肿瘤酸度和血管系统社会困境中的癌症治疗安排和动态异质性
Cancer treatment scheduling and dynamic heterogeneity in social dilemmas of tumour acidity and vasculature
摘要：
背景资料：肿瘤是多种多样的生态系统，在各种癌症标志中具有持续的异质性，如用于血管生成的生长因子生产的自给自足和用于有氧糖酵解的能量代谢的重编程。这种异质性对诊断、治疗和疾病进展有影响。方法：引入双物品博弈，运用演化博弈论研究这些特征的动态变化。我们将糖酵解酸的产生作为所有肿瘤细胞的公共产品，并将通过VEGF产生的血管形成的氧气作为有益于非糖酵解肿瘤细胞的俱乐部产品。这导致三种可行的表型策略：糖酵解、血管生成和有氧非血管生成。结果如下：我们将动力学分为三个定性不同的制度：（1）完全糖酵解，（2）完全血管生成，或（3）在所有三种细胞类型的多克隆。第三种制度允许动态异质性，即使是线性商品，这在之前的公共产品模型中是不可能的，这些模型孤立地考虑了糖酵解或生长因子的生产。结论：多克隆方案的循环动力学强调了抗糖酵解治疗（如氯尼达明）时机的重要性。定性不同的动态制度的存在突出了治疗的顺序效应。特别是，我们认为血管重整的潜力作为新辅助治疗之前，后续的干预措施，如缓冲治疗。
英文摘要：
Background: Tumours are diverse ecosystems with persistent heterogeneity in various cancer hallmarks like self-sufficiency of growth factor production for angiogenesis and reprogramming of energy-metabolism for aerobic glycolysis. This heterogeneity has consequences for diagnosis, treatment, and disease progression. Methods: We introduce the double goods game to study the dynamics of these traits using evolutionary game theory. We model glycolytic acid production as a public good for all tumour cells and oxygen from vascularization via VEGF production as a club good benefiting non-glycolytic tumour cells. This results in three viable phenotypic strategies: glycolytic, angiogenic, and aerobic non-angiogenic. Results: We classify the dynamics into three qualitatively distinct regimes: (1) fully glycolytic, (2) fully angiogenic, or (3) polyclonal in all three cell types. The third regime allows for dynamic heterogeneity even with linear goods, something that was not possible in prior public good models that considered glycolysis or growth-factor production in isolation. Conclusion: The cyclic dynamics of the polyclonal regime stress the importance of timing for anti-glycolysis treatments like lonidamine. The existence of qualitatively different dynamic regimes highlights the order effects of treatments. In particular, we consider the potential of vascular renormalization as a neoadjuvant therapy before follow up with interventions like buffer therapy.
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