PDF(Pubmed)
Abstract：
Chordomas are very rare malignant neoplasms of the bone occurring almost exclusively along the spine. As the tumours are thought to arise from notochordal remnants, the vast majority of chordomas express the TBXT gene, resulting in detectable nuclear amounts of its gene product brachyury. This T-Box transcription factor is commonly recognised as being essential in chordoma cells, and limiting TBXT expression is thought to be the key factor in controlling this tumour. Although the tumour is rare, distinct molecular differences and vulnerabilities have been described with regard to its location and the progression status of the disease, rendering it mandatory for novel cell lines to reflect all relevant chordoma subtypes. Here, we describe a novel chordoma cell line arising from the pleural effusion of a disseminated, poorly differentiated chordoma. This cell line, U-CH22, represents a highly aggressive terminal chordoma and, therefore, fills a relevant gap within the panel of available cell culture models for this orphan disease. CDK7 and CDK9 inhibition was lately identified as being effective in reducing viability in four chordoma cell lines, most likely due to a reduction in brachyury levels. In this study, we determined the capability of the CDK7 inhibitor THZ1 and the CDK1/2/5/9 inhibitor dinaciclib to reduce TBXT expression at mRNA and protein levels in a broad range of nine cell lines that are models of primary, recurrent, and metastasised chordoma of the clivus and the sacrum.
摘要：
脊索瘤是非常罕见的骨骼恶性肿瘤，几乎仅沿脊柱发生。由于肿瘤被认为是由脊索残留物引起的，绝大多数脊索瘤表达TBXT基因，导致其基因产物brachyury的可检测核量。这种T-盒转录因子通常被认为在脊索瘤细胞中是必需的，并且限制TBXT表达被认为是控制该肿瘤的关键因素。虽然肿瘤很罕见,关于其位置和疾病的进展状态，已经描述了不同的分子差异和脆弱性，新细胞系必须反映所有相关的脊索瘤亚型。这里,我们描述了一种新的脊索瘤细胞系，由播散的胸腔积液引起，低分化脊索瘤。这个细胞系,U-CH22代表高度侵袭性的晚期脊索瘤，因此,填补了该孤儿疾病可用细胞培养模型组中的相关空白。CDK7和CDK9抑制最近被确定为有效降低四种脊索瘤细胞系的活力，最有可能是由于短尾水平的降低。在这项研究中,我们确定了CDK7抑制剂THZ1和CDK1/2/5/9抑制剂dinaciclib在作为原代模型的9种细胞系中在mRNA和蛋白质水平上降低TBXT表达的能力，经常性,和转移的斜坡和骶骨脊索瘤。
