Deciphering the Signaling Mechanisms of Osteosarcoma Tumorigenesis

Abstract

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.

PNO1 promotes the progression of osteosarcoma via TGF-β and YAP/TAZ pathway

“…Due to its unclear etiology, the clinical management of osteosarcoma still remains a great challenge 20 . Osteosarcoma is a complex malignancy which is driven by multiple genetic and non-genetic factors 21 . With the development of sequencing techniques, to investigate the regulatory function and mechanisms mediated by genetic factors becomes an effective approach to provide predictive biomarkers and therapeutic targets for cancer patients.…”

The OSR9 Regimen: A New Augmentation Strategy for Osteosarcoma Treatment Using Nine Older Drugs from General Medicine to Inhibit Growth Drive

“…This paper discusses several pathogenic mediators in OS and potential already marketed repurposed drugs to inhibit these systems, but it is important to remember that many more pathogenic physiological derangements are present in OS beyond those discussed here [196,[307][308][309][310]. As with other deadly cancers, the malignant behavior of OS cells involves deranged activation and/or pathological drop-out and/or the pathologically active participation of dozens (or hundreds) of cell-signaling systems.…”

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

“…Additionally, epigenomic, transcriptomic, proteomic, metabolomic, and functional genomic approaches have constantly expanded the number of altered signaling pathways in OS. Indeed, alterations in the major signaling pathways, such as PI3K/AKT/mTOR, JAK/STAT, WNT/β-catenin, NOTCH, Hedgehog/Gli, TGF-β, MAPK, and the receptor tyrosine kinases (RTKs) signaling pathways, have been identified in OS development and metastasis [ 89 ]. In all cases, the primary consequence of each signaling cascade is the activation of specific target genes by signal-regulated transcription factors.…”

“…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.…”