One of the great unsolved puzzles in cancer biology is not why cancers occur, but rather explaining why so few cancers occur compared with the theoretical number that could occur, given the number of progenitor cells in the body and the normal mutation rate. We hypothesized that a contributory explanation is that the tumour microenvironment (TME) is not fixed due to factors such as immune cell infiltration, and that this could impair the ability of neoplastic cells to retain a high enough fitness to become a cancer. The TME has implicitly been assumed to be static in most cancer evolution models, and we therefore developed a mathematical model of spatial cancer evolution assuming that the TME, and thus the optimum cancer phenotype, changes over time. Based on simulations, we show how cancer cell populations adapt to diverse changing TME conditions and fitness landscapes. Compared with static TMEs, which generate neutral dynamics, changing TMEs lead to complex adaptations with characteristic spatio-temporal heterogeneity involving variable fitness effects of driver mutations, subclonal mixing, subclonal competition and phylogeny patterns. In many cases, cancer cell populations fail to grow or undergo spontaneous regression, and even extinction. Our analyses predict that cancer evolution in a changing TME is challenging, and can help to explain why cancer is neither inevitable nor as common as expected. Should cancer driver mutations with effects dependent of the TME exist, they are likely to be selected. Anti-cancer prevention and treatment strategies based on changing the TME are feasible and potentially effective.

中文翻译：

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为什么癌症没有更常见？不断变化的微环境可能有助于解释原因，并提出抗癌治疗策略。


癌症生物学中尚未解决的重大难题之一不是癌症发生的原因，而是解释为什么在考虑到体内祖细胞的数量和正常突变率的情况下，与可能发生的理论数量相比，癌症的发生如此之少。我们假设一个重要的解释是，由于免疫细胞浸润等因素，肿瘤微环境（TME）并未固定，这可能会损害肿瘤细胞保持足够高的适应性而成为癌症的能力。在大多数癌症进化模型中，TME 被隐含地假设为静态，因此我们开发了一个空间癌症进化的数学模型，假设 TME 以及最佳癌症表型随时间变化。基于模拟，我们展示了癌细胞群如何适应不同变化的 TME 条件和健康状况。与产生中性动态的静态 TME 相比，改变 TME 会导致具有特征时空异质性的复杂适应，涉及驱动突变、亚克隆混合、亚克隆竞争和系统发育模式的可变适应性效应。在许多情况下，癌细胞群无法生长或自发消退，甚至灭绝。我们的分析预测，在不断变化的 TME 中癌症的演变具有挑战性，并且可以帮助解释为什么癌症既不是不可避免的，也不像预期的那样常见。如果存在影响依赖于 TME 的癌症驱动突变，它们很可能会被选择。基于改变TME的抗癌预防和治疗策略是可行且潜在有效的。