肿瘤休眠的元胞自动机模型：一个分解开关的出现
A Cellular Automaton Model for Tumor Dormancy: Emergence of a Proliferative Switch
摘要：
导致患者致命后果的恶性癌症可能会在很长一段时间内处于休眠状态。虽然已经提出了细胞休眠、血管生成休眠和免疫监视等个别机制，但从基础和临床角度对癌症休眠和从休眠状态到增殖状态的“转换”的全面理解仍需加强。计算建模使人们能够探索各种可能但现实的微观休眠机制及其预测结果的场景。本文的目的是设计这样一个预测计算模型的休眠与紧急“开关”的行为。具体来说，我们概括了以前的元胞自动机（CA）模型的实体瘤的增殖生长，现在结合了各种细胞水平的肿瘤-宿主相互作用和不同的机制，肿瘤休眠，例如免疫系统的影响。我们的新CA规则在微环境中诱导肿瘤和肿瘤抑制因子之间的自然“竞争”。这种竞争要么导致一段时间的“僵局”，其中肿瘤最终获胜（自发出现）或被根除;要么导致在这种“僵局”可能发展之前肿瘤被根除的情况。我们还预测，如果肿瘤增殖边缘内活跃分裂细胞的数量达到临界但较低的水平，则休眠肿瘤很有可能恢复快速生长。我们的研究结果可能有助于对癌症休眠的基本理解。
英文摘要：
Malignant cancers that lead to fatal outcomes for patients may remain dormant for very long periods of time. Although individual mechanisms such as cellular dormancy, angiogenic dormancy and immunosurveillance have been proposed, a comprehensive understanding of cancer dormancy and the "switch" from a dormant to a proliferative state still needs to be strengthened from both a basic and clinical point of view. Computational modeling enables one to explore a variety of scenarios for possible but realistic microscopic dormancy mechanisms and their predicted outcomes. The aim of this paper is to devise such a predictive computational model of dormancy with an emergent "switch" behavior. Specifically, we generalize a previous cellular automaton (CA) model for proliferative growth of solid tumor that now incorporates a variety of cell-level tumor-host interactions and different mechanisms for tumor dormancy, for example the effects of the immune system. Our new CA rules induce a natural "competition" between the tumor and tumor suppression factors in the microenvironment. This competition either results in a "stalemate" for a period of time in which the tumor either eventually wins (spontaneously emerges) or is eradicated; or it leads to a situation in which the tumor is eradicated before such a "stalemate" could ever develop. We also predict that if the number of actively dividing cells within the proliferative rim of the tumor reaches a critical, yet low level, the dormant tumor has a high probability to resume rapid growth. Our findings may shed light on the fundamental understanding of cancer dormancy.
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