Osteosarcoma (OS) is a malignant solid tumor prone to lung metastasis that occurs in adolescents aged 15-19 years. Neoadjuvant chemotherapy and surgical treatment aimed at curing OS have gained limited progress over the last 30 years. Exploring new effective second-line therapies for OS patients is a serious challenge for researchers. Quercetin, a multiple biologically active polyphenolic flavonoid, has been used in tumor therapy. However, the exact mechanism of quercetin is still unknown, which limits the application of quercetin. In the current study, we found that quercetin could inhibit JAK2 through the JH2 domain in a non-covalent manner, resulting in the inhibition of OS proliferation and immune escape via the JAK2-STAT3-PD-L1 signaling axis. More importantly, to overcome the shortcomings of quercetin, including low water solubility and low oral availability, we encapsulated it with folic acid-modified liposomes. The transportation of quercetin by folic acid-modified liposomes may provide a feasible strategy to cure OS.

Osteosarcoma, a prevalent primary malignant bone tumor, predominantly affects both elderly and adolescent populations and usually has an unfavorable prognosis. The specific mechanisms underlying its invasive progression remain unclear. The tumor microenvironment includes not only cancer cells but also bone-related cells, immune cells, tumor-associated nerve cells, and cell-secreted factors. The cooperative and competitive interactions among these cellular components contribute to the proliferation, progression, metastasis, and immune evasion of osteosarcoma. Alterations in bone-related cells, resulting from oncogenic changes, can rapidly increase bone density or aggravate bone loss, thereby promoting the survival of osteosarcoma cells. During the progression of osteosarcoma, genetic alterations in tumor cells lead to changes in extracellular matrix components, influencing the variation in cell-secreted factors, promoting immunosuppression within the tumor microenvironment, and consequently affecting tumor proliferation and progression. This review summarizes the roles of tumor microenvironment components in the pathogenesis of osteosarcoma and discusses existing therapeutic targets. The findings suggest potential research directions for further investigation of osteosarcoma, provide novel insights into the development of osteosarcoma, and may guide the development of more effective anti-tumor strategies.

The combination of neoadjuvant chemotherapy and surgery has been promoted for the treatment of osteosarcoma; however, the local recurrence and lung metastasis rates remain high. Therefore, it is crucial to explore new therapeutic targets and strategies that are more effective. The NOTCH pathway is not only involved in normal embryonic development but also plays an important role in the development of cancers. The expression level and signaling functional status of the NOTCH pathway vary in different histological types of cancer as well as in the same type of cancer from different patients, reflecting the distinct roles of the Notch pathway in tumorigenesis. Studies have reported abnormal activation of the NOTCH signaling pathway in most clinical specimens of osteosarcoma, which is closely related to a poor prognosis. Similarly, studies have reported that NOTCH signaling affected the biological behavior of osteosarcoma through various molecular mechanisms. NOTCH-targeted therapy has shown potential for the treatment of osteosarcoma in clinical research. After the introduction of the composition and biological functions of the NOTCH signaling pathway, the review paper discussed the clinical significance of dysfunction in osteosarcoma. Then the paper reviewed the recent relevant research progress made both in the cell lines and in the animal models of osteosarcoma. Finally, the paper explored the potential of the clinical application of NOTCH-targeted therapy for the treatment of osteosarcoma.

Osteosarcoma is the most common primary malignancy of bones and primarily occurs in adolescents and young adults. However, a second smaller peak of osteosarcoma incidence was reported in the elderly aged more than 60. Elderly patients with osteosarcoma exhibit different characteristics compared to young patients, which usually results in a poor prognosis. The mechanism underlying osteosarcoma development in elderly patients is intriguing and of significant value in clinical applications. Senescent cells can accelerate tumor progression by metabolic reprogramming. Recent research has shown that methylmalonic acid (MMA) was significantly up-regulated in the serum of older individuals and played a central role in the development of aggressive characteristics. We found that the significant accumulation of MMA in elderly patients imparted proliferative potential to osteosarcoma cells. The expression of MAFB was excessively up-regulated in osteosarcoma specimens and was further enhanced in response to MMA accumulation as the patient aged. Specifically, we first confirmed a novel molecular mechanism between cellular senescence and cancer, in which the MMA-driven transcriptional reprogramming of the MAFB-NOTCH3 axis accelerated osteosarcoma progression via the activation of PI3K-AKT pathways. Moreover, the down-regulation of the MAFB-NOTCH3 axis increased the sensitivity and effect of AKT inhibitors in osteosarcoma through significant inhibition of AKT phosphorylation. In conclusion, we confirmed that MAFB is a novel age-dependent biomarker for osteosarcoma, and targeting the MAFB-NOTCH3 axis in combination with AKT inhibition can serve as a novel therapeutic strategy for elderly patients with osteosarcoma in experimental and clinical trials.

Ewing sarcoma, the second most prevalent malignant bone tumor with potential occurrence in soft tissues, exhibits a high level of aggressiveness, primarily afflicting children and adolescents. It is characterized by fusion proteins arising from chromosomal translocations. The fusion proteins induce aberrations in multiple signaling pathways and molecules, constituting a key event in oncogenic transformation. While diagnostic and therapeutic modalities have advanced in recent decades and multimodal treatments, including surgery, radiotherapy, and chemotherapy, have significantly improved survival of patients with localized tumors, patients with metastatic tumors continue to face poor prognoses. There persists a pressing need for novel alternative treatments, yet the translation of our understanding of Ewing sarcoma pathogenesis into improved clinical outcomes remains a critical challenge. Here, we provide a comprehensive review of Ewing sarcoma, including fusion proteins, various signaling pathways, pivotal pathogenetic molecules implicated in its development, and associated targeted therapies and immunotherapies. We summarize past endeavors, current advancements, and deliberate on limitations and future research directions. It is envisaged that this review will furnish novel insights into prospective treatment avenues for Ewing sarcoma.

Osteosarcoma (OS) is a rapidly progressive primary malignant bone tumor that occurs in children and adolescents aged between 15 and 19 years and adults aged over 60 years. As alternative splicing (AS) changes caused by abnormal splicing factors contribute to tumor progression, gene expression and AS analyses were performed on 44 osteosarcoma patients to create a genome-wide co-expression network of RNA-binding proteins (RBPs), AS events, and AS genes. A gain- or loss-of-function osteosarcoma cell model was established, and an interactive network analysis and enrichment analysis were performed. Karyopherin Subunit Alpha 2 (KPNA2) negatively correlated with patient survival. KPNA2 transports splicing factor Y-box Binding Protein 1 (YBX1) into the nucleus and YBX1 accelerates the degradation of the ATP-dependent RNA helicase DDX3X (DDX3X) through the nonsense-mediated decay (NMD) pathway to promote intron retention of the DDX3X gene, thus reducing DDX3X protein levels. KPNA2/YBX1 axis regulates the stability of DDX3X mRNA and cell cycle progression. KPNA2/YBX1/DDX3X axis might be potential targets for inhibiting disease progression and improving OS patient survival. It integrates AS control of DDX3X into the progression of OS and represents a potential prognostic biomarker and therapeutic target for OS therapy.