Garg N, Bakhshinyan D, Venugopal C, Mahendram S, Rosa D A, Vijayakumar T, Manoranjan B, Hallett R, McFarlane N, Delaney K H, Kwiecien J M, Arpin C C, Lai P-S, Gómez-Biagi R F, Ali A M, de Araujo E D, Ajani O A, Hassell J A, Gunning P T, Singh S K
McMaster Stem Cell and Cancer Research Institute, Hamilton, Ontario, Canada.
Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
Oncogene. 2017 Feb 2;36(5):606-617. doi: 10.1038/onc.2016.235. Epub 2016 Oct 24.
Medulloblastoma (MB), the most common malignant paediatric brain tumor, is currently treated using a combination of surgery, craniospinal radiotherapy and chemotherapy. Owing to MB stem cells (MBSCs), a subset of MB patients remains untreatable despite standard therapy. CD133 is used to identify MBSCs although its functional role in tumorigenesis has yet to be determined. In this work, we showed enrichment of CD133 in Group 3 MB is associated with increased rate of metastasis and poor clinical outcome. The signal transducers and activators of transcription-3 (STAT3) pathway are selectively activated in CD133 MBSCs and promote tumorigenesis through regulation of c-MYC, a key genetic driver of Group 3 MB. We screened compound libraries for STAT3 inhibitors and treatment with the selected STAT3 inhibitors resulted in tumor size reduction in vivo. We propose that inhibition of STAT3 signaling in MBSCs may represent a potential therapeutic strategy to treat patients with recurrent MB.
髓母细胞瘤（MB）是最常见的儿童恶性脑肿瘤，目前采用手术、全脑全脊髓放疗和化疗相结合的方法进行治疗。由于MB干细胞（MBSCs）的存在，尽管采用了标准治疗方法，仍有一部分MB患者无法治愈。CD133用于识别MBSCs，但其在肿瘤发生中的功能作用尚未确定。在这项研究中，我们发现3组MB中CD133的富集与转移率增加和临床预后不良有关。信号转导和转录激活因子3（STAT3）通路在CD133 MBSCs中被选择性激活，并通过调节c-MYC促进肿瘤发生，c-MYC是3组MB的关键基因驱动因子。我们筛选了化合物库以寻找STAT3抑制剂，用所选的STAT3抑制剂进行治疗导致体内肿瘤大小减小。我们提出，抑制MBSCs中的STAT3信号可能是治疗复发性MB患者的一种潜在治疗策略。
