Human Medulloblastoma Cell Lines: Investigating on Cancer Stem Cell-Like Phenotype (original) (raw)

Establishment of a novel human medulloblastoma cell line characterized by highly aggressive stem-like cells

Cytotechnology, 2015

Medulloblastoma is a highly aggressive brain tumor and one of the leading causes of morbidity and mortality related to childhood cancer. These tumors display differential ability to metastasize and respond to treatment, which reflects their high degree of heterogeneity at the genetic and molecular levels. Such heterogeneity of medulloblastoma brings an additional challenge to the understanding of its physiopathology and impacts the development of new therapeutic strategies. This translational effort has been the focus of most pre-clinical studies which invariably employ experimental models using human tumor cell lines. Nonetheless, compared to other cancers, relatively few cell lines of human medulloblastoma are available in central repositories, partly due to the rarity of these tumors and to the intrinsic difficulties in establishing continuous cell lines from pediatric brain tumors. Here, we report the establishment of a new human medulloblastoma cell line which, in comparison with the commonly used and well-established cell line Daoy, is characterized by enhanced proliferation and invasion capabilities, stem cell properties, increased chemoresistance, tumorigenicity in an orthotopic metastatic model, replication of original medulloblastoma behavior in vivo, strong chromosome structural instability and deregulation of genes involved in neural development. These features are advantageous for designing biologically relevant experimental models in clinically oriented studies, making this novel cell line, named USP-13-Med, instrumental for the study of medulloblastoma biology and treatment.

Aberrant signaling pathways in medulloblastomas: a stem cell connection

Arquivos de Neuro-Psiquiatria, 2010

Medulloblastoma is a highly malignant primary tumor of the central nervous system. It represents the most frequent type of solid tumor and the leading cause of death related to cancer in early childhood. Current treatment includes surgery, chemotherapy and radiotherapy which may lead to severe cognitive impairment and secondary brain tumors. New perspectives for therapeutic development have emerged with the identification of stem-like cells displaying high tumorigenic potential and increased radio- and chemo-resistance in gliomas. Under the cancer stem cell hypothesis, transformation of neural stem cells and/or granular neuron progenitors of the cerebellum are though to be involved in medulloblastoma development. Dissecting the genetic and molecular alterations associated with this process should significantly impact both basic and applied cancer research. Based on cumulative evidences in the fields of genetics and molecular biology of medulloblastomas, we discuss the possible invol...

Gene signatures associated with mouse postnatal hindbrain neural stem cells and medulloblastoma cancer stem cells identify novel molecular mediators and predict human medulloblastoma molecular classification

Cancer discovery, 2012

Medulloblastoma arises from mutations occurring in stem/progenitor cells located in restricted hindbrain territories. Here we report that the mouse postnatal ventricular zone lining the IV ventricle also harbors bona fide stem cells that, remarkably, share the same molecular profile with cerebellar white matter-derived neural stem cells (NSC). To identify novel molecular mediators involved in medulloblastomagenesis, we compared these distinct postnatal hindbrain-derived NSC populations, which are potentially tumor initiating, with murine compound Ptch/p53 mutant medulloblastoma cancer stem cells (CSC) that faithfully phenocopy the different variants of human medulloblastoma in vivo. Transcriptome analysis of both hindbrain NSCs and medulloblastoma CSCs resulted in the generation of well-defined gene signatures, each reminiscent of a specific human medulloblastoma molecular subclass. Most interestingly, medulloblastoma CSCs upregulated developmentally related genes, such as Ebfs, tha...

Identification of a cancer stem cell in human brain tumors

Cancer research, 2003

Most current research on human brain tumors is focused on the molecular and cellular analysis of the bulk tumor mass. However, there is overwhelming evidence in some malignancies that the tumor clone is heterogeneous with respect to proliferation and differentiation. In human leukemia, the tumor clone is organized as a hierarchy that originates from rare leukemic stem cells that possess extensive proliferative and selfrenewal potential, and are responsible for maintaining the tumor clone. We report here the identification and purification of a cancer stem cell from human brain tumors of different phenotypes that possesses a marked capacity for proliferation, self-renewal, and differentiation. The increased self-renewal capacity of the brain tumor stem cell (BTSC) was highest from the most aggressive clinical samples of medulloblastoma compared with low-grade gliomas. The BTSC was exclusively isolated with the cell fraction expressing the neural stem cell surface marker CD133. These CD133؉ cells could differentiate in culture into tumor cells that phenotypically resembled the tumor from the patient. The identification of a BTSC provides a powerful tool to investigate the tumorigenic process in the central nervous system and to develop therapies targeted to the BTSC.

Expression analysis of stem cell-related genes reveal OCT4 as a predictor of poor clinical outcome in medulloblastoma

Journal of Neuro-Oncology, 2011

Aberrant expression of stem cell-related genes in tumors may confer more primitive and aggressive traits affecting clinical outcome. Here, we investigated expression and prognostic value of the neural stem cell marker CD133, as well as of the pluripotency genes LIN28 and OCT4 in 37 samples of pediatric medulloblastoma, the most common and challenging type of embryonal tumor. While most medulloblastoma samples expressed CD133 and LIN28, OCT4 expression was found to be more sporadic, with detectable levels occurring in 48% of tumors. Expression levels of OCT4, but not CD133 or LIN28, were significantly correlated with shorter survival (P B 0.0001). Median survival time of patients with tumors hyperexpressing OCT4 and tumors displaying low/undetectable OCT4 expression were 6 and 153 months, respectively. More importantly, when patients were clinically stratified according to their risk of tumor recurrence, positive OCT4 expression in primary tumor specimens could discriminate patients classified as average risk but which further deceased within 5 years of diagnosis (median survival time of 28 months), a poor clinical outcome typical of high risk patients. Our findings reveal a previously unknown prognostic value for OCT4 expression status in medulloblastoma, which might be used as a further indicator of poor survival and aid postoperative treatment selection, with a particular potential benefit for clinically average risk patients.

Cancerous stem cells can arise from pediatric brain tumors

Proceedings of the …, 2003

Pediatric brain tumors are significant causes of morbidity and mortality. It has been hypothesized that they derive from self-renewing multipotent neural stem cells. Here, we tested whether different pediatric brain tumors, including medulloblastomas and gliomas, contain cells with ...