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Current Osteoporosis Reports Aug 2023This article gives a brief overview of the most recent developments in osteosarcoma treatment, including targeting of signaling pathways, immune checkpoint inhibitors,... (Review)
Review
PURPOSE OF REVIEW
This article gives a brief overview of the most recent developments in osteosarcoma treatment, including targeting of signaling pathways, immune checkpoint inhibitors, drug delivery strategies as single or combined approaches, and the identification of new therapeutic targets to face this highly heterogeneous disease.
RECENT FINDINGS
Osteosarcoma is one of the most common primary malignant bone tumors in children and young adults, with a high risk of bone and lung metastases and a 5-year survival rate around 70% in the absence of metastases and 30% if metastases are detected at the time of diagnosis. Despite the novel advances in neoadjuvant chemotherapy, the effective treatment for osteosarcoma has not improved in the last 4 decades. The emergence of immunotherapy has transformed the paradigm of treatment, focusing therapeutic strategies on the potential of immune checkpoint inhibitors. However, the most recent clinical trials show a slight improvement over the conventional polychemotherapy scheme. The tumor microenvironment plays a crucial role in the pathogenesis of osteosarcoma by controlling the tumor growth, the metastatic process and the drug resistance and paved the way of new therapeutic options that must be validated by accurate pre-clinical studies and clinical trials.
Topics: Child; Young Adult; Humans; Immune Checkpoint Inhibitors; Osteosarcoma; Lung Neoplasms; Bone and Bones; Bone Neoplasms; Tumor Microenvironment
PubMed: 37329384
DOI: 10.1007/s11914-023-00803-9 -
Molecular Cancer Jul 2023Osteosarcoma (OS) is the most prevalent orthopedic malignancy with a dismal prognosis. The high iron absorption rate in OS cells of patients suggests that ferroptosis...
BACKGROUND
Osteosarcoma (OS) is the most prevalent orthopedic malignancy with a dismal prognosis. The high iron absorption rate in OS cells of patients suggests that ferroptosis may be related to the progression of OS, but its potential molecular regulatory role is still unclear. Based on the ability to couple with exosomes for targeted delivery of signals, exosome-derived micro ribonucleic acids (miRNAs) can potentially serve as diagnostic biomarkers for OS.
METHODS
We identified ferroptosis-related miRNAs and messenger ribonucleic acids(mRNAs) in OS using bioinformatics analysis and performed survival analysis. Then we measured miRNA expression levels through exosome microarray sequencing, and used RT-qPCR and IHC to verify the expression level of miR-144-3p and ZEB1. Stable gene expression cell lines were fabricated for in vitro experiments. Cell viability, migration and invasion were determined by CCK-8 and transwell experiment. Use the corresponding reagent kit to detect GSH/GSSG ratio, Fe level, MDA level and ROS level, and measure the expression levels of GPX4, ACSL4 and xCT through RT-qPCR and WB. We also constructed nude mice model for in vivo experiments. Finally, the stability of the miRNA/mRNA axis was verified through functional rescue experiments.
RESULTS
Low expression of miR-144-3p and high expression of ZEB1 in OS cell lines and tissues was observed. Overexpression of miR-144-3p can promote ferroptosis, reduce the survival ability of OS cells, and prevent the progression of OS. In addition, overexpression of miR-144-3p can downregulate the expression of ZEB1 in cell lines and nude mice. Knockdown of miR-144-3p has the opposite effect. The functional rescue experiment validated that miR-144-3p can regulate downstream ZEB1, and participates in the occurrence and development of OS by interfering with redox homeostasis and iron metabolism.
CONCLUSIONS
MiR-144-3p can induce the occurrence of ferroptosis by negatively regulating the expression of ZEB1, thereby inhibiting the proliferation, migration, and invasion of OS cells.
Topics: Animals; Mice; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Exosomes; Ferroptosis; Iron; Mice, Nude; MicroRNAs; Osteosarcoma; Humans
PubMed: 37461104
DOI: 10.1186/s12943-023-01804-z -
Cell Reports Sep 2023Metastasis is the major cause of cancer deaths, and cancer cells evolve to adapt to various tumor microenvironments, which hinders the treatment of tumor metastasis....
