Medulloblastoma, the most common brain cancer in children, may arise from biological abnormalities in neural stem cells or neuronal precursors during embryonic development. Indeed, the clinical challenges of treatment resistance and tumor recurrence in patients with medulloblastomas appear to be related to the presence of cancer stem cells within medulloblastoma tumors.
Brazilian researchers working in the Cancer and Neurobiology Laboratory at the Federal University of Rio Grande do Sul (Universidade Federal do Rio Grande do Sul, UFRGS), its university hospital (Hospital de Clínicas de Porto Alegre, HCPA), and the Children's Cancer Institute (Instituto do Câncer Infantil, ICI) in Porto Alegre, in collaboration with Canadian scientists working at the Hospital for Sick Children and the University of Toronto, analyzed gene expression in medulloblastoma tumors from patients. They demonstrated that all medulloblastoma tumor subtypes express two stem cell markers, namely the proto-oncogene protein BMI1 and the cell surface protein CD133. When DNA is in a tightly compacted chromatin state, the expression of genes that promote cell differentiation is reduced, thereby keeping cancer cells in a stem cell-like state. Accordingly, this team of researchers treated medulloblastoma cells with an epigenetic compound that inhibits histone deacetylase (HDAC) activity, leading to chromatin relaxation, and found that they could thereby reduce BMI1 and CD133 expression and hinder tumor cell viability.
Further analysis of tumor samples revealed that expression of these "stemness" markers appeared to be associated with activity of the mitogen-activated protein kinase (MAPK)/ERK intracellular signaling pathway. To test the importance of MAPK/ERK signaling in carcinogenesis, the researchers examined the effects of inhibiting MAPK/ERK in medulloblastoma cells. They found that MAPK/ERK inhibition reduced the cellular content of stemness markers and decreased cancer stem cell formation in culture. Importantly, these antitumor effects were potentiated when the tumor cells were exposed to HDAC inhibitors and MAPK/ERK inhibitors at the same time.
According to the lead author of the article reporting these findings, Dr. Mariane da Cunha Jaeger, "these findings suggest that combining HDAC and MAPK/ERK inhibitors may be a novel and effective approach to preventing medulloblastoma cell proliferation by altering the tumor stem cell phenotype".
The study findings will be reported in an upcoming issue of the Journal of Molecular Neuroscience. Preprints of the report are available at http://www.biorxiv.org. Professor Rafael Roesler, senior author of the study, underscores that this work demonstrates how "integrating gene expression data from patient tumors with cell culture experiments can enable the identification of novel potential therapy combinations".
Commenting on the research team's research outlook in light of these promising findings, the ICI Research Director Dr. André T. Brunetto has said, "We are focusing on finding translational opportunities that can be explored in innovative clinical studies on childhood cancers".
Journal of Molecular Neuroscience