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

Abstract

SUMMARY Malignant astrocytomas are infiltrative and incurable brain tumors. Despite profound therapeutic implications, the identity of the cell(s) of origin has not been rigorously determined. We previously reported mouse models based on conditional inactivation of 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 multi-lineage differentiation during tumorigenesis. Tumor suppressor heterozygous neural stem/progenitor cultures from pre-symptomatic mice show aberrant growth advantage and altered differentiation, thus identifying a pre-tumorigenic cell population. Significance Identification of the original cell that gives rise to a tumor and whether it is a limited cell type has crucial implications for understanding cancer development. This knowledge is also requisite for rigorous investigation of tumor initiation mechanisms. Using fully penetrant mouse models, we identify neural stem/progenitor cells as cancer-initiating cells and derive insight into the behavior of these tumors. We also report malignant astrocytoma mouse models wherein tumor suppressor inactivation at embryonic, early postnatal, or adult ages induces tumor formation, and demonstrates the capacity of tumor cells to differentiate within the tumor. Our studies on pre-symptomatic mutant progenitor cultures indicate that the disease could be disseminating and acquire growth advantage long before the onset of clinical manifestations.

Cytomegalovirus Contributes to Glioblastoma in the Context of Tumor Suppressor Mutations

“…26). We established and maintained neurosphere cultures from mouse subventricular zone (SVZ) as previously described (27, 28), except using EGF from Daewoong Pharmaceutical Co., Ltd and TrypLE (Invitrogen). For infection, we seeded cells in 6-well plates and treated with CMV or mock (purified extract from uninfected fibroblasts) the next day.…”

Key concepts in glioblastoma therapy

“…Because glioblastoma TICs share many common properties with neural stem cells, it is proposed that TICs originated from stem cells. While there are some data supporting this hypothesis,6 the universality of this hypothesis remains controversial.…”

“…Protein markers to prospectively identify and isolate these putative TICs have been reported, such as the transmembrane glycoprotein CD133 (prominin-1) in glioblastomas 6. However, the value of CD133 as a single marker of glioblastoma TICs remains controversial, partly because CD133-negative glioblastoma cells could also give rise to tumours in an intracranial mouse xenograft model 38–40.…”

“…The best available evidence suggests that glioblastomas originate from cells that give rise to glial cells 6 7. These glial-derived tumours are graded by WHO into four categories, termed WHO grade 1–4.…”

Eliminating barriers to personalized medicine

“…With the development of numerous accurate small-animal (genetically engineered mouse; GEM) models of NF1-associated nervous system tumors (table 1), [8][9][10][11][12][13][14][15][16][17][18] the creation of the NF Clinical Trials Consortium, 19 and the establishment of response criteria for NF1 clinical trials, 20 the stage has been set for the discovery and validation of promising therapeutic strategies and their translation to people affected with NF1. However, despite these advances, there are currently no effective therapies, which likely reflects the striking biological and clinical heterogeneity inherent to this condition.…”