Little progress has been made in the treatment of gliomas during the past 25 years. One reason is our poor understanding of the cell of origin in these tumors and of the mechanisms that bring that cell into a malignant state. This review argues that gliomas arise from neural stem cells and discusses the clinical implications of this concept.

Neural stem cells and the origin of gliomas.

Publisher Summary This chapter reviews the sequence of cellular and other changes during cancer development in selected sites in experimental animals and in humans. It highlights the similarities and differences among the carcinogenic processes and discusses the evident generalities and working hypotheses derived from the analyses. It also discusses some perspective concerning the possible relationship of carcinogenesis to other types of chronic pathological processes such as some forms of adaptation and evolution. Major emphasis is given to three sites—namely, skin, liver, and breast. Several other sites or types of neoplasms are also discussed in the chapter, including urinary bladder, brain, kidney, uterine cervix, and foreign-body sarcoma. It focuses on the development of cancer with chemicals in experimental animals and in humans. To date, the major evidence for a beneficial role for new cell populations occurring during the preneoplastic phase of carcinogenesis concerns the liver. However, it seems appropriate to explore other systems from this point of view. In other organs or tissues, appropriate physiological or environmental factors should be sought as possible influences on early carcinogen-induced new cell populations. These influences might well constitute naturally occurring “promoting” environments in at least some carcinogenic process.

The sequential analysis of cancer development.

Recent studies demonstrate that glioblastoma multiforme (GBM) contains a subpopulation of cancer cells with stem cell characteristics, including self-renewal and multipotentiality; these cancer stem cells can propagate tumors in vivo.1–4 The adult human brain harbors astrocyte-like neural stem cells within the subventricular zone (SVZ), which is located just under the ependyma of the brain ventricles5,6 (Fig. 1A). In animal models, gliomas—including GBM—can be induced from SVZ cells.7–9 These accumulating data have thus given rebirth to the notion that human gliomas may arise from SVZ neural stem cells (reviewed in Sanai et al.10), an idea that was first suggested in the first half of the 20th century.11–13



Fig. 1

(A) Neural stem cells (red circles) are found in the walls of the adult brain ventricles (blue). An axial section (black trapezoid) is indicated on this cartoon, representing the approximate level of section of the MR images shown. (B) Multiple hypotheses ...



GBM is a pathologically and clinically heterogeneous disease. While some GBMs may arise from transformed SVZ stem cells, other gliomas may be initiated by neoplastic transformation of non-SVZ progenitor cells or mature glial cells that have undergone dedifferentiation14 (Fig. 1B). Identifying a subset of GBMs that are related to tumor stem cells in the SVZ would have significant therapeutic implications:15 stem-cell–derived GBM may need treatment that attends to both the primary lesion(s) and the SVZ. To better understand the histogenetic and clinical heterogeneity of GBM, we developed an MRI-based classification of GBMs based on their involvement of the SVZ and cortex.

We identified a subset of GBMs that are more likely to be SVZ stem cell – related based on the spatial relationship of the tumor to the SVZ, involvement of cortex, multifocality, and recurrence pattern. Another GBM subset is more likely related to non-SVZ progenitor cells or dedifferentiated glial cells. This study provides MRI evidence suggesting a relationship between a subset of GBMs and tumor stem cells in the SVZ.

Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype

We report the development of a new method to induce glioblastoma multiforme in adult immunocompetent mice by injecting Cre-loxP–controlled lentiviral vectors expressing oncogenes. Cell type- or region-specific expression of activated forms of the oncoproteins Harvey-Ras and AKT in fewer than 60 glial fibrillary acidic protein–positive cells in the hippocampus, subventricular zone or cortex of mice heterozygous for the gene encoding the tumor suppressor Tp53 were tested. Mice developed glioblastoma multiforme when transduced either in the subventricular zone or the hippocampus. However, tumors were rarely detected when the mice were transduced in the cortex. Transplantation of brain tumor cells into naive recipient mouse brain resulted in the formation of glioblastoma multiforme–like tumors, which contained CD133+ cells, formed tumorspheres and could differentiate into neurons and astrocytes. We suggest that the use of Cre-loxP–controlled lentiviral vectors is a novel way to generate a mouse glioblastoma multiforme model in a region- and cell type-specific manner in adult mice.

https://www.salk.edu/pdf/otmd/Verma/S07006B/NatureMedicine_152008.pdf

Development of a novel mouse glioma model using lentiviral vectors

The early events in neoplastic transformation can be understood only by comparison of the neoplastic cell with its nontransformed counterpart. The most common central nervous system gliomas traditionally are thought to arise from mature astrocytes and oligodendrocytes. We examined the possibility that gliomas arise from a population of glia that has properties of oligodendrocyte progenitors. These glial cells express the NG2 chondroitin sulfate proteoglycan and the α receptor of platelet-derived growth factor in vivo. We identified NG2 and the α receptor of platelet-derived growth factor expression in tissue from seven of seven oligodendrogliomas, three of three pilocytic astrocytomas, and one of five glioblastoma multiforme. These data provide evidence that glial tumors arise from glial progenitor cells. Molecules expressed by these progenitor cells should be considered as targets for novel therapeutics.

https://www.pnas.org/content/pnas/96/18/10361.full.pdf

Expression of oligodendrocyte progenitor cell antigens by gliomas: Implications for the histogenesis of brain tumors

A sequential study of rat brains treated transplacentally with the neurotropic carcinogen ethylnitrosourea reveals small foci of cell proliferations from the age of 8 weeks. These lesions consist mainly of undifferentiated cells of the subependymal plate type. They occur in those areas in which gliomas develop and represent the earliest, histologically detectable, changes in the development of brain tumours.

P. L. Lantos

Papers

The origin of experimental brain tumours: a sequential study.