title: Strategies of eradicating glioma cells: a multi-scale mathematical model with MiR-451-AMPK-mTOR control.
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.
authors: Department of Mathematics, Konkuk University, Seoul, 143-701, Republic of Korea; Department of Mathematics, Ohio State University, Columbus, OH 43210, USA.
authors: Yangjin
authors: Y
authors: Kim
authors: Division of Mathematics, University of Dundee, Dundee, UK; Department of Mathematics, Swansea University, Swansea, UK.
authors: Gibin
authors: G
authors: Powathil
authors: Department of Mathematics, Konkuk University, Seoul, 143-701, Republic of Korea.
authors: Hyunji
authors: H
authors: Kang
authors: Division of Mathematics, University of Dundee, Dundee, UK.
authors: Dumitru
authors: D
authors: Trucu
authors: Department of Physics, Konkuk University, Seoul, 143-701, Republic of Korea.
authors: Hyeongi
authors: H
authors: Kim
authors: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston MA 02115, USA.
authors: Sean
authors: S
authors: Lawler
authors: Division of Mathematics, University of Dundee, Dundee, UK.
authors: Mark
authors: M
authors: Chaplain
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D000465:Algorithms; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D016896:Treatment Outcome; D059016:Tumor Microenvironment
chemical_list: C531201:MIRN451 microRNA, human; D035683:MicroRNAs; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
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