Modeling boundary conditions for balanced proliferation in metastatic latency.
Modeling boundary conditions for balanced proliferation in metastatic latency.
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DOI：
10.1158/1078-0432.ccr-12-3180
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发表时间：
2013-03-01
期刊：
影响因子：
--
通讯作者：
Wells A
中科院分区：
文献类型：
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作者：
Taylor DP;Wells JZ;Savol A;Chennubhotla C;Wells A
近一半的癌症转移在原发性肿瘤治疗后5年或更长时间内变得临床明显;因此转移细胞存活而不出现较长时间。这种休眠至少可以用两种相反的情况来解释：细胞静止和平衡增殖;这些都需要二分法的机制病因学。为了检查平衡增殖的边界参数，我们进行了计算机模拟。为了阐明平衡增殖假说，我们探讨了特定的边界概率下，增殖微转移将保持休眠状态。一个两状态马尔可夫链蒙特卡罗模型模拟微转移增殖和死亡，根据随机生存概率。我们在100名模拟患者中改变这些概率，每个患者有1，000个转移性沉积物，并记录微转移是否超过100万个细胞，死亡或保持休眠状态（存活1，218代）。模拟显示了一个狭窄的生存概率窗口（49.7 - 50.8%），允许在一系列起始细胞数量中休眠，即使这样，也只有一小部分微转移。大多数微转移瘤迅速死亡，即使在生存概率，导致一个子集的微转移瘤的快速出现。在休眠转移，细胞群体依赖于小的生存概率增量敏感。转移性休眠仅用平衡增殖来解释，其生存概率非常小。考虑到更大的生存变异性认为参加流动微环境，这是更有可能的，这些微转移结节经历至少一段时间的静止，而不是完全由平衡的增殖控制。
Nearly half of cancer metastases become clinically evident five or more years after primary tumor treatment; thus metastatic cells survived without emerging for extended periods. This dormancy has been explained by at least two countervailing scenarios: cellular quiescence and balanced proliferation; these entail dichotomous mechanistic etiologies. To examine the boundary parameters for balanced proliferation, we performed in silico modeling. To illuminate the balanced proliferation hypothesis, we explored the specific boundary probabilities under which proliferating micrometastases would remain dormant. A two-state Markov chain Monte Carlo model simulated micrometastatic proliferation and death according to stochastic survival probabilities. We varied these probabilities across 100 simulated patients each with 1,000 metastatic deposits and documented whether the micrometastases exceeded one million cells, died out, or remained dormant (survived 1,218 generations). The simulations revealed a narrow survival probability window (49.7 – 50.8 percent) that allowed for dormancy across a range of starting cell numbers, and even then for only a small fraction of micrometastases. The majority of micrometastases died out quickly even at survival probabilities that led to rapid emergence of a subset of micrometastases. Within dormant metastases, cell populations depended sensitively on small survival probability increments. Metastatic dormancy as explained solely by balanced proliferation is bounded by very tight survival probabilities. Considering the far larger survival variability thought to attend fluxing microenvironments, it is more probable that these micrometastatic nodules undergo at least periods of quiescence rather than exclusively being controlled by balanced proliferation.