Chu Hyunho, Lee Daewon, Cho Kwang-Hyun
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
PLoS One. 2015 Oct 6;10(10):e0140172. doi: 10.1371/journal.pone.0140172. eCollection 2015.
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.
从系统科学的角度来看，肿瘤发生可以被假设为分子相互作用网络状态空间中增殖吸引子和凋亡吸引子之间的关键转变（从一种状态到另一种状态的突然转变），其中吸引子被定义为所有初始状态最终收敛的稳定状态，收敛区域称为吸引域。在关键转变之前，由于分子相互作用中固有随机性引起的噪声，细胞状态可能在凋亡吸引子的吸引域和增殖吸引子的吸引域之间转变。随着细胞状态接近吸引域边界，这种闪烁状态转变（由于噪声影响，替代吸引子的吸引域之间的状态转变）会变得更加频繁，这会增加各自吸引域大小估计的变化。为了研究结直肠癌发生的这种情况，我们构建了一个分子相互作用网络的随机布尔网络模型，该模型包含一组已知参与癌症的重要蛋白质。特别地，我们考虑了驱动结直肠癌发生的20种基因突变的100个代表性序列。我们通过检查凋亡、静止和增殖吸引子的吸引域大小以及结直肠癌发生过程中基因突变的顺序积累来研究癌细胞的出现。我们引入了一种测量方法来检测闪烁状态转变，即由于噪声影响，三种表型吸引子的吸引域大小估计的变化。有趣的是，我们发现在一定水平的随机噪声下，在大多数基因突变序列的结直肠癌发生过程中，这种测量值在细胞癌变之前会突然增加。这表明频繁的闪烁状态转变可能是结直肠癌发生的临界前现象。
