Méndez-López Luis Fernando, Davila-Velderrain Jose, Domínguez-Hüttinger Elisa, Enríquez-Olguín Christian, Martínez-García Juan Carlos, Alvarez-Buylla Elena R
Centro de Investigación y Desarrollo en Ciencias de la Salud (CIDICS), Universidad Autonoma de Nuevo Leon, A. P. 14-740, México, 07300, D.F, México.
Centro de Ciencias de la Complejidad, UNAM, Cd. Universitaria, México, 04510, D.F, México.
BMC Syst Biol. 2017 Feb 16;11(1):24. doi: 10.1186/s12918-017-0393-5.
Tumorigenic transformation of human epithelial cells in vitro has been described experimentally as the potential result of spontaneous immortalization. This process is characterized by a series of cell-state transitions, in which normal epithelial cells acquire first a senescent state which is later surpassed to attain a mesenchymal stem-like phenotype with a potentially tumorigenic behavior. In this paper we aim to provide a system-level mechanistic explanation to the emergence of these cell types, and to the time-ordered transition patterns that are common to neoplasias of epithelial origin. To this end, we first integrate published functional and well-curated molecular data of the components and interactions that have been found to be involved in such cell states and transitions into a network of 41 molecular components. We then reduce this initial network by removing simple mediators (i.e., linear pathways), and formalize the resulting regulatory core into logical rules that govern the dynamics of each of the network components as a function of the states of its regulators.
Computational dynamic analysis shows that our proposed Gene Regulatory Network model recovers exactly three attractors, each of them defined by a specific gene expression profile that corresponds to the epithelial, senescent, and mesenchymal stem-like cellular phenotypes, respectively. We show that although a mesenchymal stem-like state can be attained even under unperturbed physiological conditions, the likelihood of converging to this state is increased when pro-inflammatory conditions are simulated, providing a systems-level mechanistic explanation for the carcinogenic role of chronic inflammatory conditions observed in the clinic. We also found that the regulatory core yields an epigenetic landscape that restricts temporal patterns of progression between the steady states, such that recovered patterns resemble the time-ordered transitions observed during the spontaneous immortalization of epithelial cells, both in vivo and in vitro.
Our study strongly suggests that the in vitro tumorigenic transformation of epithelial cells, which strongly correlates with the patterns observed during the pathological progression of epithelial carcinogenesis in vivo, emerges from underlying regulatory networks involved in epithelial trans-differentiation during development.
体外人上皮细胞的致瘤转化已通过实验描述为自发永生化的潜在结果。这一过程的特征是一系列细胞状态转变，其中正常上皮细胞首先获得衰老状态，随后超越该状态以获得具有潜在致瘤行为的间充质干细胞样表型。在本文中，我们旨在为这些细胞类型的出现以及上皮起源肿瘤常见的时间顺序转变模式提供系统层面的机理解释。为此，我们首先将已发表的关于参与此类细胞状态和转变的成分及相互作用的功能和精心整理的分子数据整合到一个由41个分子成分组成的网络中。然后，我们通过去除简单的介导因子（即线性途径）来简化这个初始网络，并将所得的调控核心形式化为逻辑规则，这些规则根据其调节因子的状态来控制每个网络成分的动态变化。
计算动力学分析表明，我们提出的基因调控网络模型精确地恢复了三个吸引子，每个吸引子分别由对应于上皮、衰老和间充质干细胞样细胞表型的特定基因表达谱定义。我们表明，尽管即使在未受干扰的生理条件下也能达到间充质干细胞样状态，但在模拟促炎条件时，收敛到该状态的可能性会增加，这为临床观察到的慢性炎症条件的致癌作用提供了系统层面的机理解释。我们还发现，调控核心产生了一种表观遗传景观，限制了稳态之间进展的时间模式，使得恢复的模式类似于上皮细胞在体内和体外自发永生化过程中观察到的时间顺序转变。
我们的研究强烈表明，上皮细胞的体外致瘤转化与体内上皮癌发生病理进展过程中观察到的模式密切相关，它源于发育过程中参与上皮转分化的潜在调控网络。
