Simulating the impact of a molecular 'decision-process' on cellular phenotype and multicellular patterns in brain tumors

被引:83
作者
Athale, C [1 ]
Mansury, Y [1 ]
Deisboeck, TS [1 ]
机构
[1] Harvard Univ, MIT,Complex Biosyst Modeling Lab, HST,Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA
关键词
glioma; epidermal growth factor receptor; gene-protein network; agent-based model; migration; proliferation;
D O I
10.1016/j.jtbi.2004.10.019
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Experimental evidence indicates that human brain cancer cells proliferate or migrate, yet do not display both phenotypes at the same time. Here, we present a novel computational model simulating this cellular decision-process leading up to either phenotype based on a molecular interaction network of genes and proteins. The model's regulatory network consists of the epidermal growth factor receptor (EGFR), its ligand transforming growth factor-alpha (TGF alpha), the downstream enzyme phospholipaseC-gamma (PLC gamma) and a mitosis-associated response pathway. This network is activated by autocrine TGFa secretion, and the EGFR-dependent downstream signaling this step triggers, as well as modulated by an extrinsic nutritive glucose gradient. Employing a framework of mass action kinetics within a multiscale agent-based environment, we analyse both the emergent multicellular behavior of tumor growth and the single-cell molecular profiles that change over time and space. Our results show that one can indeed simulate the dichotomy between cell migration and proliferation based solely on an EGFR decision network. It turns out that these behavioral decisions on the single cell level impact the spatial dynamics of the entire cancerous system. Furthermore, the simulation results yield intriguing experimentally testable hypotheses also on the sub-cellular level such as spatial cytosolic polarization of PLC gamma towards an extrinsic chemotactic gradient. Implications of these results for future works, both on the modeling and experimental side are discussed. (c) 2004 Elsevier Ltd. All rights reserved.
引用
收藏
页码:469 / 481
页数:13
相关论文
共 80 条
  • [1] MOBILITY MEASUREMENT BY ANALYSIS OF FLUORESCENCE PHOTOBLEACHING RECOVERY KINETICS
    AXELROD, D
    KOPPEL, DE
    SCHLESSINGER, J
    ELSON, E
    WEBB, WW
    [J]. BIOPHYSICAL JOURNAL, 1976, 16 (09) : 1055 - 1069
  • [2] Epidermal growth factor receptor distribution during chemotactic responses
    Bailly, M
    Wyckoff, J
    Bouzahzah, B
    Hammerman, R
    Sylvestre, V
    Cammer, M
    Pestell, R
    Segall, JE
    [J]. MOLECULAR BIOLOGY OF THE CELL, 2000, 11 (11) : 3873 - 3883
  • [3] Berens Michael E., 1999, Neoplasia (New York), V1, P208, DOI 10.1038/sj.neo.7900034
  • [4] Mitogenic signaling and the relationship to cell cycle regulation in astrocytomas
    Besson, A
    Yong, VW
    [J]. JOURNAL OF NEURO-ONCOLOGY, 2001, 51 (03) : 245 - 264
  • [5] TACE is required for the activation of the EGFR by TGF-α in tumors
    Borrell-Pagès, M
    Rojo, F
    Albanell, J
    Baselga, J
    Arribas, J
    [J]. EMBO JOURNAL, 2003, 22 (05) : 1114 - 1124
  • [6] Differential feedback regulation of the MAPK cascade underlies the quantitative differences in EGF and NGF signalling in PC12 cells
    Brightman, FA
    Fell, DA
    [J]. FEBS LETTERS, 2000, 482 (03) : 169 - 174
  • [7] RELATIONSHIP BETWEEN THE MAP KINASE-ACTIVITY AND THE DUAL EFFECT OF EGF ON A431 CELL-PROLIFERATION
    CHAJRY, N
    MARTIN, PM
    PAGES, G
    COCHET, C
    AFDEL, K
    BERTHOIS, Y
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1994, 203 (02) : 984 - 990
  • [8] Mitogenic signaling from the EGF receptor is attenuated by a phospholipase C-gamma/protein kinase C feedback mechanism.
    Chen, P
    Xie, H
    Wells, A
    [J]. MOLECULAR BIOLOGY OF THE CELL, 1996, 7 (06) : 871 - 881
  • [9] EPIDERMAL GROWTH-FACTOR RECEPTOR-MEDIATED CELL MOTILITY - PHOSPHOLIPASE-C ACTIVITY IS REQUIRED, BUT MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVITY IS NOT SUFFICIENT FOR INDUCED CELL-MOVEMENT
    CHEN, P
    XIE, H
    SEKAR, MC
    GUPTA, K
    WELLS, A
    [J]. JOURNAL OF CELL BIOLOGY, 1994, 127 (03) : 847 - 857
  • [10] Mitogens as motogens
    Chicoine, MR
    Silbergeld, DL
    [J]. JOURNAL OF NEURO-ONCOLOGY, 1997, 35 (03) : 249 - 257