MacLean Adam L, Harrington Heather A, Stumpf Michael P H, Hansen Marc D H
Theoretical Systems Biology, Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, London SW7 2AZ, UK.
Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
Biomedicines. 2014 Dec 9;2(4):384-402. doi: 10.3390/biomedicines2040384.
Signaling from the c-Met receptor tyrosine kinase is associated with progression and metastasis of epithelial tumors. c-Met, the receptor for hepatocyte growth factor, triggers epithelial-mesenchymal transition (EMT) of cultured cells, which is thought to drive migration of tumor cells and confer on them critical stem cell properties. Here, we employ mathematical modeling to better understand how EMT affects population dynamics in metastatic tumors. We find that without intervention, micrometastatic tumors reach a steady-state population. While the rates of proliferation, senescence and death only have subtle effects on the steady state, changes in the frequency of EMT dramatically alter population dynamics towards exponential growth. We also find that therapies targeting cell proliferation or cell death are markedly more successful when combined with one that prevents EMT, though such therapies do little when used alone. Stochastic modeling reveals the probability of tumor recurrence from small numbers of residual differentiated tumor cells. EMT events in metastatic tumors provide a plausible mechanism by which clinically detectable tumors can arise from dormant micrometastatic tumors. Modeling the dynamics of this process demonstrates the benefit of a treatment that eradicates tumor cells and reduces the rate of EMT simultaneously.
c-Met受体酪氨酸激酶发出的信号与上皮肿瘤的进展和转移相关。c-Met是肝细胞生长因子的受体，可触发培养细胞的上皮-间质转化（EMT），这被认为会驱动肿瘤细胞迁移并赋予它们关键的干细胞特性。在此，我们采用数学建模来更好地理解EMT如何影响转移性肿瘤中的种群动态。我们发现，在没有干预的情况下，微转移瘤会达到稳定状态的种群数量。虽然增殖、衰老和死亡的速率对稳态只有细微影响，但EMT频率的变化会显著改变种群动态，使其朝着指数增长方向发展。我们还发现，靶向细胞增殖或细胞死亡的疗法与防止EMT的疗法联合使用时明显更有效，不过单独使用这些疗法效果甚微。随机建模揭示了少量残留分化肿瘤细胞导致肿瘤复发的概率。转移性肿瘤中的EMT事件提供了一种合理的机制，通过该机制临床上可检测到的肿瘤可能源自休眠的微转移瘤。对这一过程的动态进行建模证明了一种既能根除肿瘤细胞又能同时降低EMT速率的治疗方法的益处。
