Abstract
The cellular dispersion and therapeutic control of glioblastoma, the most aggressive type of primary brain cancer, depends critically on the migration patterns after surgery and intracellular responses of the individual cancer cells in response to external biochemical and biomechanical cues in the microenvironment. Recent studies have shown that a particular microRNA, miR-451, regulates downstream molecules including AMPK and mTOR to determine the balance between rapid proliferation and invasion in response to metabolic stress in the harsh tumor microenvironment. Surgical removal of main tumor is inevitably followed by recurrence of the tumor due to inaccessibility of dispersed tumor cells in normal brain tissue. In order to address this multi-scale nature of glioblastoma proliferation and invasion and its response to conventional treatment, we propose a hybrid model of glioblastoma that analyses spatio-temporal dynamics at the cellular level, linking individual tumor cells with the macroscopic behaviour of cell organization and the microenvironment, and with the intracellular dynamics of miR-451-AMPK-mTOR signaling within a tumour cell. The model identifies a key mechanism underlying the molecular switches between proliferative phase and migratory phase in response to metabolic stress and biophysical interaction between cells in response to fluctuating glucose levels in the presence of blood vessels (BVs). The model predicts that cell migration, therefore efficacy of the treatment, not only depends on oxygen and glucose availability but also on the relative balance between random motility and strength of chemoattractants. Effective control of growing cells near BV sites in addition to relocalization of invisible migratory cells back to the resection site was suggested as a way of eradicating these migratory cells.
Highlights
Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor with a median survival time of approximately 15 months from the time of diagnosis [1,2,3]
We propose that chemoattractant injection on the periphery of the tumor resection site immediately after surgery would bring most of those cells back to the resection site, making them detectable by Magnetic resonance imaging (MRI), and the follow-up surgery or radiation may improve survival rate of the patients by eradicating the remaining tumor cells
The glioma cells seem to posses specific characteristics that allow for diffusive infiltration [37]
Summary
Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor with a median survival time of approximately 15 months from the time of diagnosis [1,2,3]. In order to sustain their rapid growth, cancerous cells modify their metabolic activity by increasing glycolysis even in the presence of oxygen. This process requires high levels of glucose uptake and is known as the Warburg effect [7, 8]. Cancer cells activate the 50adenosine monophosphate activated protein kinase (AMPK) pathway, the master cellular sensor of energy availability [12]. This way they enhance glucose uptake and to conserve energy [12], avoiding cell death
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