Sheila R. Alcantara Llaguno

Malignant Astrocytomas Originate from Neural Stem/Progenitor Cells in a Somatic Tumor Suppressor Mouse Model

Malignant astrocytomas are infiltrative and incurable brain tumors. Despite profound therapeutic implications, the identity of the cell (or cells) of origin has not been rigorously determined. We previously reported mouse models based on conditional inactivation of the human astrocytoma-relevant tumor suppressors p53, Nf1, and Pten, wherein through somatic loss of heterozygosity, mutant mice develop tumors with 100% penetrance. In the present study, we show that tumor suppressor inactivation in neural stem/progenitor cells is both necessary and sufficient to induce astrocytoma formation. We demonstrate in vivo that transformed cells and their progeny undergo infiltration and multilineage differentiation during tumorigenesis. Tumor suppressor heterozygous neural stem/progenitor cultures from presymptomatic mice show aberrant growth advantage and altered differentiation, thus identifying a pretumorigenic cell population.

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.

Glioblastoma multiforme: a perspective on recent findings in human cancer and mouse models

Gliomas are the most frequently occurring primary malignancies in the central nervous system, and glioblastoma multiforme (GBM) is the most common and most aggressive of these tumors. Despite vigorous basic and clinical studies over past decades, the median survival of patients with this disease remains at about one year. Recent studies have suggested that GBMs contain a subpopulation of tumor cells that displays stem cell characteristics and could therefore be responsible for in vivo tumor growth. We will summarize the major oncogenic pathways abnormally regulated in gliomas, and review the recent findings from mouse models that our laboratory as well as others have developed for the study of GBM. The concept of cancer stem cells in GBM and their potential therapeutic importance will also be discussed.

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. (Clin Cancer Res 2009;15(23):7124–9)

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.