Precritical State Transition Dynamics in the Attractor Landscape of a Molecular Interaction Network Underlying Colorectal Tumorigenesis.
Precritical State Transition Dynamics in the Attractor Landscape of a Molecular Interaction Network Underlying Colorectal Tumorigenesis.
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DOI：
10.1371/journal.pone.0140172
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Cho KH
中科院分区：
文献类型：
--
作者：
Chu H;Lee D;Cho KH
从系统科学的角度来看，肿瘤发生可以被假设为一个关键的转变（从一个状态到另一个突然转变）之间的增殖和凋亡的吸引子的状态空间的分子相互作用网络，吸引子被定义为一个稳定的状态，所有的初始状态最终收敛，收敛的区域被称为吸引盆。在临界转变之前，由于分子相互作用中固有的随机性引起的噪声，细胞状态可能在凋亡吸引子的吸引盆和增殖吸引子的吸引盆之间过渡。当细胞状态接近吸引盆的边界附近时，这种闪烁状态转换（来自噪声影响的替代吸引子的吸引盆之间的状态转换）将变得更加频繁，这可以增加相应盆大小的估计的变化。为了研究结直肠肿瘤的发生，我们构建了一个随机布尔网络模型的分子相互作用网络，其中包含一组重要的蛋白质已知参与癌症。特别是，我们考虑了驱动结直肠肿瘤发生的20个基因突变的100个代表性序列。我们通过检查凋亡、静止和增殖吸引子的盆地大小沿着结直肠肿瘤发生过程中基因突变的顺序积累来研究癌细胞的外观。我们引入了一种检测闪烁状态转换的措施，作为对三表型吸引子的盆大小的估计的变化，从噪声的影响。有趣的是，我们发现，在一定水平的随机噪声下，在结直肠肿瘤发生期间，大多数基因突变序列中的细胞癌变之前，该测量值突然增加。这表明频繁的闪烁状态转换可能是结直肠肿瘤发生的一种前临界现象。
From the perspective of systems science, tumorigenesis can be hypothesized as a critical transition (an abrupt shift from one state to another) between proliferative and apoptotic attractors on the state space of a molecular interaction network, for which an attractor is defined as a stable state to which all initial states ultimately converge, and the region of convergence is called the basin of attraction. Before the critical transition, a cellular state might transit between the basin of attraction for an apoptotic attractor and that for a proliferative attractor due to the noise induced by the inherent stochasticity in molecular interactions. Such a flickering state transition (state transition between the basins of attraction for alternative attractors from the impact of noise) would become more frequent as the cellular state approaches near the boundary of the basin of attraction, which can increase the variation in the estimate of the respective basin size. To investigate this for colorectal tumorigenesis, we have constructed a stochastic Boolean network model of the molecular interaction network that contains an important set of proteins known to be involved in cancer. In particular, we considered 100 representative sequences of 20 gene mutations that drive colorectal tumorigenesis. We investigated the appearance of cancerous cells by examining the basin size of apoptotic, quiescent, and proliferative attractors along with the sequential accumulation of gene mutations during colorectal tumorigenesis. We introduced a measure to detect the flickering state transition as the variation in the estimate of the basin sizes for three-phenotype attractors from the impact of noise. Interestingly, we found that this measure abruptly increases before a cell becomes cancerous during colorectal tumorigenesis in most of the gene mutation sequences under a certain level of stochastic noise. This suggests that a frequent flickering state transition can be a precritical phenomenon of colorectal tumorigenesis.