-
Journal of Cancer Research and Clinical... Aug 2023Osteosarcoma is a common primary malignant tumour of the bone that usually occurs in children and adolescents. It is characterised by difficult treatment, recurrence and... (Review)
Review
BACKGROUND
Osteosarcoma is a common primary malignant tumour of the bone that usually occurs in children and adolescents. It is characterised by difficult treatment, recurrence and metastasis, and poor prognosis. Currently, the treatment of osteosarcoma is mainly based on surgery and auxiliary chemotherapy. However, for recurrent and some primary osteosarcoma cases, owing to the rapid progression of disease and chemotherapy resistance, the effects of chemotherapy are poor. With the rapid development of tumour-targeted therapy, molecular-targeted therapy for osteosarcoma has shown promise.
PURPOSE
In this paper, we review the molecular mechanisms, related targets, and clinical applications of targeted osteosarcoma therapy. In doing this, we provide a summary of recent literature on the characteristics of targeted osteosarcoma therapy, the advantages of its clinical application, and development of targeted therapy in future. We aim to provide new insights into the treatment of osteosarcoma.
CONCLUSION
Targeted therapy shows potential in the treatment of osteosarcoma and may offer an important means of precise and personalised treatment in the future, but drug resistance and adverse effects may limit its application.
Topics: Adolescent; Child; Humans; Bone Neoplasms; Osteosarcoma; Bone and Bones; Molecular Targeted Therapy
PubMed: 36807762
DOI: 10.1007/s00432-023-04614-4 -
Phytomedicine : International Journal... Jul 2023Osteosarcomas (OS) is a kind of malignant bone tumor which occurs primarily in children and adolescents, and the clinical therapeutics remain disappointing. As a new...
BACKGROUND
Osteosarcomas (OS) is a kind of malignant bone tumor which occurs primarily in children and adolescents, and the clinical therapeutics remain disappointing. As a new programmed cell death, ferroptosis is characterized by iron dependent and intracellular oxidative accumulation, which provides a potential alternative intervene for the OS treatment. Baicalin, a major bioactive flavone derived from traditional Chinese medicine Scutellaria baicalensis, has been proved to have anti-tumor properties in OS. Whether ferroptosis participated in the baicalin mediated anti-OS activity is an interesting project.
PURPOSE
To explore the pro-ferroptosis effect and mechanisms of baicalin in OS.
METHODS/STUDY DESIGN
Pro-ferroptosis effect of baicalin on cell death, cell proliferation, iron accumulation, lipid peroxidation production was determined in MG63 and 143B cells. The levels of glutathione (GSH), oxidized (GSSG) glutathione and malondialdehyde (MDA) were determined by enzyme linked immunosorbent assay (ELISA). The expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), Glutathione peroxidase 4 (GPX4) and xCT were detected by western blot in baicalin-mediated ferroptosis regulation. In vivo, a xenograft mice model was adopted to explore the anticancer effect of baicalin.
RESULTS
In the present study, it was found that baicalin significantly suppress tumor cell growth in vitro and in vivo. By promoting the Fe accumulation, ROS formation, MDA production and suppressing the ratio of GSH/GSSG, baicalin was found to trigger ferroptosis in OS and ferroptosis inhibitor ferrostatin-1 (Fer-1) successfully reversed these suppressive effects, indicating that ferroptosis participated in the baicalin mediated anti-OS activity. Mechanistically, baicalin physically interacted with Nrf2, a critical regulator of ferroptosis, and influenced its stability via inducing ubiquitin degradation, which suppressed the Nrf2 downstream targets GPX4 and xCT expression, and led to stimulating ferroptosis.
CONCLUSIONS
Our findings for the first time indicated that baicalin exerted anti-OS activity through a novel Nrf2/xCT/GPX4-dependent ferroptosis regulatory axis, which hopefully provides a promising candidate for OS treatment.
Topics: Humans; Animals; Mice; Ferroptosis; NF-E2-Related Factor 2; Glutathione Disulfide; Osteosarcoma; Disease Models, Animal; Bone Neoplasms
PubMed: 37209607
DOI: 10.1016/j.phymed.2023.154881 -
The Veterinary Clinics of North... May 2024Clinical care of osteosarcoma (OSA) in dogs has seen little change during the past 2 decades, relying on amputation and platinum-based chemotherapy for pain control and... (Review)
Review
Clinical care of osteosarcoma (OSA) in dogs has seen little change during the past 2 decades, relying on amputation and platinum-based chemotherapy for pain control and survival. Recent advancements offer hope for improved outcomes. Genomic research reveals shared genetic abnormalities between canine and human OSA. Multidimensional imaging provides valuable staging and prognostic information. Limb-sparing approaches including stereotactic body radiation therapy are routine. Ablative therapies such as microwave ablation and histotripsy show promise. Immunotherapy including cell therapy and immune checkpoint inhibition are available. Radiopharmaceuticals are tuned to target OSA cells directly. These innovations may enhance treatment and prognosis for dogs with OSA.
