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Mechanism of the PD‐1/PD‐L1 signaling pathway in OS. The immune checkpoint proteins PD‐1 on the surface of T cells interact with the ligands PD‐L1/PD‐L2 on OS cells, IFN‐γ produced by T lymphocytes induces PD‐L1 expression in angiosarcoma, resulting in immune tolerance.
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Osteosarcoma (OS) is a highly prevalent bone malignancy among adolescents, accounting for 40% of all primary malignant bone tumors. Neoadjuvant chemotherapy combined with limb-preserving surgery has effectively reduced patient disability and mortality, but pulmonary metastases and OS cells' resistance to chemotherapeutic agents are pressing challen...
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Osteosarcoma, the most common primary malignant bone tumor, is characterized by malignant cells producing osteoid or immature bone tissue. Most osteosarcoma patients require reconstructive surgery to restore the functional and structural integrity of the injured bone. Metal orthopedic implants are commonly used to restore the limb integrity in post...
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... Alteration of different molecular pathways is known to be involved in OS onset and progression. Among them, the PI3K/AKT/mTOR signaling pathway has been demonstrated to have the ability to enhance the cell cycle, inhibit apoptosis, and promote cellular proliferation, invasion, and metastasis in OS [380]. Interestingly, several studies indicate that circRNAs may play an important role in the regulation of the PI3K/ AKT/mTOR pathway. ...
... Another pathway playing a crucial role in OS development is the Wnt/β-catenin signaling pathway. The Wnt/ β-catenin pathway is a well-known oncogenic pathway responsible for cell fate determination, stem cell replication, survival, differentiation, cell polarity, and osteogenic differentiation [380,382]. In this regard, circ_001350, that is upregulated in OS tissues, is able to activate the Wnt pathway by inducing the β-catenin protein expression and its downstream effector cyclin D1, and c-myc. ...
... It is well recognized that abnormal activation of the AKT/mTOR signaling pathway is one pivotal cause of OS development and progression [380]. PF4V1 is a negative regulator of the AKT signaling pathway and negatively regulates OS progression [386]. ...
Osteosarcoma (OS) is the most prevalent and fatal type of bone tumor. It is characterized by great heterogeneity of genomic aberrations, mutated genes, and cell types contribution, making therapy and patients management particularly challenging. A unifying picture of molecular mechanisms underlying the disease could help to transform those challenges into opportunities.This review deeply explores the occurrence in OS of large-scale RNA regulatory networks, denominated "competing endogenous RNA network" (ceRNET), wherein different RNA biotypes, such as long non-coding RNAs, circular RNAs and mRNAs can functionally interact each other by competitively binding to shared microRNAs. Here, we discuss how the unbalancing of any network component can derail the entire circuit, driving OS onset and progression by impacting on cell proliferation, migration, invasion, tumor growth and metastasis, and even chemotherapeutic resistance, as distilled from many studies. Intriguingly, the aberrant expression of the networks components in OS cells can be triggered also by the surroundings, through cytokines and vesicles, with their bioactive cargo of proteins and non-coding RNAs, highlighting the relevance of tumor microenvironment. A comprehensive picture of RNA regulatory networks underlying OS could pave the way for the development of innovative RNA-targeted and RNA-based therapies and new diagnostic tools, also in the perspective of precision oncology.
... International Publisher molecular targeted therapy, and traditional Chinese medicine (TCM) has significantly decreased morbidity and mortality among patients with OS. These diverse therapeutic approaches have increased the 5-year survival rate of patients with OS without distant metastases to 60% [4,5]. Despite these advancements, overall survival rates for OS have not improved over the past three decades [6]. ...
Background: T-box transcription factor 3 (TBX3) has been implicated in various malignant tumors, while its exact involvement in osteosarcoma (OS) remains unknown.
Methods: Utilizing microarray data and bulk and single-cell RNA-seq data and qRT-PCR, we compared TBX3 mRNA expression levels in different stages of OS. Diagnostic ability testing and prognosis analysis were conducted to better understand the clinical importance of TBX3. Enrichment analysis was performed using gene groups with biological functions similar to TBX3 in different stages of OS to investigate the potential role of TBX3 in OS progression. In addition, we predicted medications targeted at TBX3 and identified downstream target genes to gain a comprehensive understanding of its therapeutic direction and regulatory mechanism.
