NOTCH Signaling in Osteosarcoma

Zhang, Zhenhao; Wu, Wei; Shao, Zhang

doi:10.3390/cimb45030146

Cited by 10 publications

(6 citation statements)

References 127 publications

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“…The NOTCH signaling pathway not only promotes OS tumor progression but is also involved in tumor metastasis. The expressions of NOTCH1, NOTCH2, HES1, and DLL1 were significantly upregulated in a highly invasive and metastatic LM7 cell compared to normal human osteoblasts and the SaOS-2 cell line, which have lower metastatic potential [98,99]. JAG1 expression was significantly higher in the highly metastatic F5M2 cell lines compared to the less metastatic F4 OS cells [97].…”

Section: Notch Signaling Pathwaymentioning

confidence: 91%

Deciphering the Signaling Mechanisms of Osteosarcoma Tumorigenesis

Nirala

Yamamichi

Yustein

2023

IJMS

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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 p53, RB, and ATRX, and hyperactivation of the tumor promoter genes, including MYC and MDM2, 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.

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Section: Notch Signaling Pathwaymentioning

confidence: 91%

Deciphering the Signaling Mechanisms of Osteosarcoma Tumorigenesis

Nirala

Yamamichi

Yustein

2023

IJMS

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“…Inter-cellular cross-communication via the Hedgehog pathway supports OS's invasion and metastasis, supporting various oncogenic pathways in tumor progression and metastasis. Moreover, overexpression of Hes/Hey proteins involved downstream of the NOTCH signaling pathway was correlated to poor prognosis and survival [66] (Figure 3 and Table 5). The Wnt/β-catenin pathway also plays a pivotal role in OS-CSC renewal, embryogenesis, and tissue regeneration [70,74].…”

Section: Signaling Pathwaysmentioning

confidence: 95%

“…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].…”

Section: Signaling Pathwaysmentioning

confidence: 99%

“…Besides the pathways mentioned, studies also implicate the RANK/RANKL/OPG pathway and exosomal/vesicle-based cellular communication in the initiation and progression of OS, proliferation EMT, invasion, and metastasis [45,56,66,[94][95][96][97][98]. Summary of the commonly studied signaling pathways involved in osteosarcoma, presented with their rate of expression and implicated effects.…”

Section: Signaling Pathwaysmentioning

confidence: 99%

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Unveiling the Protective Role of Melatonin in Osteosarcoma: Current Knowledge and Limitations

Al-Ansari,

Samuel,

Büsselberg

2024

Biomolecules

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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.

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“…Coactivation of NF-κB and NOTCH signaling has been previously demonstrated as well [ 105 , 106 ]. Notch activation can induce the expression of a large fraction of classical NF-κB gene targets in T-cell progenitors [ 107 ], and as a key player in osteogenic differentiation, bone healing, and in the development of the skeleton [ 108 ], its abnormal activation has been observed in most OS clinical specimens with a close relation with poorer prognosis [ 89 , 109 ]. In this regard, NOTCH3 knockdown has been shown to deeply impair proliferation, apoptosis, and invasion in OS cells, while it reduced the number of metastatic lesions in vivo.…”

Section: Nf-κb Dysregulation and Cancermentioning

confidence: 99%

Amicis Omnia Sunt Communia: NF-κB Inhibition as an Alternative to Overcome Osteosarcoma Heterogeneity

Medeiros,

Guenka,

Bastos

et al. 2024

Pharmaceuticals

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Tumor heterogeneity poses a significant challenge in osteosarcoma (OS) treatment. In this regard, the “omics” era has constantly expanded our understanding of biomarkers and altered signaling pathways (i.e., PI3K/AKT/mTOR, WNT/β-catenin, NOTCH, SHH/GLI, among others) involved in OS pathophysiology. Despite different players and complexities, many commonalities have been described, among which the nuclear factor kappa B (NF-κB) stands out. Its altered activation is pervasive in cancer, with pleiotropic action on many disease-relevant traits. Thus, in the scope of this article, we highlight the evidence of NF-κB dysregulation in OS and its integration with other cancer-related pathways while we summarize the repertoire of compounds that have been described to interfere with its action. In silico strategies were used to demonstrate that NF-κB is closely coordinated with other commonly dysregulated signaling pathways not only by functionally interacting with several of their members but also by actively participating in the regulation of their transcription. While existing inhibitors lack selectivity or act indirectly, the therapeutic potential of targeting NF-κB is indisputable, first for its multifunctionality on most cancer hallmarks, and secondly, because, as a common downstream effector of the many dysregulated pathways influencing OS aggressiveness, it turns complex regulatory networks into a simpler picture underneath molecular heterogeneity.

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NOTCH Signaling in Osteosarcoma

Cited by 10 publications

References 127 publications

Deciphering the Signaling Mechanisms of Osteosarcoma Tumorigenesis

Deciphering the Signaling Mechanisms of Osteosarcoma Tumorigenesis

Unveiling the Protective Role of Melatonin in Osteosarcoma: Current Knowledge and Limitations

Amicis Omnia Sunt Communia: NF-κB Inhibition as an Alternative to Overcome Osteosarcoma Heterogeneity

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