Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a relatively rare cancer but is the most common form of soft-tissue sarcomas in young adults children and children. RMS can originate as a consequence of myogenic precursors failing to differentiate into normal muscle and is characterised by two major subtypes, embryonal RMS (ERMS) and alveolar RMS (ARMS). ERMS is the most common form of the disease, comprises about 60% of cases, and has a more favourable outcome than ARMS. It’s characterized by a wide range of genetic aberrations and the most frequent is the loss of heterozygosity at the 11p15 locus, a region that encodes insulin-like growth factor 2 (IGF2). ARMS is the most aggressive form of RMS with a poorer prognosis and more prone to metastasis. It’s characterized by genetic translocations that result in chimeric protein that fuse the DNA binding domain of the paired box proteins 3 or 7 (PAX3 or PAX7) to the transactivation domain of a forkhead transcription factor (FOXO1). RMS display many defects in growth-factor signalling pathways and cell-cycle checkpoints that lead to cell growth and proliferation. The most frequently affected pathways are fibroblast growth factor (FGF), insulin-like growth factor (IGF), hepatocyte growth factor, and platelet-derived growth factor. PAX-FOXO1 proteins can activate these pathways by transcriptional activation of IGFR1, FGFR4, MET (c-Met) and PDGFRA genes. In 93% of RMS cases there is an alteration of the receptor tyrosine kinase/RAS/ PI3K axis and that alterations appeared to hinge on the FGF and IGF pathways. FGF and IGF pathways converge on cell-cycle regulators such as the cell-cycle regulator p21 (CDKN1A), and the cell-cycle regulator p14 (CDKN2A). p21 is induced in myoblast differentiation and blocks cell-cycle progression ; is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these proteins in RMS contributes to the silencing of p21. p14 is tumour suppressor and copy number deletions in CDKN2A were found in 2% of the RMS cancers. TBX2, a T-box gene family member, is overexpressed in both ERMS and ARMS cells. it is regulated by PAX3 and was found to induce a downregulation of p14 and to be a direct repressor of p21 in RMS.

横纹肌肉瘤（Rhabdomyosarcoma, RMS）是一类相对罕见的恶性肿瘤，却是儿童与年轻成人群体中最常见的软组织肉瘤。RMS可由肌源性前体无法分化为正常肌肉所引发，主要分为两大亚型：胚胎性横纹肌肉瘤（embryonal RMS, ERMS）与腺泡状横纹肌肉瘤（alveolar RMS, ARMS）。胚胎性横纹肌肉瘤是该病最常见的类型，约占所有病例的60%，预后优于腺泡状横纹肌肉瘤。该亚型以广泛的遗传畸变为特征，其中最常见的是11p15位点的杂合性缺失——该区域编码胰岛素样生长因子2（insulin-like growth factor 2, IGF2）。腺泡状横纹肌肉瘤是RMS中侵袭性最强的亚型，预后更差且更易发生远处转移，其特征为遗传易位形成的嵌合蛋白：将配对盒蛋白3或7（paired box proteins 3 or 7, PAX3 or PAX7）的DNA结合结构域，与叉头框转录因子（forkhead transcription factor, FOXO1）的转录激活结构域相融合。RMS存在诸多生长因子信号通路与细胞周期检查点的缺陷，进而导致细胞异常生长与增殖。最常受累的通路包括成纤维细胞生长因子（fibroblast growth factor, FGF）、胰岛素样生长因子（insulin-like growth factor, IGF）、肝细胞生长因子以及血小板衍生生长因子。PAX-FOXO1融合蛋白可通过转录激活IGFR1、FGFR4、MET（c-Met）及PDGFRA基因，从而激活上述通路。93%的RMS病例存在受体酪氨酸激酶/RAS/PI3K通路的异常，这类异常似乎与成纤维细胞生长因子及胰岛素样生长因子通路密切相关。FGF与IGF通路共同作用于细胞周期调控因子，例如细胞周期调控因子p21（CDKN1A）与p14（CDKN2A）。p21可在成肌细胞分化过程中被诱导表达，并阻滞细胞周期进程；在正常肌细胞中，p21的表达受MyoD与肌细胞生成素调控，而RMS中这两种蛋白的失活会导致p21的表达沉默。p14属于肿瘤抑制因子，CDKN2A的拷贝数缺失在2%的RMS病例中被检出。T-box基因家族成员TBX2在ERMS与ARMS细胞中均存在过表达，其表达受PAX3调控，且被证实可诱导p14表达下调，并作为p21的直接阻遏因子参与RMS的发生发展。