| Abstract |
Glioblastoma is the most malignant brain cancer among adults, according to the World Health Organization (WHO). It is characterized by excessive proliferation and infiltration, along with extensive inter- and intra-tumoral heterogeneity. Current standard therapy includes maximal safe surgical resection, followed by concurrent radiation and/or Glioblastoma adjuvant chemotherapy. However, in spite of intensive treatment, patients have a poor prognosis, due to the high recurrence potential of Glioblastoma. Identifying Glioblastoma biomarkers could help diagnose the disease earlier, characterize specific features regarding the tumor physiology and aggressiveness and even help in building new therapeutic strategies.
There is recent evidence suggesting, high expression of the Promyelocytic Leukemia Protein (PML), a tumor suppressor and cell regulator, in primary Glioblastoma samples. PML is expressed in all tissues and implicated in various ways to cancer biology. In brain, PML participates in the physiological migration of the neural progenitor cells, which have been also hypothesized to serve as the cell of origin of Glioblastoma. Recent studies in PML knocked-down mice indicate a common PML-mediated migratory pathway in both adult neurogenesis and Glioblastoma invasion within the central nervous system.
In this work, the invasive capacity of the well-described T98G and U87MG Glioblastoma cell lines is being explored. The role of PML in Glioblastoma pathophysiology, regarding the cell growth and invasive properties of the tumor, is investigated under PML overexpression in the U87MG cells. A combined in vitro-in silico approach is presented by using three dimensional biological models and translating biological observations in order to initialize, parametrize and validate a discrete mathematical model. The PML-mediated effects are estimated and visualized using conventional optical, along with light sheet fluorescence and confocal microscopy and the Glioblastoma tumor evolution is simulated in silico, in order to differentiate the observed biological phenomena.
Our overall findings indicate that PML overexpression suppresses cell proliferation, while it induces the invasive capacity of the U87MG Glioblastoma cells, by regulating distinct cellular mechanisms. Elucidating further the role of PML in Glioblastoma physiology could set PML as a potential biomarker of the tumor physiology and as a therapeutic target aiming at eliminating multiple sub-clones depending on their proliferative and/or invasive phenotype within the heterogeneous Glioblastoma tumor mass.
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Image guided brain cancer modeling : the role of promyelocytic leukemia protein in glioblastoma physiology
