Role of extracellular matrix and microenvironment in regulation of tumor growth and LAR-mediated invasion in glioblastoma
(A-F) Trajectories of concentrations of core control system variables (miR-451, AMPK, mTOR) in miR-451-AMPK-mTOR space, in response to low (G = 0.1, (A)), intermediate (G = 0.45, (B)), and high (G = 1.0, (C)) glucose levels. (G-I) Time courses of miR-451 (M), AMPK complex (A), and mTOR (R) in response to low (C), intermediate (F) and high (I) glucose levels. Initial conditions: M(0) = 2.2, A(0) = 3.0, R(0) = 2.2 (solid lines), M(0) = 1.8, A(0) = 3.0, R(0) = 1.8 (dotted lines). *Dotted box = migratory zone (), Solid box = proliferative zone () in (A-F). (J) Steady-state bifurcation diagrams (adapted from ). High and low glucose levels (G) provide an on-off switch of miR-451 over-expression and determine the dichotomous behavior: cell proliferation or migration. Y-axis = steady state (SS) of miR-451 (in (A)), AMPK (in (B)), and mTOR (in (C)). Wb = = a window of bi-stability. (K) Characterization of proliferation and migration of glioma cells (adapted from ). The proliferative region is defined as the region where the miR-451 level is above a threshold, thM (M > thM), the AMPK level is below a threshold, thA (A > thA), and the mTOR level is above a threshold, thR (R > thR), while the levels of miR-451, AMPK, and mTOR in the migratory region satisfies M < thM, A > thA, R < thR. We set thM = 2.0, thA = 2.0, thR = 3.0.