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

本研究的目的是基于癌症系统异常的系统生物学分析，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畸变。将阅读方向作为时间轴，首次尝试将非趋势波动分析应用于拷贝数谱，结果表明，较高的长期分形缩放指数与胶质母细胞瘤患者较长的生存期密切相关。蛋白质组学技术使用SELDI-TOF MS（表面增强激光解吸/电离飞行时间质谱）和MALDI（基质辅助激光解吸/电离）TOF MS鉴定出多营养蛋白是神经干细胞的特异性生长因子，转甲状腺素是脑缺血特异性蛋白。Petri-Net模拟表明，可溶性FasL的三聚体形成对增强细胞凋亡活性至关重要。在胶质母细胞瘤生物分子系统中发现了冗余性、多样性、反馈性、模块化和解耦性四种生物鲁棒性分子机制。PathwayAssist软件建立的分子连接网络具有集线器存在、幂律义务、所谓小世界和领结结构等无标度网络特征。对枢纽蛋白/子系统的故意攻击似乎很容易破坏癌症的无标度网络。

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.