Metastasis is the major cause of cancer deaths, and cancer cells evolve to adapt to various tumor microenvironments, which hinders the treatment of tumor metastasis. Platelets play critical roles in tumor development, especially during metastasis. Here, we elucidate the role of platelet mitochondria in tumor metastasis. Cancer cells are reprogrammed to a metastatic state through the acquisition of platelet mitochondria via the PINK1/Parkin-Mfn2 pathway. Furthermore, platelet mitochondria regulate the GSH/GSSG ratio and reactive oxygen species (ROS) in cancer cells to promote lung metastasis of osteosarcoma. Impairing platelet mitochondrial function has proven to be an efficient approach to impair metastasis, providing a direction for osteosarcoma therapy. Our findings demonstrate mitochondrial transfer between platelets and cancer cells and suggest a role for platelet mitochondria in tumor metastasis.
Topics: Humans; Reactive Oxygen Species; Blood Platelets; Osteosarcoma; Bone Neoplasms; Mitochondria; Tumor Microenvironment
PubMed: 37756158
DOI: 10.1016/j.celrep.2023.113147 -
Clinical Cancer Research : An Official... Dec 2023Despite limited genetic and histologic heterogeneity, Ewing sarcoma (EwS) tumor cells are transcriptionally heterogeneous and display varying degrees of mesenchymal...
PURPOSE
Despite limited genetic and histologic heterogeneity, Ewing sarcoma (EwS) tumor cells are transcriptionally heterogeneous and display varying degrees of mesenchymal lineage specification in vitro. In this study, we investigated if and how transcriptional heterogeneity of EwS cells contributes to heterogeneity of tumor phenotypes in vivo.
EXPERIMENTAL DESIGN
Single-cell proteogenomic-sequencing of EwS cell lines was performed and integrated with patient tumor transcriptomic data. Cell subpopulations were isolated by FACS for assessment of gene expression and phenotype. Digital spatial profiling and human whole transcriptome analysis interrogated transcriptomic heterogeneity in EwS xenografts. Tumor cell subpopulations and matrix protein deposition were evaluated in xenografts and patient tumors using multiplex immunofluorescence staining.
RESULTS
We identified CD73 as a biomarker of highly mesenchymal EwS cell subpopulations in tumor models and patient biopsies. CD73+ tumor cells displayed distinct transcriptional and phenotypic properties, including selective upregulation of genes that are repressed by EWS::FLI1, and increased migratory potential. CD73+ cells were distinguished in vitro and in vivo by increased expression of matrisomal genes and abundant deposition of extracellular matrix (ECM) proteins. In epithelial-derived malignancies, ECM is largely deposited by cancer-associated fibroblasts (CAF), and we thus labeled CD73+ EwS cells, CAF-like tumor cells. Marked heterogeneity of CD73+ EwS cell frequency and distribution was detected in tumors in situ, and CAF-like tumor cells and associated ECM were observed in peri-necrotic regions and invasive foci.
CONCLUSIONS
EwS tumor cells can adopt CAF-like properties, and these distinct cell subpopulations contribute to tumor heterogeneity by remodeling the tumor microenvironment. See related commentary by Kuo and Amatruda, p. 5002.
Topics: Humans; Sarcoma, Ewing; Cancer-Associated Fibroblasts; Tumor Microenvironment; Cell Line, Tumor; RNA-Binding Protein EWS; Gene Expression Profiling; Oncogene Proteins, Fusion; Proto-Oncogene Protein c-fli-1; Gene Expression Regulation, Neoplastic
PubMed: 37471463
DOI: 10.1158/1078-0432.CCR-23-1111 -
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 -
Clinical Cancer Research : An Official... Nov 2023This phase Ib study defined the safety, MTD, and recommended phase II dose (RP2D) of regorafenib combined with vincristine and irinotecan (VI). Secondary objectives were...
PURPOSE
This phase Ib study defined the safety, MTD, and recommended phase II dose (RP2D) of regorafenib combined with vincristine and irinotecan (VI). Secondary objectives were evaluation of antitumor activity and pharmacokinetics (PK) of regorafenib and irinotecan.
PATIENTS AND METHODS
Patients aged 6 months to <18 years with relapsed/refractory solid malignancies [≥50% with rhabdomyosarcoma (RMS)] received regorafenib (starting dose 72 mg/m2/day) concomitantly or sequentially with vincristine 1.5 mg/m2 on days 1 and 8, and irinotecan 50 mg/m2 on days 1-5 (21-day cycle). Adverse events (AE) and tumor response were assessed. PK (regorafenib and irinotecan) were evaluated using a population PK model.