Topics: Humans; Animals; Dogs; Bone Neoplasms; Dog Diseases; Prognosis; Radiosurgery; Osteosarcoma
PubMed: 38158305
DOI: 10.1016/j.cvsm.2023.12.007 -
Journal of Biomedical Science Jan 2024Metabolic remodeling and changes in tumor immune microenvironment (TIME) in osteosarcoma are important factors affecting prognosis and treatment. However, the...
BACKGROUND
Metabolic remodeling and changes in tumor immune microenvironment (TIME) in osteosarcoma are important factors affecting prognosis and treatment. However, the relationship between metabolism and TIME needs to be further explored.
METHODS
RNA-Seq data and clinical information of 84 patients with osteosarcoma from the TARGET database and an independent cohort from the GEO database were included in this study. The activity of seven metabolic super-pathways and immune infiltration levels were inferred in osteosarcoma patients. Metabolism-related genes (MRGs) were identified and different metabolic clusters and MRG-related gene clusters were identified using unsupervised clustering. Then the TIME differences between the different clusters were compared. In addition, an MRGs-based risk model was constructed and the role of a key risk gene, ST3GAL4, in osteosarcoma cells was explored using molecular biological experiments.
RESULTS
This study revealed four key metabolic pathways in osteosarcoma, with vitamin and cofactor metabolism being the most relevant to prognosis and to TIME. Two metabolic pathway-related clusters (C1 and C2) were identified, with some differences in immune activating cell infiltration between the two clusters, and C2 was more likely to respond to two chemotherapeutic agents than C1. Three MRG-related gene clusters (GC1-3) were also identified, with significant differences in prognosis among the three clusters. GC2 and GC3 had higher immune cell infiltration than GC1. GC3 is most likely to respond to immune checkpoint blockade and to three commonly used clinical drugs. A metabolism-related risk model was developed and validated. The risk model has strong prognostic predictive power and the low-risk group has a higher level of immune infiltration than the high-risk group. Knockdown of ST3GAL4 significantly inhibited proliferation, migration, invasion and glycolysis of osteosarcoma cells and inhibited the M2 polarization of macrophages.
CONCLUSION
The metabolism of vitamins and cofactors is an important prognostic regulator of TIME in osteosarcoma, MRG-related gene clusters can well reflect changes in osteosarcoma TIME and predict chemotherapy and immunotherapy response. The metabolism-related risk model may serve as a useful prognostic predictor. ST3GAL4 plays a critical role in the progression, glycolysis, and TIME of osteosarcoma cells.
Topics: Humans; Osteosarcoma; Vitamins; Immunotherapy; Bone Neoplasms; Metabolic Networks and Pathways; Tumor Microenvironment; Prognosis
PubMed: 38212768
DOI: 10.1186/s12929-024-00999-7 -
Pediatric Blood & Cancer Sep 2023The Children's Oncology Group (COG) Bone Tumor Committee is responsible for clinical trials and biological research on localized, metastatic, and recurrent osteosarcoma...
The Children's Oncology Group (COG) Bone Tumor Committee is responsible for clinical trials and biological research on localized, metastatic, and recurrent osteosarcoma and Ewing sarcoma (EWS). Results of clinical trials in localized disease completed and published in the past 10 years have led to international standard-of-care chemotherapy for osteosarcoma and EWS. A recent focus on identifying disease subgroups has led to the identification of biological features associated with poor outcomes including the presence of circulating tumor DNA (ctDNA) at diagnosis, and specific genomic alterations-MYC amplification for osteosarcoma and STAG2 and TP53 mutation for EWS. Studies validating these potential biomarkers are under way. Clinical trials evaluating the addition of multitargeted kinase inhibitors, which are active in relapsed bone sarcomas, to standard chemotherapy are under way in osteosarcoma and planned in EWS. In addition, the Committee has data analyses and a clinical trial under way to evaluate approaches to local management of the primary tumor and metastatic sites. Given the rarity of bone sarcomas, we have prioritized international interactions and are in the process of forming an international data-sharing consortium to facilitate refinement of risk stratification and study of rare disease subtypes.
