Raychaudhuri Subhadip
Subhadip Raychaudhuri, Department of Biomedical Engineering, Biophysics Graduate Group, Graduate Group in Immunology, and Graduate Group in Applied Mathematics, University of California, Davis, CA 95616, United States.
World J Clin Oncol. 2010 Nov 10;1(1):24-8. doi: 10.5306/wjco.v1.i1.24.
Cancer cells are widely known to be protected from apoptosis, a phenomenon that is a major hurdle to successful anticancer therapy. Over-expression of several anti-apoptotic proteins, or mutations in pro-apoptotic factors, has been recognized to confer such resistance. Development of new experimental strategies, such as in silico modeling of biological pathways, can increase our understanding of how abnormal regulation of apoptotic pathway in cancer cells can lead to tumour chemoresistance. Monte Carlo simulations are in particular well suited to study inherent variability, such as spatial heterogeneity and cell-to-cell variations in signaling reactions. Using this approach, often in combination with experimental validation of the computational model, we observed that large cell-to-cell variability could explain the kinetics of apoptosis, which depends on the type of pathway and the strength of stress stimuli. Most importantly, Monte Carlo simulations of apoptotic signaling provides unexpected insights into the mechanisms of fractional cell killing induced by apoptosis-inducing agents, showing that not only variation in protein levels, but also inherent stochastic variability in signaling reactions, can lead to survival of a fraction of treated cancer cells.
众所周知，癌细胞能够免受细胞凋亡的影响，而这一现象是成功进行抗癌治疗的主要障碍。多种抗凋亡蛋白的过度表达或促凋亡因子的突变被认为赋予了这种抗性。新实验策略的开发，如生物途径的计算机模拟，可以增进我们对癌细胞凋亡途径异常调节如何导致肿瘤化疗耐药性的理解。蒙特卡洛模拟特别适合研究内在变异性，如空间异质性和信号反应中的细胞间差异。使用这种方法，通常结合计算模型的实验验证，我们观察到细胞间的巨大变异性可以解释细胞凋亡的动力学，这取决于途径的类型和应激刺激的强度。最重要的是，凋亡信号的蒙特卡洛模拟为凋亡诱导剂诱导的部分细胞杀伤机制提供了意想不到的见解，表明不仅蛋白质水平的变化，而且信号反应中固有的随机变异性，都可能导致一部分经治疗的癌细胞存活。
