Translational Cell & Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
Pigment Cell Melanoma Res. 2012 Jul;25(4):454-65. doi: 10.1111/j.1755-148X.2012.01004.x. Epub 2012 May 3.
Despite recent advances in melanoma therapy, disseminated melanoma still lacks effective treatment, and recurrence of the tumor frequently occurs, even after high-dose chemotherapy. The mechanisms responsible for this chemoresistance or for the formation of new relapses remain poorly understood. Using a human 'model', in which the isolated limb is perfused with high doses of the chemotherapeutic melphalan (ILP), we identified a five-gene set (ATF3, CYR61, IER5, IL6, and PTGS2) of stress-induced genes that was consistently upregulated after ILP in all in-transit metastatic melanoma samples as well as in three melphalan-treated melanoma cell lines. Early post-ILP relapses retained these elevated expressions, whereas the expression of these genes returned to their original levels in late post-ILP recurrences. In addition, we identified upregulation of these genes in the A375 cell line's side population (SP) and melanospheres, established methods to enrich for candidate cancer stem cells (CSCs), which are considered chemoresistant and tumorigenic, and thus proposed to be responsible for tumor relapse. Our data identify an immediate and short-term upregulation of early stress-responsive genes that are potentially linked to chemoresistance and CSCs.
尽管近年来黑色素瘤治疗取得了进展，但转移性黑色素瘤仍然缺乏有效治疗方法，即使在高剂量化疗后，肿瘤仍经常复发。导致这种化疗耐药或新复发的机制仍知之甚少。我们使用一种人体“模型”，即通过高剂量的化疗药物美法仑对隔离肢体进行灌注（ILP），在所有转移性黑色素瘤样本和三种用美法仑治疗的黑色素瘤细胞系中，我们发现了一组五个与应激相关的基因（ATF3、CYR61、IER5、IL6 和 PTGS2）在 ILP 后持续上调。早期 ILP 后复发保留了这些升高的表达，而这些基因的表达在 ILP 后晚期恢复到原始水平。此外，我们还发现这些基因在 A375 细胞系的侧群（SP）和黑素球体中上调，建立了富集候选癌症干细胞（CSC）的方法，这些细胞被认为具有化疗耐药性和致瘤性，因此被认为是导致肿瘤复发的原因。我们的数据确定了早期应激反应基因的即时和短期上调，这些基因可能与化疗耐药性和 CSC 有关。
