Cell of origin of glioma: biological and clinical implications.

The cellular origin of gliomas remains a topic of controversy in cancer research. Advances in neurobiology, molecular genetics, and functional genomics have ushered new insights through exploiting the development of more sophisticated tools to address this question. Diverse distinct cell populations in the adult brain have been reported to give rise to gliomas, although how these studies relate physiologically to mechanisms of spontaneous tumour formation via accumulation of tumour-initiating mutations within a single cell are less well developed. Recent studies in animal models indicate that the lineage of the tumour-initiating cell may contribute to the biological and genomic phenotype of glioblastoma. These results suggest that the cell of origin may not only serve as a source of diversity for these tumours, but may also provide new avenues for improved diagnostics and therapeutic targeting that may prolong the lives of patients.

Cell of Origin and Cancer Stem Cells in Tumor Suppressor Mouse Models of Glioblastoma.

The cellular origins and the mechanisms of progression, maintenance of tumorigenicity, and therapeutic resistance are central questions in the glioblastoma multiforme (GBM) field. Using tumor suppressor mouse models, our group recently reported two independent populations of adult GBM-initiating central nervous system progenitors. We found different functional and molecular subtypes depending on the tumor-initiating cell lineage, indicating that the cell of origin is a driver of GBM subtype diversity. Using an in vivo model, we also showed that GBM cancer stem cells (CSCs) or glioma stem cells (GSCs) contribute to resistance to chemotherapeutic agents and that genetic ablation of GSCs leads to a delay in tumor progression. These studies are consistent with the cell of origin and CSCs as critical regulators of the pathogenesis of GBM.

Adult Lineage-Restricted CNS Progenitors Specify Distinct Glioblastoma Subtypes.

A central question in glioblastoma multiforme (GBM) research is the identity of the tumor-initiating cell, and its contribution to the malignant phenotype and genomic state. We examine the potential of adult lineage-restricted progenitors to induce fully penetrant GBM using CNS progenitor-specific inducible Cre mice to mutate Nf1, Trp53, and Pten. We identify two phenotypically and molecularly distinct GBM subtypes governed by identical driver mutations. We demonstrate that the two subtypes arise from functionally independent pools of adult CNS progenitors. Despite histologic identity as GBM, these tumor types are separable based on the lineage of the tumor-initiating cell. These studies point to the cell of origin as a major determinant of GBM subtype diversity.

Suppression of peroxiredoxin 4 in glioblastoma cells increases apoptosis and reduces tumor growth.

Glioblastoma multiforme (GBM), the most common and aggressive primary brain malignancy, is incurable despite the best combination of current cancer therapies. For the development of more effective therapies, discovery of novel candidate tumor drivers is urgently needed. Here, we report that peroxiredoxin 4 (PRDX4) is a putative tumor driver. PRDX4 levels were highly increased in a majority of human GBMs as well as in a mouse model of GBM. Reducing PRDX4 expression significantly decreased GBM cell growth and radiation resistance in vitro with increased levels of ROS, DNA damage, and apoptosis. In a syngenic orthotopic transplantation model, Prdx4 knockdown limited GBM infiltration and significantly prolonged mouse survival. These data suggest that PRDX4 can be a novel target for GBM therapies in the future.

Stem cells in brain tumor development.

Gliomas are highly infiltrative and aggressive brain tumors that are resistant to conventional therapies. Recent studies have implicated neural stem cells (NSCs) in brain tumor initiation and development. Subpopulations of stem-like cancer cells have also been isolated from brain tumors, and are purported to be important mediators of malignant behavior and therapeutic resistance. Similar signaling pathways may be operative in both neural and cancer stem cells, suggesting that neural developmental systems may provide important clues on brain tumorigenesis. Transcriptional regulators such as microRNAs may also contribute to NSC and brain tumor development. Understanding the biology of neural and cancer stem cells and their regulatory mechanisms may directly impact current efforts for more directed therapeutics against these highly aggressive tumors.

Signaling in malignant astrocytomas: role of neural stem cells and its therapeutic implications.

Malignant astrocytomas are infiltrative and aggressive brain tumors. Conventional forms of therapy have not been effective in controlling this incurable disease. Recent advances in understanding the molecular biology of these tumors have revealed potential mechanisms by which astrocytoma cells undergo tumor initiation, progression, and maintenance, as well as possible avenues for targeted therapeutics. Studies on the role of neural stem cells as cells of origin and tumor-propagating cells have also greatly increased our understanding of the biology and clinical behavior of these tumors. An integrated view of the genetics, signal transduction, and cell biology of astrocytomas, as well as clinical data from patients, will provide a more useful approach in designing novel therapies for this devastating disease.