Department of Urology, University of Rochester Medical Center, Rochester, NY, 14642, USA.
Department of Pathology, University of Rochester Medical Center, Rochester, NY, 14642, USA.
Sci Rep. 2019 May 15;9(1):7425. doi: 10.1038/s41598-019-43641-5.
Recent data suggest that patients with a basal/stem-like bladder cancer (BC) subtype tend to have metastatic disease, but this is unconfirmed. Here we report the identification of murine MB49 cell line sub-clones with stem-like characteristics in culture. Subcutaneous implantation of S2 and S4 MB49 sub-clones into immunocompetent mice resulted in lung metastases in 50% and 80% of mice respectively, whereas none of the mice implanted with the parental cells developed metastasis. Gene profiling of cells cultured from S2 and S4 primary and metastatic tumors revealed that a panel of genes with basal/stem-like/EMT properties is amplified during metastatic progression. Among them, ITGB1, TWIST1 and KRT6B are consistently up-regulated in metastatic tumors of both MB49 sub-clones. To evaluate clinical relevance, we examined these genes in a human public dataset and found that ITGB1 and KRT6B expression in BC patient tumor samples are positively correlated with tumor grade. Likewise, the expression levels of these three genes are correlated with worse clinical outcomes. This MB49 BC metastatic pre-clinical model provides a unique opportunity to validate and recapitulate results discovered in patient studies and to pursue future mechanistic therapeutic interventions for BC metastasis.
最近的数据表明，基底/干细胞样膀胱癌（BC）亚型的患者往往患有转移性疾病，但这尚未得到证实。在这里，我们报告了在培养物中鉴定出具有干细胞样特征的鼠 MB49 细胞系亚克隆。将 S2 和 S4 MB49 亚克隆皮下植入免疫功能正常的小鼠，分别导致 50%和 80%的小鼠发生肺转移，而植入亲本细胞的小鼠均未发生转移。对 S2 和 S4 原代和转移性肿瘤培养细胞的基因谱分析表明，一组具有基底/干细胞样/EMT 特性的基因在转移进展过程中被扩增。其中，ITGB1、TWIST1 和 KRT6B 在两个 MB49 亚克隆的转移性肿瘤中均持续上调。为了评估临床相关性，我们在人类公共数据集检查了这些基因，发现 ITGB1 和 KRT6B 在 BC 患者肿瘤样本中的表达与肿瘤分级呈正相关。同样，这三个基因的表达水平与更差的临床结果相关。这个 MB49 BC 转移性临床前模型为验证和再现患者研究中发现的结果提供了独特的机会，并为 BC 转移的未来机制治疗干预提供了途径。
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