Topics: Child; Humans; Neoplasm Recurrence, Local; Bone Neoplasms; Sarcoma, Ewing; Osteosarcoma; Neuroectodermal Tumors, Primitive, Peripheral
PubMed: 37501549
DOI: 10.1002/pbc.30583 -
International Journal of Molecular... Jul 2023Osteosarcoma (OS) is the predominant primary bone tumor in the pediatric and adolescent populations. It has high metastatic potential, with the lungs being the most... (Review)
Review
Osteosarcoma (OS) is the predominant primary bone tumor in the pediatric and adolescent populations. It has high metastatic potential, with the lungs being the most common site of metastasis. In contrast to many other sarcomas, OS lacks conserved translocations or genetic mutations; instead, it has heterogeneous abnormalities, including somatic DNA copy number alteration, ploidy, chromosomal amplification, and chromosomal loss and gain. Unfortunately, clinical outcomes have not significantly improved in over 30 years. Currently, no effective molecularly targeted therapies are available for this disease. Several genomic studies showed inactivation in the tumor suppressor genes, including , , and and hyperactivation of the tumor promoter genes, including and , in OS. Alterations in the major signaling pathways, including the PI3K/AKT/mTOR, JAK/STAT, Wnt/β-catenin, NOTCH, Hedgehog/Gli, TGF-β, RTKs, RANK/RANKL, and NF-κB signaling pathways, have been identified in OS development and metastasis. Although OS treatment is currently based on surgical excision and systematic multiagent therapies, several potential targeted therapies are in development. This review focuses on the major signaling pathways of OS, and we propose a biological rationale to consider novel and targeted therapies in the future.
Topics: Adolescent; Humans; Child; Phosphatidylinositol 3-Kinases; Hedgehog Proteins; Osteosarcoma; Carcinogenesis; Cell Transformation, Neoplastic; Bone Neoplasms
PubMed: 37511127
DOI: 10.3390/ijms241411367 -
International Journal of Biological... 2024A growing number of studies have revealed an association between proteasome activator complex subunit 2 (PSME2) and the progression of various forms of cancer. However,...
A growing number of studies have revealed an association between proteasome activator complex subunit 2 (PSME2) and the progression of various forms of cancer. However, the effect of PSME2 on osteosarcoma progression is unknown. Pan-cancer analyses focused on the immunological activity and prognostic relevance of PSME2 have yet to be conducted. The Cancer Genome Atlas and Genome-Tissue Expression databases were leveraged to evaluate PSME2 expression and activity across 33 cancer types. Significant PSME2 dysregulation was noted in a wide range of cancer types and this gene was found to offer significant diagnostic and prognostic utility in most analyzed cancers. From a mechanistic perspective, PSME2 expression levels were correlated with DNA methylation, DNA repair, genomic instability, and TME scores in multiple cancer types. PSME2 was subsequently established as a pan-cancer biomarker of M1 macrophage infiltration based on a combination of bulk, single-cell, and spatial transcriptomic data and confirmatory fluorescent staining results. In osteosarcoma cells, overexpressing PSME2 significantly suppressed tumor proliferative, migratory, and invasive activity. Screening efforts also successfully identified the PSME2-activating drug irinotecan, which can synergistically promote the death of osteosarcoma cells when combined with the chemotherapeutic drug paclitaxel. As a biomarker of M1 macrophage infiltration, PSME2 expression levels may offer insight into tumor development and progression for a wide range of cancers including osteosarcoma, emphasizing its potential utility as a prognostic and therapeutic target worthy of further study.
Topics: Humans; Osteosarcoma; Phenotype; Biomarkers, Tumor; Macrophages; Bone Neoplasms; Proteasome Endopeptidase Complex
PubMed: 38385075
DOI: 10.7150/ijbs.90226 -
Current Opinion in Otolaryngology &... Aug 2023There is no clear consensus guideline that specifies the optimum course of treatment for adult head and neck osteosarcoma (HNO) because of its rarity. The review's goal... (Review)
Review
PURPOSE OF REVIEW
There is no clear consensus guideline that specifies the optimum course of treatment for adult head and neck osteosarcoma (HNO) because of its rarity. The review's goal is to examine the most recent research on the presentation, diagnosis, prognosis, and therapy of head and neck osteosarcoma.
RECENT FINDINGS
Due to overlapping symptoms with various benign disorders of the lower jaw and midface bone, these patients present with a noticeable delay. The greatest results for these malignancies can be achieved with surgery with sufficient margins. However, it may not be able to achieve sufficient margins in tumours of the midface and skull base, and the significance of adjuvant radiation/chemotherapy needs to be investigated. The use of adjuvant radiation in instances with an advanced stage, poor prognostic indicators, and inadequate resection is supported by evidence. Nonetheless, there are divergent opinions regarding the advantages of chemotherapy in adjuvant and neoadjuvant conditions, and further multicentric randomized control trials are required to provide robust evidence.