Results: TBX3 expression was highly upregulated in OS and was predominantly expressed in osteoblastic OS cells, with higher expression levels in metastatic tissues. TBX3 expression appeared somewhat suitable for discriminating between OS and normal samples, as well as different stages of OS. We found that TBX3 increased the malignant development of OS by altering cell cycle and cell adhesion molecules; exisulind and tacrolimus, which are targeted small-molecule medicines, were anticipated to counteract this dysregulation. The expression of CCNA2 could potentially be regulated by TBX3, contributing to OS advancement.
Conclusion: TBX3 emerges as a potential biomarker for OS. In-depth research into its underlying molecular processes may offer new perspectives on treating OS.
... In addition to point mutations, osteosarcoma can present structural genomic changes, such as copy number variations, chromosomal rearrangements, deletions, or amplifications that can affect the function of key genes in the control of cell growth [20]. Also, the gene expression analysis can identify genes that are overexpressed or downregulated in tumor cells [5] and alterations in cellular signaling pathways, such as the insulin-like growth factor 3 (IGF) pathway or the epidermal growth factor (EGF) pathway, may be involved in the growth and survival of tumor cells [21]. Furthermore, phenomena of chromothripsis (massive genomic rearrangement that occurs in a single event) and kataegis (localized hypermutation) have been demonstrated in osteosarcomas. ...
Osteosarcoma (OS) are the most prevalent malignant bone tumors in adolescents and young adults.. OS cells grow in a permissive local microenvironment which modulates their behavior and facilitates all steps in tumor development (e.g., proliferation/quiescence, invasion/migration, drug resistance) and contributes to their intrinsic heterogeneity. The lung parenchyma is the most common metastatic site in OS, and metastatic foci are frequently associated with a poor clinical outcome. Although multiple factors may be responsible for the disease, including genetic mutations (e.g., Rb, p53), the molecular mechanism of development of OS remains unclear and the conventional treatment for OS is still based on a sequential approach that combines chemotherapy and surgery. Also, despite the increase in clinical trials, the survival rates for OS have not improved. Non-specific targeting therapies thus show poor therapeutic effects with side effects at high doses. For these reasons, many efforts have been done to characterize the complex genome of osteosarcoma thanks to the whole exome analysis with the aim to identify predictive biomarkers to give to these patients a better therapeutic option. This review aims to summarize and discuss the main recent advances in OS molecular research for precision medicine.
... Abnormal expression of oncogenes and tumor suppressor genes secondary to changes in epigenetic and genetic elements leads to anomalies in cell biology, leading to aberrant signal transduction mechanisms and abnormal communication between various cellular processes and gene expressions. Many pathways are implicated in cancer cell formation, progression, survival, and metastasis in OS ( Figure 3 and Table 5) [3,43,66,[68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84]. ...
... Studies have showcased significant gene mutations correlated to OS's PI3K/Akt and MAPK/ERK pathways [41,85] (Figure 3 and Table 5). The JAK/STAT3 pathway also has a prominent role in OS proliferation, prevention of apoptosis, and immune regulation, where GFs (FGF, VGEF, etc.) and cytokines (IL-6, IL-10, IL-11, etc.) inappropriately activate STAT-3 protein and encourage OS progression [72,81,86]. Several other pathways (illustrated in Figure 3), such as the Hedgehog pathway, Wnt, SIRT1 and NOTCH signaling pathways, and TLR pathways, support tumor progression through the modulation of cell cycle progression and inhibiting cellular mechanisms of cell death and apoptosis. ...
Melatonin, an endogenous neurohormone produced by the pineal gland, has received increased interest due to its potential anti-cancer properties. Apart from its well-known role in the sleep-wake cycle, extensive scientific evidence has shown its role in various physiological and pathological processes, such as inflammation. Additionally, melatonin has demonstrated promising potential as an anti-cancer agent as its function includes inhibition of tumorigenesis, induction of apoptosis, and regulation of anti-tumor immune response. Although a precise pathophysiological mechanism is yet to be established, several pathways related to the regulation of cell cycle progression , DNA repair mechanisms, and antioxidant activity have been implicated in the anti-neoplastic potential of melatonin. In the current manuscript, we focus on the potential anti-cancer properties of melatonin and its use in treating and managing pediatric osteosarcoma. This aggressive bone tumor primarily affects children and adolescents and is treated mainly by surgical and radio-oncological interventions , which has improved survival rates among affected individuals. Significant disadvantages to these interventions include disease recurrence, therapy-related toxicity, and severe/debilitating side effects that the patients have to endure, significantly affecting their quality of life. Melatonin has therapeutic effects when used for treating osteosarcoma, attributed to its ability to halt cancer cell proliferation and trigger apoptotic cell death, thereby enhancing chemotherapeutic efficacy. Furthermore, the antioxidative function of melatonin alleviates harmful side effects of chemotherapy-induced oxidative damage, aiding in decreasing therapeutic toxicities. The review concisely explains the many mechanisms by which melatonin targets osteosarcoma, as evidenced by significant results from several in vitro and animal models. Nevertheless, if further explored, human trials remain a challenge that could shed light and support its utility as an adjunctive therapeutic modality for treating osteosarcoma.
