Exploring brain cancer pathogenesis in a novel mouse model of glioblastoma (GBM)

Date
2018-06-08
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Abstract
The molecular architecture of glioblastoma (GBM) has been well documented, but the cause of the disease, especially the primary adult form, remains elusive. Although it has been hypothesized that amplification of platelet-derived growth factor A (PDGFA) and p53 mutations are early alterations, how these orchestrate tumour initiation has yet to be discerned. Considering the poor prognosis and minimal benefit received from current treatment, understanding the early events of tumour initiation may be the only way to find more effective or preventative treatment strategies. It is well known that p53 has multiple functions as a tumour suppressor, but the outcome of its loss and the role this aberration plays in GBM remains unknown. Similarly, as a growth factor, PDGFA is hypothesized to promote rapid proliferation leading to cellular transformation, but this has yet to be demonstrated or modelled in GBM. Using a mouse model of GBM developed in the Cairncross lab, I show that, unlike most growth factors, subventricular zone (SVZ) cells struggle to proliferate in PDGFA. When p53 is present, PDGFA-cultured SVZ cells undergo apoptosis, eventually resulting in a total loss of cell culture viability. When p53 is absent, cells undergo a crisis-like period, and eventually transform. Detailed characterization of the crisis period in PDGFA demonstrates the cells undergo abnormal mitosis, likely due to abnormal centrosome numbers, and sustain gross chromosomal alterations that lead to alterations in pathways similar to those observed in human GBM. These analyses clarify how PDGFA and the absence of p53 promote gliomagenesis: PDGFA supports attenuated proliferation concurrent to inducing chromosomal instability, while the absence of p53 enables cells to evade apoptosis and continue through the crisis period until transformation is achieved.
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Keywords
Glioblastoma, PDGFA, p53
Citation
Bohm, A. K. (2018). Exploring brain cancer pathogenesis in a novel mouse model of glioblastoma (GBM) (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/31979