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Frontiers in Endocrinology 2024
Topics: Humans; Osteoporosis; Bone Neoplasms
PubMed: 38818500
DOI: 10.3389/fendo.2024.1429246 -
Science Advances Jan 2024Bone is one of the most common sites of tumor metastases. During the last step of bone metastasis, cancer cells colonize and disrupt the bone matrix, which is maintained...
Bone is one of the most common sites of tumor metastases. During the last step of bone metastasis, cancer cells colonize and disrupt the bone matrix, which is maintained mainly by osteocytes, the most abundant cells in the bone microenvironment. However, the role of osteocytes in bone metastasis is still unclear. Here, we demonstrated that osteocytes transfer mitochondria to metastatic cancer cells and trigger the cGAS/STING-mediated antitumor response. Blocking the transfer of mitochondria by specifically knocking out mitochondrial Rho GTPase 1 () or mitochondrial mitofusin 2 () in osteocytes impaired tumor immunogenicity and consequently resulted in the progression of metastatic cancer toward the bone matrix. These findings reveal the protective role of osteocytes against cancer metastasis by transferring mitochondria to cancer cells and potentially offer a valuable therapeutic strategy for preventing bone metastasis.
Topics: Humans; Osteocytes; Bone and Bones; Bone Neoplasms; GTP Phosphohydrolases; Mitochondria; Tumor Microenvironment
PubMed: 38232158
DOI: 10.1126/sciadv.adi4298 -
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 -
Endocrine-related Cancer Sep 2023Prostate cancer (PCa) is an increasingly prevalent health problem in the developed world. Effective treatment options exist for localized PCa, but metastatic PCa has... (Review)
Review
Prostate cancer (PCa) is an increasingly prevalent health problem in the developed world. Effective treatment options exist for localized PCa, but metastatic PCa has fewer treatment options and shorter patient survival. PCa and bone health are strongly entwined, as PCa commonly metastasizes to the skeleton. Since androgen receptor signaling drives PCa growth, androgen-deprivation therapy whose sequelae reduce bone strength constitutes the foundation of advanced PCa treatment. The homeostatic process of bone remodeling - produced by concerted actions of bone-building osteoblasts, bone-resorbing osteoclasts, and regulatory osteocytes - may also be subverted by PCa to promote metastatic growth. Mechanisms driving skeletal development and homeostasis, such as regional hypoxia or matrix-embedded growth factors, may be subjugated by bone metastatic PCa. In this way, the biology that sustains bone is integrated into adaptive mechanisms for the growth and survival of PCa in bone. Skeletally metastatic PCa is difficult to investigate due to the entwined nature of bone biology and cancer biology. Herein, we survey PCa from origin, presentation, and clinical treatment to bone composition and structure and molecular mediators of PCa metastasis to bone. Our intent is to quickly yet effectively reduce barriers to team science across multiple disciplines that focuses on PCa and metastatic bone disease. We also introduce concepts of tissue engineering as a novel perspective to model, capture, and study complex cancer-microenvironment interactions.
Topics: Male; Humans; Prostatic Neoplasms; Bone Neoplasms; Androgen Antagonists; Bone and Bones; Treatment Outcome; Tumor Microenvironment
PubMed: 37226936
DOI: 10.1530/ERC-22-0360 -
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 -
Chinese Medical Journal Oct 2023Osteosarcoma (OS) is the most common primary malignant bone tumor that more commonly occurs in children and adolescents. The most commonly used treatment for OS is... (Review)
Review
Osteosarcoma (OS) is the most common primary malignant bone tumor that more commonly occurs in children and adolescents. The most commonly used treatment for OS is surgery combined with chemotherapy, but the treatment outcomes are typically unsatisfactory. High rates of metastasis and post-treatment recurrence rates are major challenges in the treatment of OS. This underlines the need for studying the in-depth characterization of the pathogenetic mechanisms of OS and development of more effective therapeutic modalities. Previous studies have demonstrated the important role of the bone microenvironment and the regulation of signaling pathways in the occurrence and development of OS. In this review, we discussed the available evidence pertaining to the mechanisms of OS development and identified therapeutic targets for OS. We also summarized the available treatment modalities for OS and identified future priorities for therapeutics research.
Topics: Child; Adolescent; Humans; Bone Neoplasms; Signal Transduction; Bone and Bones; Treatment Outcome; Osteosarcoma; Tumor Microenvironment
PubMed: 37649421
DOI: 10.1097/CM9.0000000000002800 -
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 -
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 -
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 -
JNCI Cancer Spectrum Oct 2023
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Bone Neoplasms; Radium; Magnetic Resonance Imaging
PubMed: 37952210
DOI: 10.1093/jncics/pkad083