Evolutionarily stable anti-cancer therapies by autologous cell defection.
Evolutionarily stable anti-cancer therapies by autologous cell defection.
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DOI：
10.1093/emph/eot014
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Archetti M
中科院分区：
文献类型：
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作者：
Archetti M
博弈论提出了一种基于使用破坏肿瘤内合作的修饰癌细胞的抗癌治疗方法。从患者身上获取癌细胞，在体外敲除产生基本生长因子的基因，然后将细胞重新植入肿瘤，在那里它们导致肿瘤崩溃。博弈论提出了一种基于使用破坏肿瘤内合作的修饰癌细胞的抗癌治疗方法。从患者身上获取癌细胞，在体外敲除产生基本生长因子的基因，然后将细胞重新植入肿瘤，在那里它们导致肿瘤崩溃。背景和目的：目前基于基因治疗的抗癌药物和治疗方法容易发生耐药性的进化，因为癌症是一个克隆选择的过程：耐药细胞株具有选择性优势，因此频率增加，最终导致对整个肿瘤的耐药性并导致复发。有效的治疗方法必须在进化上稳定，即对耐药突变细胞的入侵具有免疫力。这项研究展示了如何通过使用改良的癌细胞进行自体细胞疗法来实现这种治疗，这些癌细胞被敲除了编码生长因子等扩散因子的基因。方法：在相互作用邻域和更新邻域解耦的结构化种群中，利用非线性公共产品博弈分析产生扩散因子的细胞种群的进化动力学。对系统动力学的分析揭示了什么干预措施可以将人口推向稳定的平衡，在这种平衡中不会产生扩散因素。结果：基于自体基因敲除细胞疗法的治疗可以导致肿瘤的自发性崩溃，而不直接针对癌细胞、其生长因子或其受体。确定了能够使治疗有效的关键参数。进化博弈论和机制设计中的概念，其中一些是违反直觉的，可以用来优化治疗。结论和启示：虽然它与其他基于基因治疗和RNA干扰的方法有相似之处，但在某些条件下，这里提出的方法在进化上是稳定的。这种方法被称为自体细胞缺陷，可以利用现有的分子生物学和细胞治疗技术进行。
Game theory suggests an anti-cancer treatment based on the use of modified cancer cells that disrupt cooperation within the tumor. Cancer cells are harvested from the patient, the genes for the production of essential growth factors are knocked out in vitro and the cells are then reinserted in the tumor, where they lead to its collapse. Game theory suggests an anti-cancer treatment based on the use of modified cancer cells that disrupt cooperation within the tumor. Cancer cells are harvested from the patient, the genes for the production of essential growth factors are knocked out in vitro and the cells are then reinserted in the tumor, where they lead to its collapse. Background and objectives: Current anti-cancer drugs and treatments based on gene therapy are prone to the evolution of resistance, because cancer is a process of clonal selection: resistant cell lines have a selective advantage and therefore increase in frequency, eventually conferring resistance to the whole tumor and leading to relapse. An effective treatment must be evolutionarily stable, that is, immune to the invasion of resistant mutant cells. This study shows how such a treatment can be achieved by autologous cell therapy using modified cancer cells, knocked out for genes coding for diffusible factors like growth factors. Methodology: The evolutionary dynamics of a population of cells producing diffusible factors are analyzed using a nonlinear public goods game in a structured population in which the interaction neighborhood and the update neighborhood are decoupled. The analysis of the dynamics of the system reveals what interventions can drive the population to a stable equilibrium in which no diffusible factors are produced. Results: A treatment based on autologous knockout cell therapy can be designed to lead to the spontaneous collapse of a tumor, without targeting directly the cancer cells, their growth factors or their receptors. Critical parameters that can make the therapy effective are identified. Concepts from evolutionary game theory and mechanism design, some of which are counterintuitive, can be adopted to optimize the treatment. Conclusions and implications: Although it shares similarities with other approaches based on gene therapy and RNA interference, the method suggested here is evolutionarily stable under certain conditions. This method, named autologous cell defection, can be carried out using existing molecular biology and cell therapy techniques.