neoplasms; Tumor Microenvironment
PubMed: 37465666
DOI: 10.3389/fimmu.2023.1202725 -
Advances in Protein Chemistry and... 2024Osteosarcoma is a malignant osseous neoplasm. Osteosarcoma is a primary bone malignancy capable of producing osteoid tissue or immature bones. A subsequent malignant... (Review)
Review
Osteosarcoma is a malignant osseous neoplasm. Osteosarcoma is a primary bone malignancy capable of producing osteoid tissue or immature bones. A subsequent malignant degeneration of the primary bone pathology occurs less frequently in adults. The over-expression of several proteins, including Heat shock proteins, Cofilin, Annexins, Insulin-like growth factor, transforming growth factor-β, Receptor tyrosine kinase, Ezrin, Runx2, SATB2, ATF4, Annexins, cofilin, EGFR, VEGF, retinoblastoma 1 (Rb1) and secreted protein, has been associated to the development and progression of osteosarcoma. These proteins are involved in cell adhesion, migration, invasion, and the control of cell cycle and apoptosis. In genomic studies, osteosarcoma has been associated with several genetic abnormalities, including chromosomal rearrangements, gene mutations, and gene amplifications. These differentially expressed proteins could be used as early identification biomarkers or treatment targets. Proteomics and genomics play significant parts in enhancing our molecular understanding of osteosarcoma, and their integration provides essential insights into this aggressive bone cancer. This review will discuss the tumour biology that has assisted in helping us better understand the causes of osteosarcoma and how they could potentially be used to find new treatment targets and enhance the survival rate for osteosarcoma patients.
Topics: Adult; Humans; Proteomics; Osteosarcoma; Genomics; Bone Neoplasms; Actin Depolymerizing Factors; Annexins
PubMed: 38220428
DOI: 10.1016/bs.apcsb.2023.06.001 -
BMC Cancer Aug 2023Bone sarcomas are rare tumors representing 0.2% of all cancers. While osteosarcoma and Ewing sarcoma mainly affect children and young adults, chondrosarcoma and chordoma... (Review)
Review
Bone sarcomas are rare tumors representing 0.2% of all cancers. While osteosarcoma and Ewing sarcoma mainly affect children and young adults, chondrosarcoma and chordoma have a preferential incidence in people over the age of 40. Despite this range in populations affected, all bone sarcoma patients require complex transdisciplinary management and share some similarities. The cornerstone of all bone sarcoma treatment is monobloc resection of the tumor with adequate margins in healthy surrounding tissues. Adjuvant chemo- and/or radiotherapy are often included depending on the location of the tumor, quality of resection or presence of metastases. High dose radiotherapy is largely applied to allow better local control in case of incomplete primary tumor resection or for unresectable tumors. With the development of advanced techniques such as proton, carbon ion therapy, radiotherapy is gaining popularity for the treatment of bone sarcomas, enabling the delivery of higher doses of radiation, while sparing surrounding healthy tissues. Nevertheless, bone sarcomas are radioresistant tumors, and some mechanisms involved in this radioresistance have been reported. Hypoxia for instance, can potentially be targeted to improve tumor response to radiotherapy and decrease radiation-induced cellular toxicity. In this review, the benefits and drawbacks of radiotherapy in bone sarcoma will be addressed. Finally, new strategies combining a radiosensitizing agent and radiotherapy and their applicability in bone sarcoma will be presented.
Topics: Child; Young Adult; Humans; Sarcoma; Osteosarcoma; Bone Neoplasms; Sarcoma, Ewing; Chondrosarcoma
PubMed: 37563551
DOI: 10.1186/s12885-023-11232-3 -
European Journal of Pharmacology Oct 2023Osteosarcoma (OS) is a highly fatal bone tumor characterized by high degree of malignancy and early lung metastasis. Traditional chemotherapy fails in improving the...
