Translational Research Laboratory, Breast Cancer Unit, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), Gran via 199, L'Hospitalet del Llobregat, Barcelona 08908, Catalonia, Spain.
Integr Biol (Camb). 2012 Sep;4(9):1038-48. doi: 10.1039/c2ib20052j. Epub 2012 Jul 18.
The products of genes mutated or differentially expressed in cancer tend to occupy central positions within the network of protein-protein interactions, or the interactome network. Integration of different types of gene and protein relationships has considerably increased the understanding of the mechanisms of carcinogenesis, while also enhancing the applicability of expression signatures. In this scenario, however, it remains unknown how cancer develops, progresses and responds to therapies in a potentially controlled manner at the systems level. Here, by applying the concepts of load transfer and cascading failures in power grids, we examine the impact and transmission of cancer-related gene expression changes in the interactome network. Relative to random perturbations, this study reveals topological robustness associated with all cancer conditions. In addition, experimental perturbation of a central cancer node, which consists of over-expression of the α-synuclein (SNCA) protein in MCF7 breast cancer cells, also reveals robustness. Conversely, a search for proteins with an opposite topological impact identifies the autophagy pathway. Mechanistically, the existence of smaller shortest paths among cancer-related proteins appears to be a topological feature that partially contributes to the restricted perturbation of the network. Together, the results of this study suggest that cancer develops, progresses and responds to therapies following controlled, restricted perturbation of the interactome network.
在癌症中发生突变或差异表达的基因产物往往占据蛋白质-蛋白质相互作用网络（即互作网络）的核心位置。不同类型的基因和蛋白质关系的整合极大地提高了对致癌机制的理解，同时也增强了表达谱的适用性。然而，在这种情况下，人们仍然不知道癌症如何在系统水平上以潜在可控的方式发展、进展和对治疗做出反应。在这里，我们通过应用电网中的负载转移和级联故障的概念，研究了互作网络中与癌症相关的基因表达变化的影响和传递。与随机扰动相比，本研究揭示了与所有癌症情况相关的拓扑鲁棒性。此外，对中央癌症节点的实验扰动，即 MCF7 乳腺癌细胞中α-突触核蛋白（SNCA）的过表达，也显示出了鲁棒性。相反，寻找具有相反拓扑影响的蛋白质可以确定自噬途径。从机制上讲，癌症相关蛋白质之间存在较短的最短路径似乎是网络受到限制的部分原因。总之，这项研究的结果表明，癌症的发展、进展和对治疗的反应遵循互作网络的受控、受限扰动。