RESULTS
We enrolled 21 patients [median age, 10 years; 12, RMS; 5, Ewing sarcoma (EWS)]. The MTD/RP2D of regorafenib in the sequential schedule was 82 mg/m2. The concomitant dosing schedule was discontinued because of dose-limiting toxicities in 2 of 2 patients treated. Most common grade 3/4 (>30% of patients) AEs were neutropenia, anemia, thrombocytopenia, and leukopenia. The overall response rate was 48% and disease control rate [complete response (CR)/partial response/stable disease/non-CR/non-progressive disease] was 86%. Median progression-free survival was 7.0 months [95% confidence interval (CI), 2.9-14.8] and median overall survival was 8.7 months (95% CI, 5.5-16.3). When combined with VI, regorafenib PK was similar to single-agent PK in children and adults (treated with regorafenib 160 mg/day).
CONCLUSIONS
Regorafenib can be combined sequentially with standard dose VI in pediatric patients with relapsed/refractory solid tumors with appropriate dose modifications. Clinical activity was observed in patients with RMS and EWS (ClinicalTrials.gov NCT02085148).
Topics: Adult; Child; Humans; Irinotecan; Vincristine; Antineoplastic Combined Chemotherapy Protocols; Rhabdomyosarcoma; Sarcoma, Ewing; Therapies, Investigational
PubMed: 37606641
DOI: 10.1158/1078-0432.CCR-23-0257 -
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 -
Cancer Medicine Aug 2023Osteosarcoma (OS) is a highly malignant primary bone tumor. Family of homology 60A (FAM60A) reportedly contributes to the malignant growth of some tumors.
BACKGROUND
Osteosarcoma (OS) is a highly malignant primary bone tumor. Family of homology 60A (FAM60A) reportedly contributes to the malignant growth of some tumors.
METHODS
Herein we investigated the mRNA expression level of FAM60A by combining OS and non-cancer samples from public databases. Immunohistochemistry was performed to determine protein expression levels of FAM60A in patients with OS. Further, RT-qPCR and western blotting were conducted to evaluate FAM60A expression in various OS cell lines. CCK-8 assay, colony formation assay, and flow cytometry were applied to determine the function of FAM60A. Finally, functional enrichment analysis was performed based on FAM60A co-expressed genes.
RESULTS
FAM60A mRNA expression level was found to be significantly upregulated (standardized mean difference = 1.27, 95% CI [0.67-1.88]). Survival analyses suggested that higher expression of FAM60A was indicative of poor prognoses. Similarly, FAM60A protein expression level was also observed to be upregulated. Knocking down FAM60A expression inhibited OS cell proliferation, increased apoptosis, and blocked cells from entering the S phase. Besides, cell cycle was the most prominently enriched pathway, and BUB1, DTL, and EXO1 were identified as hub genes.
CONCLUSIONS
FAM60A expression was found to be markedly upregulated in OS; furthermore, FAM60A was observed to promote OS cell proliferation, inhibit apoptosis, and participate in cell cycle regulation. Besides, FAM60A may interact with hub genes to participate in the progress of OS.
Topics: Humans; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; MicroRNAs; Osteosarcoma; RNA, Messenger; DNA-Binding Proteins
PubMed: 37439040
DOI: 10.1002/cam4.6343 -
Current Opinion in Oncology Jul 2024There is an unmet need to improve outcomes for patients for Ewing sarcoma, a rare, aggressive sarcoma with a peak incidence in adolescents and young adults (AYA).... (Review)
Review
PURPOSE OF REVIEW
There is an unmet need to improve outcomes for patients for Ewing sarcoma, a rare, aggressive sarcoma with a peak incidence in adolescents and young adults (AYA). Current therapy at diagnosis involves multiagent chemotherapy and local therapy, but despite intensification of treatment, those with metastases at diagnosis and recurrent disease have poor outcomes.
RECENT FINDINGS
Improved understanding of Ewing sarcoma biology has identified novel targets with promising activity in Ewing sarcoma patients, including tyrosine kinase inhibitors that are now undergoing evaluation as combination and maintenance therapy. Other emerging therapies include those that target the EWSR1::FLI1 fusion oncoprotein, and act on DNA damage, cell cycle and apoptotic pathways. Immunotherapeutic approaches, particularly CAR-T-cell therapy directed at GD2, also hold promise. Recent collaborative clinical trials that have defined an international standard of care for patients with newly diagnosed Ewing sarcoma and novel platform studies with adaptive designs offer unique opportunities to investigate these therapies inclusive of all ages.
SUMMARY
Close international collaboration between clinicians and biologists will allow us to prioritize promising emerging therapies and develop biomarkers to facilitate their incorporation into standard of care and more rapidly translate into benefit for Ewing sarcoma patients.
Topics: Humans; Sarcoma, Ewing; Bone Neoplasms; Oncogene Proteins, Fusion; Molecular Targeted Therapy; Immunotherapy, Adoptive
PubMed: 38775200
DOI: 10.1097/CCO.0000000000001048