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International Journal of Molecular... Apr 2024Oxidative stress and lipid peroxidation play important roles in numerous physiological and pathological processes, while the bioactive products of lipid peroxidation,... (Review)
Review
Oxidative stress and lipid peroxidation play important roles in numerous physiological and pathological processes, while the bioactive products of lipid peroxidation, lipid hydroperoxides and reactive aldehydes, act as important mediators of redox signaling in normal and malignant cells. Many types of cancer, including osteosarcoma, express altered redox signaling pathways. Such redox signaling pathways protect cancer cells from the cytotoxic effects of oxidative stress, thus supporting malignant transformation, and eventually from cytotoxic anticancer therapies associated with oxidative stress. In this review, we aim to explore the status of lipid peroxidation in osteosarcoma and highlight the involvement of lipid peroxidation products in redox signaling pathways, including the involvement of lipid peroxidation in osteosarcoma therapies.
Topics: Osteosarcoma; Humans; Lipid Peroxidation; Signal Transduction; Oxidation-Reduction; Oxidative Stress; Bone Neoplasms; Animals
PubMed: 38674143
DOI: 10.3390/ijms25084559 -
Medicina (Kaunas, Lithuania) Sep 2023The RANK-RANKL-OPG system is a complex signaling pathway that plays a critical role in bone metabolism, mammary epithelial cell development, immune function, and cancer.... (Review)
Review
The RANK-RANKL-OPG system is a complex signaling pathway that plays a critical role in bone metabolism, mammary epithelial cell development, immune function, and cancer. RANKL is a ligand that binds to RANK, a receptor expressed on osteoclasts, dendritic cells, T cells, and other cells. RANKL signaling promotes osteoclast differentiation and activation, which leads to bone resorption. OPG is a decoy receptor that binds to RANKL and inhibits its signaling. In cancer cells, RANKL expression is often increased, which can lead to increased bone resorption and the development of bone metastases. RANKL-neutralizing antibodies, such as denosumab, have been shown to be effective in the treatment of skeletal-related events, including osteoporosis or bone metastases, and cancer. This review will provide a comprehensive overview of the functions of the RANK-RANKL-OPG system in bone metabolism, mammary epithelial cells, immune function, and cancer, together with the potential therapeutic implications of the RANK-RANKL pathway for cancer management.
Topics: Humans; Receptor Activator of Nuclear Factor-kappa B; Osteoprotegerin; RANK Ligand; Osteoclasts; Bone Neoplasms; Bone Resorption; Homeostasis
PubMed: 37893470
DOI: 10.3390/medicina59101752 -
Frontiers in Endocrinology 2023
Topics: Humans; Bone Neoplasms; Bone and Bones; Bone Marrow Diseases
PubMed: 37564977
DOI: 10.3389/fendo.2023.1256406 -
Cancer Biology & Therapy Dec 2023Osteosarcoma is a highly metastatic malignant bone tumor, necessitating the development of new treatments to target its metastasis. Recent studies have revealed the...
Osteosarcoma is a highly metastatic malignant bone tumor, necessitating the development of new treatments to target its metastasis. Recent studies have revealed the significance of VAMP8 in regulating various signaling pathways in various types of cancer. However, the specific functional role of VAMP8 in osteosarcoma progression remains unclear. In this study, we observed a significant downregulation of VAMP8 in osteosarcoma cells and tissues. Low levels of VAMP8 in osteosarcoma tissues were associated with patients' poor prognosis. VAMP8 inhibited the migration and invasion capability of osteosarcoma cells. Mechanically, we identified DDX5 as a novel interacting partner of VAMP8, and the conjunction of VAMP8 and DDX5 promoted the degradation of DDX5 via the ubiquitin-proteasome system. Moreover, reduced levels of DDX5 led to the downregulation of β-catenin, thereby suppressing the epithelial-mesenchymal transition (EMT). Additionally, VAMP8 promoted autophagy flux, which may contribute to the suppression of osteosarcoma metastasis. In conclusion, our study anticipated that VAMP8 inhibits osteosarcoma metastasis by promoting the proteasomal degradation of DDX5, consequently inhibiting WNT/β-catenin signaling and EMT. Dysregulation of autophagy by VAMP8 is also implicated as a potential mechanism. These findings provide new insights into the biological nature driving osteosarcoma metastasis and highlight the modulation of VAMP8 as a potential therapeutic strategy for targeting osteosarcoma metastasis.
Topics: Humans; beta Catenin; Cell Line, Tumor; Wnt Signaling Pathway; Osteosarcoma; Bone Neoplasms; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Cell Movement; Cell Proliferation; R-SNARE Proteins
PubMed: 37405957
DOI: 10.1080/15384047.2023.2230641 -
Scientific Reports Oct 2023This study aimed at establishing more accurate predictive models based on novel machine learning algorithms, with the overarching goal of providing clinicians with...
