Dedifferentiation of Neurons and Astrocytes by Oncogenes Can Induce Gliomas in Mice

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in humans. Here, we show that gliomas can originate from differentiated cells in the central nervous system (CNS), including cortical neurons. Transduction by oncogenic lentiviral vectors of neural stem cells (NSCs), astrocytes, or even mature neurons in the brain of mice can give rise to malignant gliomas. All the tumors, irrespective of the site of injection (initiating population), share common features of high expression of stem or progenitor markers and low expression of differentiation markers. Microarray analysis revealed that tumors of astrocytic and neuronal origin match the mesenchymal GBM subtype. We propose that most differentiated cells in the CNS upon defined genetic alterations undergo dedifferentiation to generate a NSC or progenitor state to initiate and maintain the tumor progression, as well as to give rise to the heterogeneous populations observed in malignant gliomas.

Retinoic acid signaling and neuronal differentiation

“…It is currently unknown whether most brain tumors originate from mutated NSCs within the perivascular niche [237,238] or if normal cells acquire mutations that cause their dedifferentiation into immature, carcinogenic neural progenitors [239]. Tumorigenesis could take a hierarchical or linear pathway from cancer stem cells to malignant tumor cells or could result from normal tissue losing differentiation markers (e.g., b-Tubulin) and gaining proliferation markers (e.g., Sox2, Nestin) (reviewed in [240]).…”

“…Tumorigenesis could take a hierarchical or linear pathway from cancer stem cells to malignant tumor cells or could result from normal tissue losing differentiation markers (e.g., b-Tubulin) and gaining proliferation markers (e.g., Sox2, Nestin) (reviewed in [240]). Within the last few years, dedifferentiation as a mode of action in tumorigenesis has been re-evaluated and re-popularized in a variety of cancers including intestinal [241,242], respiratory [243], breast [244], and brain [239,245]. Molecular evidence from Drosophila revealed that dedifferentiation is associated with the loss of a neural-specific zinc-finger protein Lola-N that normally functions to repress cell cycle genes like cdc25 in post-mitotic neurons [245].…”

Early-Stage Glioblastomas: MR Imaging–Based Classification and Imaging Evidence of Progressive Growth

“…We believe this finding may serve as indirect evidence, along with that found in the mouse glioma models, 15,16 to suggest that some GBs may originate from GM. Moreover, the WM FLAIR/T2-weighted hyperintensity of type II lesions may correspond to GB infiltration rather than just edema.…”

“…15 Another study also found that a glioblastoma could originate from cortical neurons. 16 However, there is always concern about whether results from animal studies can be transferred to humans. It is not known whether gliomas growing in mice with genetic alterations and different microenvironments resemble spontaneous human GBs.…”

Cancer stem cells don’t waste their time cleaning—low proteasome activity, a marker for cancer stem cell function

“…As is becoming more and more clear, extrinsic factors such as the microenvironment are crucial for stem cell function (30,84). Bidirectional interconversion between non-CSC's and CSC's has been demonstrated in several types of cancer (85)(86)(87). This tumor cell plasticity might be an important reason for therapy failure.…”