Osteosarcoma (OS) is a highly fatal bone tumor characterized by high degree of malignancy and early lung metastasis. Traditional chemotherapy fails in improving the efficacy and survival rate of patients with OS. Butyrate (NaBu) has been reported as a new antitumor drug for inhibiting proliferation and inducing apoptosis in various cancer cells. However, the effect of NaBu on the ferroptosis of OS is still unknown. This study aimed to investigate whether NaBu promotes erastin-induced ferroptosis in OS cells and to uncover the underlying mechanism. Here, we found that NaBu significantly enhanced erastin-induced ferroptosis in vitro and in vivo. Compared with the group that erastin used alonely, pre-treating with NaBu exacerbated erastin-meditated GSH depletion, lipid peroxidation, and mitochondrial morphologic changes in OS cells. In a subcutaneous OS model, NaBu combined with erastin significantly reduced tumor growth and increased the levels of 4-HNE. Mechanistically, NaBu downregulated SLC7A11 transcription via regulating ATF3 expression. Overexpression of ATF3 facilitated erastin to induce ferroptosis, while ATF3 knockdown attenuated NaBu-induced ferroptosis sensitivity. In conclusion, our findings revealed a previously unidentified role of NaBu in erastin-induced ferroptosis by regulating SLC7A11, suggesting that NaBu may be a potential therapeutic agent for OS treatment.
Topics: Humans; Ferroptosis; Butyrates; Osteosarcoma; Bone Neoplasms; Amino Acid Transport System y+; Activating Transcription Factor 3
PubMed: 37619784
DOI: 10.1016/j.ejphar.2023.176009 -
Medicine Dec 2023Bladder cancer and osteosarcoma are 2 types of cancers that originate from epithelial tissues inside the bladder and bone or muscle tissues. Ultrasound-guided biopsies...
Bladder cancer and osteosarcoma are 2 types of cancers that originate from epithelial tissues inside the bladder and bone or muscle tissues. Ultrasound-guided biopsies provide crucial support for the diagnosis and treatment of bladder cancer and osteosarcoma. However, the relationship between myosin light chain kinase (MYLK) and caldesmon (CALD1) and bladder cancer and osteosarcoma remains unclear. The bladder cancer datasets GSE65635 and GSE100926, the osteosarcoma dataset GSE39058, were obtained from gene expression omnibus. Differentially expressed genes (DEGs) were screened and weighted gene co-expression network analysis was performed. The construction and analysis of protein-protein interaction network, functional enrichment analysis, gene set enrichment analysis. Gene expression heat map was drawn and immune infiltration analysis was performed. The comparative toxicogenomics database analysis were performed to find disease most related to core gene. Western blotting experiments were performed. TargetScan screened miRNAs that regulated central DEGs. We obtained 54 DEGs. Functional enrichment analysis revealed significant enrichment in terms of cellular differentiation, cartilage development, skeletal development, muscle actin cytoskeleton, actin filament, Rho GTPase binding, DNA binding, fibroblast binding, MAPK signaling pathway, apoptosis, and cancer pathways. Gene set enrichment analysis indicated that DEGs were primarily enriched in terms of skeletal development, cartilage development, muscle actin cytoskeleton, MAPK signaling pathway, and apoptosis. The immune infiltration analysis showed that when T cells regulatory were highly expressed, Eosinophils exhibited a similar high expression, suggesting a strong positive correlation between T cells regulatory and Eosinophils, which might influence the disease progression in osteosarcoma. We identified 6 core genes (SRF, CTSK, MYLK, VCAN, MEF2C, CALD1). MYLK and CALD1 were significantly correlated with survival rate and exhibited lower expression in bladder cancer and osteosarcoma samples compared to normal samples. Comparative toxicogenomics database analysis results indicated associations of core genes with osteosarcoma, bladder tumors, bladder diseases, tumors, inflammation, and necrosis. The results of Western blotting showed that the expression levels of MYLK and CALD1 in bladder cancer and osteosarcoma were lower than those in normal tissues. MYLK and CALD1 likely play a role in regulating muscle contraction and smooth muscle function in bladder cancer and osteosarcoma. The lower expression of MYLK and CALD1 is associated with poorer prognosis.
Topics: Humans; Calmodulin-Binding Proteins; Myosin-Light-Chain Kinase; Gene Expression Profiling; Biomarkers, Tumor; Osteosarcoma; Bone Neoplasms; Urinary Bladder Neoplasms; Ultrasonography, Interventional; Gene Regulatory Networks; Computational Biology
PubMed: 38050320
DOI: 10.1097/MD.0000000000036414