Development of new strategies for cancer treatment based in system biological-analysis of cancer system abnormality

本研究的目的是在对癌症系统异常进行系统生物学分析的基础上，开发新的癌症治疗策略。通过基于微阵列的比较基因组杂交，在胶质母细胞瘤细胞中发现了新的基因组异常。首次尝试以阅读方向为时间轴，对拷贝数谱进行去趋势波动分析，结果表明，较高的长期分形标度指数与胶质母细胞瘤患者较长的生存期有很好的相关性。利用SELDI-TOF MS(表面增强激光解吸/电离飞行时间质谱仪)和MALDI(基质辅助激光解吸/电离)TOF MS的蛋白质组学技术鉴定了多营养素是神经干细胞的特异性生长因子，而转甲状腺激素是脑缺血特异性蛋白。Petri网模拟表明，可溶性FasL的三聚体形成对于增强细胞的促凋亡活性是必不可少的。在胶质母细胞瘤生物分子系统中发现了冗余性、多样性、反馈、模块化和解偶性四种生物稳健性的分子机制。利用Path Assistant软件建立的分子连接网络具有无标度网络的特点，如枢纽的存在、幂定律的义务、所谓的小世界和蝴蝶结结构等。对HUB蛋白/子系统的蓄意攻击似乎很容易摧毁癌症的无标度网络。

The purpose of this research is to develop the new strategies of cancer treatment based on systems biological analysis of cancer system abnormality. New genomic aberrations were found in glioblastoma cells by microarray-based comparative genomic hybridization. The first attempts to apply detrended fluctuation analysis to copy number profiles by considering the reading direction as the time axis demonstrated that higher long-term fractal scaling exponents correlated well with longer survival of glioblastoma patients. Proteomic technique using both SELDI-TOF MS(surface enhanced laser desorption/ionization time-of-flight mass spectrometry) and MALDI(matrix assisted laser desorption/ionization) TOF MS identified pleiotrophin as a specific growth factor of neural stem cells and transthyretin as a brain ischemia-specific protein. Petri-Net simulation demonstrated that trimer formation of soluble FasL is essential to enhance apoptotic enhancing activity. The four molecular mechanisms of biological robustness such as redundancy, diversity, feedback, modularity and decoupling were found in glioblastoma biomolecular system. Molecular connection network established by PathwayAssist software had the characteristics of scale-free networks such as existence of hub, obligation of power law, so-called small world and bow-tie structure. The intentional attack to hub protein/subsystem seems to easily destroy the scale-free network of cancer.