SUMMARY
Multimodality treatments seem to yield better results for advanced HNO with adverse features and incomplete resections.
Topics: Adult; Humans; Osteosarcoma; Combined Modality Therapy; Prognosis; Mandible; Bone Neoplasms
PubMed: 37144500
DOI: 10.1097/MOO.0000000000000900 -
Clinical and Translational Medicine Feb 2024Osteosarcoma (OSA) presents a clinical challenge and has a low 5-year survival rate. Currently, the lack of advanced stratification models makes personalized therapy...
BACKGROUND
Osteosarcoma (OSA) presents a clinical challenge and has a low 5-year survival rate. Currently, the lack of advanced stratification models makes personalized therapy difficult. This study aims to identify novel biomarkers to stratify high-risk OSA patients and guide treatment.
METHODS
We combined 10 machine-learning algorithms into 101 combinations, from which the optimal model was established for predicting overall survival based on transcriptomic profiles for 254 samples. Alterations in transcriptomic, genomic and epigenomic landscapes were assessed to elucidate mechanisms driving poor prognosis. Single-cell RNA sequencing (scRNA-seq) unveiled genes overexpressed in OSA cells as potential therapeutic targets, one of which was validated via tissue staining, knockdown and pharmacological inhibition. We characterized changes in multiple phenotypes, including proliferation, colony formation, migration, invasion, apoptosis, chemosensitivity and in vivo tumourigenicity. RNA-seq and Western blotting elucidated the impact of squalene epoxidase (SQLE) suppression on signalling pathways.
RESULTS
The artificial intelligence-derived prognostic index (AIDPI), generated by our model, was an independent prognostic biomarker, outperforming clinicopathological factors and previously published signatures. Incorporating the AIDPI with clinical factors into a nomogram improved predictive accuracy. For user convenience, both the model and nomogram are accessible online. Patients in the high-AIDPI group exhibited chemoresistance, coupled with overexpression of MYC and SQLE, increased mTORC1 signalling, disrupted PI3K-Akt signalling, and diminished immune infiltration. ScRNA-seq revealed high expression of MYC and SQLE in OSA cells. Elevated SQLE expression correlated with chemoresistance and worse outcomes in OSA patients. Therapeutically, silencing SQLE suppressed OSA malignancy and enhanced chemosensitivity, mediated by cholesterol depletion and suppression of the FAK/PI3K/Akt/mTOR pathway. Furthermore, the SQLE-specific inhibitor FR194738 demonstrated anti-OSA effects in vivo and exhibited synergistic effects with chemotherapeutic agents.
CONCLUSIONS
AIDPI is a robust biomarker for identifying the high-risk subset of OSA patients. The SQLE protein emerges as a metabolic vulnerability in these patients, providing a target with translational potential.
Topics: Humans; Artificial Intelligence; Biomarkers; Bone Neoplasms; Osteosarcoma; Phosphatidylinositol 3-Kinases; Prognosis; Proto-Oncogene Proteins c-akt; Squalene Monooxygenase
PubMed: 38372422
DOI: 10.1002/ctm2.1586 -
Science Advances Nov 2023Osteosarcoma is a highly aggressive cancer and lacks effective therapeutic targets. We found that L3MBTL2 acts as a tumor suppressor by transcriptionally repressing in...
Osteosarcoma is a highly aggressive cancer and lacks effective therapeutic targets. We found that L3MBTL2 acts as a tumor suppressor by transcriptionally repressing in osteosarcoma. L3MBTL2 recruits the components of Polycomb repressive complex 1.6 to form condensates via both Pho-binding pockets and polybasic regions within carboxyl-terminal intrinsically disordered regions; the L3MBTL2-induced condensates are required for its tumor suppression. Multi-monoubiquitination of L3MBTL2 by UBE2O results in its proteasomal degradation, and the UBE2O/L3MBTL2 axis was crucial for osteosarcoma growth. There is a reverse correlation between L3MBTL2 and UBE2O in osteosarcoma tissues, and higher UBE2O and lower L3MBTL2 are associated with poorer prognosis in osteosarcoma. Pharmacological blockage of UBE2O by arsenic trioxide can enhance L3MBTL2-induced condensates and consequently suppress osteosarcoma growth. Our findings unveil a crucial biological function of L3MBTL2-induced condensates in mediating tumor suppression, proposing the UBE2O-L3MBTL2 axis as a potential cancer therapeutic target in osteosarcoma.
Topics: Humans; Bone Neoplasms; Cell Line, Tumor; Osteosarcoma; Polycomb Repressive Complex 1; Ubiquitin-Conjugating Enzymes; Ubiquitination
PubMed: 37992172
DOI: 10.1126/sciadv.adi0889