The cell of origin dictates the temporal course of neurofibromatosis-1 (Nf1) low-grade glioma formation

Abstract

Low-grade gliomas are one of the most common brain tumors in children, where they frequently form within the optic pathway (optic pathway gliomas; OPGs). Since many OPGs occur in the context of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome, we have previously employed Nf1 genetically-engineered mouse (GEM) strains to study the pathogenesis of these low-grade glial neoplasms. In the light of the finding that human and mouse low-grade gliomas are composed of Olig2+ cells and that Olig2+ oligodendrocyte precursor cells (OPCs) give rise to murine high-grade gliomas, we sought to determine whether Olig2+ OPCs could be tumor-initiating cells for Nf1 optic glioma. Similar to the GFAP-Cre transgenic strain previously employed to generate Nf1 optic gliomas, Olig2+ cells also give rise to astrocytes in the murine optic nerve in vivo. However, in contrast to the GFAP-Cre strain where somatic Nf1 inactivation in embryonic neural progenitor/stem cells (Nf1flox/mut; GFAP-Cre mice) results in optic gliomas by 3 months of age in vivo, mice with Nf1 gene inactivation in Olig2+ OPCs (Nf1flox/mut; Olig2-Cre mice) do not form optic gliomas until 6 months of age. These distinct patterns of glioma latency do not reflect differences in the timing or brain location of somatic Nf1 loss. Instead, they most likely reflect the cell of origin, as somatic Nf1 loss in CD133+ neural progenitor/stem cells during late embryogenesis results in optic gliomas at 3 months of age. Collectively, these data demonstrate that the cell of origin dictates the time to tumorigenesis in murine optic glioma.

Insights into optic pathway glioma vision loss from mouse models of neurofibromatosis type 1

“…Finally, studies using the Nf1 flox/null , Prom1‐cre mouse strain, in which Cre recombinase activity is induced with tamoxifen exposure (L. Zhu et al, ), assessed the consequence of somatic Nf1 inactivation at different developmental time points. In these studies, Nf1 loss in Prom1 ‐expressing cells was required prior to postnatal day 1 for optic gliomas to form, arguing that there is a developmental window during which somatic Nf1 gene inactivation must occur in order to facilitate gliomagenesis (Solga et al, ). Taken together, these findings argue that mouse Nf1 optic glioma formation is heavily influenced by the cell of origin and by the requirement for somatic Nf1 gene inactivation to occur in specific cell types during brain development, consistent with the clinical observation that NF1‐OPGs are largely a tumor of young children.…”

“…Commensurately, OPCs may also serve as a potential cell of origin for optic glioma. Somatic Nf1 loss in Olig2 ‐expressing cells in an Nf1 GEM model (i.e., Nf1 flox/null , Olig2‐cre mice) leads to optic gliomagenesis, however, with a prolonged latency (6 months vs. 3 months) relative to neuroglial stem/progenitor cells expressing Gfap , Prom1 , or Blbp (Solga et al, ).…”

“…Second, specifically in female mice, gonadal estradiol acts through the estrogen receptor β (ERβ) to stimulate Nf1‐ mutant microglia, thereby causing Nf1 ‐mutant RGC death, thinning of the RNFL (which comprises RGC axons), and decreased visual acuity (Diggs‐Andrews, Brown, Gianino, Rubin, et al, ; Toonen, Solga, Ma, & Gutmann, ). Sexually dimorphic retinal pathology in Nf1 optic glioma mice is independent of tumor size and can be corrected by pharmacologic inhibition of microglial activation, ERβ blockade, or chemical or surgical ovariectomy (Toonen, Solga, et al, ). In this cell nonautonomous mechanism, microglia are hypothesized to secrete neurotoxic cytokines (e.g., IL‐1β) that either directly or indirectly damage RGC axons (Figure d), perhaps through disruption of normal axo‐glial contacts as seen in other forms of axonal injury (Howell et al, ).…”

Spatiotemporal switching signals for cancer stem cell activation in pediatric origins of adulthood cancer: Towards a watch-and-wait lifetime strategy for cancer treatment

“…All these imply “the single-cell origin of cancer in colon cancer, which is supported for clonal origins of synchronous multifocal tumors in the hepatobiliary and pancreatic system”[ 49 ] and in the same subclone of cells of colorectal cancer[ 50 ]. Another report shows the patterns of glioma cell of origin, as somatic Nf1 loss in CD133+ neural progenitor/stem cells during late embryogenesis results in optic gliomas at three months of age, demonstrating that the cell of origin dictates the time to tumorigenesis[ 7 ], which can expose a break time or a “therapeutic window” of cancer progression[ 40 ].…”

“…“Cancer genomic research has come to a crossroads with the realization that intratumoral spatial and temporal heterogeneity is a confounding factor”[ 4 ]. The discovery of this intratumoral spatiotemporal heterogeneity drives our understanding of epigenetics, which in turn defines the role of the environment[ 5 ], including chemical factors, cellular[ 6 ], and physical factors like tissue elasticity[ 7 ]. Managing tumor microenvironment may offer a holistic regimen for cancer patients with better ratio of benefit over risks[ 8 ].…”