Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA 30322, USA.
Int J Mol Sci. 2023 Jul 12;24(14):11367. doi: 10.3390/ijms241411367.
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 , , and and hyperactivation of the tumor promoter genes, including and , 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.
骨肉瘤（OS）是儿童和青少年人群中主要的原发性骨肿瘤。它具有很高的转移潜力，肺部是最常见的转移部位。与许多其他肉瘤不同，OS 缺乏保守的易位或基因突变；相反，它具有异质性的异常，包括体细胞 DNA 拷贝数改变、倍性、染色体扩增和染色体丢失和获得。不幸的是，30 多年来，临床结果并没有显著改善。目前，这种疾病没有有效的分子靶向治疗方法。几项基因组研究表明，OS 中存在肿瘤抑制基因的失活，包括 、 、 和肿瘤促进基因的过度激活，包括 和 。在 OS 的发展和转移过程中，已经确定了主要信号通路的改变，包括 PI3K/AKT/mTOR、JAK/STAT、Wnt/β-catenin、NOTCH、Hedgehog/Gli、TGF-β、RTKs、RANK/RANKL 和 NF-κB 信号通路。尽管 OS 的治疗目前基于手术切除和系统的多药治疗，但正在开发几种潜在的靶向治疗方法。本综述重点介绍了 OS 的主要信号通路，并提出了一个生物学基础，以考虑未来的新型和靶向治疗方法。
