1. CD133 + brain tumor-initiating cells are dependent on STAT3 signaling to drive medulloblastoma recurrence.
- Author
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Garg N, Bakhshinyan D, Venugopal C, Mahendram S, Rosa DA, Vijayakumar T, Manoranjan B, Hallett R, McFarlane N, Delaney KH, Kwiecien JM, Arpin CC, Lai PS, Gómez-Biagi RF, Ali AM, de Araujo ED, Ajani OA, Hassell JA, Gunning PT, and Singh SK
- Subjects
- AC133 Antigen immunology, Animals, Brain Neoplasms immunology, Cell Line, Tumor, Cell Proliferation physiology, Female, Heterografts, Humans, Male, Medulloblastoma immunology, Mice, Neoplasm Recurrence, Local immunology, Neoplastic Stem Cells immunology, Neoplastic Stem Cells metabolism, STAT3 Transcription Factor metabolism, Signal Transduction, Small Molecule Libraries pharmacology, Up-Regulation, AC133 Antigen biosynthesis, Brain Neoplasms drug therapy, Brain Neoplasms pathology, Medulloblastoma drug therapy, Medulloblastoma pathology, Neoplasm Recurrence, Local pathology, Neoplastic Stem Cells pathology, STAT3 Transcription Factor antagonists & inhibitors
- Abstract
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.- Published
- 2017
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