This study aimed at establishing more accurate predictive models based on novel machine learning algorithms, with the overarching goal of providing clinicians with effective decision-making assistance. We retrospectively analyzed the breast cancer patients recorded in the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2016. Multivariable logistic regression analyses were used to identify risk factors for bone metastases in breast cancer, whereas Cox proportional hazards regression analyses were used to identify prognostic factors for breast cancer with bone metastasis (BCBM). Based on the identified risk and prognostic factors, we developed diagnostic and prognostic models that incorporate six machine learning classifiers. We then used the area under the receiver operating characteristic (ROC) curve (AUC), learning curve, precision curve, calibration plot, and decision curve analysis to evaluate performance of the machine learning models. Univariable and multivariable logistic regression analyses showed that bone metastases were significantly associated with age, race, sex, grade, T stage, N stage, surgery, radiotherapy, chemotherapy, tumor size, brain metastasis, liver metastasis, lung metastasis, breast subtype, and PR. Univariate and multivariate Cox regression analyses revealed that age, race, marital status, grade, surgery, radiotherapy, chemotherapy, brain metastasis, liver metastasis, lung metastasis, breast subtype, ER, and PR were closely associated with the prognosis of BCBM. Among the six machine learning models, the XGBoost algorithm predicted the most accurate results (Diagnostic model AUC = 0.98; Prognostic model AUC = 0.88). According to the Shapley additive explanations (SHAP), the most critical feature of the diagnostic model was surgery, followed by N stage. Interestingly, surgery was also the most critical feature of prognostic model, followed by liver metastasis. Based on the XGBoost algorithm, we could effectively predict the diagnosis and survival of bone metastasis in breast cancer and provide targeted references for the treatment of BCBM patients.
Topics: Humans; Female; Breast Neoplasms; Retrospective Studies; Bone Neoplasms; Brain Neoplasms; Liver Neoplasms; Lung Neoplasms; Machine Learning
PubMed: 37880320
DOI: 10.1038/s41598-023-45438-z -
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 -
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 -
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 -
Tissue Engineering. Part B, Reviews Apr 2024In the past decades, anticancer drug development brought the field of tumor engineering to a new level by the need of robust test systems. Simulating tumor... (Review)
Review
In the past decades, anticancer drug development brought the field of tumor engineering to a new level by the need of robust test systems. Simulating tumor microenvironment remains a challenge, and osteosarcoma-the most common primary bone cancer-is no exception. The growing evidence points to the inevitable connection between biomechanical stimuli and tumor chemosensitivity and aggressiveness, thus making this component of the microenvironment a mandatory requirement to the developed models. In this review, we addressed the question: is the "" gap in osteosarcoma engineering bridged from the perspective of biomechanical stimuli? The most notable biomechanical cues in the tumor cell microenvironment are observed and compared in the contexts of conditions and engineered three-dimensional models. Impact statement The importance of biomechanical stimuli in three-dimensional models for drug testing is becoming more pronounced nowadays. This review might assist in understanding the key players of the biophysical environment of primary bone cancer and the current state of bone tumor engineering from this perspective.
Topics: Humans; Bone Neoplasms; Osteosarcoma; Tumor Microenvironment; Cellular Microenvironment; Models, Biological
PubMed: 37830183
DOI: 10.1089/ten.TEB.2023.0106 -
International Journal of Molecular... Aug 2023Phytoestrogens are plant-derived bioactive compounds with estrogen-like properties. Their potential health benefits, especially in cancer prevention and treatment, have... (Review)
Review
Phytoestrogens are plant-derived bioactive compounds with estrogen-like properties. Their potential health benefits, especially in cancer prevention and treatment, have been a subject of considerable research in the past decade. Phytoestrogens exert their effects, at least in part, through interactions with estrogen receptors (ERs), mimicking or inhibiting the actions of natural estrogens. Recently, there has been growing interest in exploring the impact of phytoestrogens on osteosarcoma (OS), a type of bone malignancy that primarily affects children and young adults and is currently presenting limited treatment options. Considering the critical role of the estrogen/ERs axis in bone development and growth, the modulation of ERs has emerged as a highly promising approach in the treatment of OS. This review provides an extensive overview of current literature on the effects of phytoestrogens on human OS models. It delves into the multiple mechanisms through which these molecules regulate the cell cycle, apoptosis, and key pathways implicated in the growth and progression of OS, including ER signaling. Moreover, potential interactions between phytoestrogens and conventional chemotherapy agents commonly used in OS treatment will be examined. Understanding the impact of these compounds in OS holds great promise for developing novel therapeutic approaches that can augment current OS treatment modalities.
Topics: Child; Young Adult; Humans; Phytoestrogens; Osteosarcoma; Apoptosis; Estrogens; Bone Neoplasms
PubMed: 37686148
DOI: 10.3390/ijms241713344