Akt and c-Myc Induce Stem-Cell Markers in Mature Primary p53−/− Astrocytes and Render These Cells Gliomagenic in the Brain of Immunocompetent Mice

Abstract

Astrocytomas and their most malignant variant glioblastoma multiforme (GBM) represent the vast majority of primary brain tumors. Despite the current progress in neurosurgery, radiation therapy and chemotherapy, most astrocytomas remain fatal disorders. Although brain tumor biology is a matter of intense research, the cell-of-origin and the complete astrocytoma-inducing signaling pathway remain unknown. To further identify the mechanisms leading to gliomagenesis, we transduced primary astrocytes on a p53−/− background with c-Myc, constitutively active myr-Akt or both, myr-Akt and c-Myc. Transduced astrocytes showed oncogene-specific alterations of morphology, proliferation and differentiation. Following prolonged periods of cultivation, oncogene-transduced astrocytes expressed several stem-cell markers. Furthermore, astrocytes coexpressing c-Myc and Akt were tumorigenic when implanted into the brain of immunocompetent C57BL/6 mice. Our results reveal that the loss of p53 combined with oncogene overexpression in mature astrocytes simulates pivotal features of glioma pathogenesis, providing a good model for assessing the development of secondary glioblastomas.

Glia to glioma: A wrathful journey

“…Gradually, successive interplay of differentiation and de-differentiation aid the transformation of radial astrocytic stem cells into neuron of hippocampal region via respective transformation to type 1 to type 2 to type 3 neural stem cells, while the ependymal cells lining the region of cerebrospinal fluid are under the crucial influence of various growth factors and their intricate signaling system such as Notch, Wnt, TGF-β, BMP, etc [61,62] . Periventricular adult NSC has been characterized to express a high level of GFAP-positive astrocytes, which along with combined loss of tumor suppressors p16 and p19 (causing increased expression of eGFr) and loss of p53 (causing over-expression of oncogenes such as c-myc) clearly indicate the de-differentiated property of astrocytes to give origin to GBM [63][64][65] . Parallel to these modifications, the formation of type C progenitor cells from SvZ, which later become restricted to neuroblast and oligodendrocyte precursor cells (OPC), seem to inculcate a number of genetic alterations to manifest initial gliomagenesis [66,67] .…”

Tumor Microenvironment — Perivascular and Perinecrotic Niches

“…By combining activation of specific oncogenes and loss of tumor suppressor genes, it is possible to induce GBM from cortical astrocytes [56]. Examples are the combination of p16(INK4a)-p19(ARF) loss with K-Ras and Akt activation [57], p16(INK4a) and p19(ARF) loss with EGFR activation [58] and p53 loss with myr-Akt and cMyc overexpression in mature astrocytes [59]. Basically, the capacity of transformation inversely correlates with differentiation.…”

Glioblastomas and the Special Role of Adhesion Molecules in Their Invasion

“…Recent studies have shown that brain tumors can arise both from differentiated cells (Friedmann-Morvinski et al 2012;Radke et al 2013) and from the cancer stem-like cells (Chen et al 2012). In some GBM patients, a spatial relationship between the tumor location and the neural stem cell niche is observed, while in other patients this association does not exist (Lim et al 2007).…”