... This immunological pathway, pivotal to immune modulation, has been pinpointed as a prospective therapeutic target across various cancer types, including osteosarcoma. By obstructing the PD-1 and PD-L1 interaction, these agents hold the potential to bolster the immune system's proficiency in detecting and annihilating osteosarcoma cells [88][89][90][91]. In tandem with this, there is burgeoning interest in angiogenesis inhibitors. ...
Osteosarcoma, a predominant malignant bone tumor, poses significant challenges due to its high metastatic and recurrent nature. Although various therapeutic strategies are currently in use, they often inadequately target osteosarcoma metastasis. This review focuses on the potential of nanoscale drug delivery systems to bridge this clinical gap. It begins with an overview of the molecular mechanisms underlying metastatic osteosarcoma, highlighting the limitations of existing treatments. The review then transitions to an in-depth examination of nanoscale drug delivery technologies, emphasizing their potential to enhance drug bioavailability and reduce systemic toxicity. Central to this review is a discussion of recent advancements in utilizing nanotechnology for the potential intervention of metastatic osteosarcoma, with a critical analysis of several preclinical studies. This review aims to provide insights into the potential applications of nanotechnology in metastatic osteosarcoma therapy, setting the stage for future clinical breakthroughs and innovative cancer treatments.
Osteosarcoma stem cells (OSCs) contribute to the pathogenesis of osteosarcoma (OS), which is the most common malignant primary bone tumor. The significance and underlying mechanisms of action of proteoglycans (PGs) and glycosaminoglycans (GAGs) in OSC phenotypes and OS malignancy are largely unknown. This study aimed to investigate the role of PG/GAG biosynthesis and the corresponding candidate genes in OSCs and poor clinical outcomes in OS using scRNA-seq and bulk RNA-seq datasets of clinical OS specimens, accompanied by biological validation by in vitro genetic and pharmacological analyses. The expression of β-1,3-glucuronyltransferase 3 (B3GAT3), one of the genes responsible for the biosynthesis of the common core tetrasaccharide linker region of PGs, was significantly upregulated in both OSC populations and OS tissues and was associated with poor survival in patients with OS with high stem cell properties. Moreover, the genetic inactivation of B3GAT3 by RNA interference and pharmacological inhibition of PG biosynthesis abrogated the self-renewal potential of OSCs. Collectively, these findings suggest a pivotal role for B3GAT3 and PG/GAG biosynthesis in the regulation of OSC phenotypes and OS malignancy, thereby providing a potential target for OSC-directed therapy.
Osteosarcoma is a highly aggressive cancer prevalent among adolescents and young adults, notorious for its tendency to metastasize to the lungs. This research delves into the molecular foundations of osteosarcoma by examining the role of the Hippo signaling pathway and its interaction with the tumor immune microenvironment (TME). Through analysis of transcriptomic data from the TARGET‐OS dataset and control samples from GTEx, we identified a set of 131 genes that link high expression profiles in osteosarcoma with the Hippo pathway. A focused examination through univariate Cox regression analysis revealed eight key genes (DLG5, WNT11, TGFB2, DLG4, WNT16, ID2, WNT10B, and WNT10A) with a significant correlation to patient outcomes. Hierarchical clustering of these genes delineated two distinct patient groups with significantly different survival rates, a finding supported by Kaplan–Meier survival analysis. Further investigation into immune cell infiltration and expression profiles of immunoregulatory factors uncovered a notable pattern of immune evasion in the group with poorer prognosis, marked by reduced effector immune cell activity and lower levels of immunostimulatory factors. Single‐cell sequencing highlighted the cellular diversity within osteosarcoma samples and identified markers differentiating malignant from nonmalignant cells, correlating these markers with prognostic risk scores. Our results emphasize the critical prognostic value of Hippo pathway genes and the TME in osteosarcoma, shedding light on new avenues for therapeutic intervention and patient‐specific treatment strategies.
