Intratumoral molecular cancer cell heterogeneity is conventionally ascribed to the accumulation of random mutations that occasionally generate fitter phenotypes. This model is built upon the “mutation-selection” paradigm in which mutations drive ever-fitter cancer cells independent of environmental circumstances. An alternative model posits spatio-temporal variation (e.g., blood flow heterogeneity) drives speciation by selecting for cancer cells adapted to each different environment. Here, spatial genetic variation is the consequence rather than the cause of intratumoral evolution. In nature, spatially heterogenous environments are frequently coupled through migration. Drawing from ecological models, we investigate adjacent well-perfused and poorly-perfused tumor regions as “source” and “sink” habitats respectively. The source habitat has a high carrying capacity resulting in more emigration than immigration. Sink habitats may support a small (“soft-sink”) or no (“hard-sink”) local population. Ecologically, sink habitats can result in reductions in the population size of the source habitat so that, for example, the density of cancer cells directly around blood vessels may be lower than expected. Evolutionarily, sink habitats can exert a selective pressure favoring traits different from those in the source habitat so that, for example, cancer cells adjacent to blood vessels may be suboptimally adapted for that habitat. Soft sinks favor a generalist cancer cell type that moves between the environment but can, under some circumstances, produce speciation events forming source and sink habitat specialists resulting in significant molecular variation in cancer cells separated by small distances. Finally, sink habitats, with limited blood supply, may receive reduced concentrations of systemic drug treatments; and local hypoxia and acidosis may further decrease drug efficacy allowing cells to survive treatment and evolve resistance. In such cases, the sink transforms into the source habitat for resistant cancer cells, leading to treatment failure and tumor progression. We note these dynamics will result in spatial variations in molecular properties as an alternative to the conventional branched evolution model and will result in cellular migration as well as variation in cancer cell phenotype and proliferation currently described by the stem cell paradigm.

中文翻译：

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耦合的源汇栖息地产生癌细胞分子特性的空间和时间变化，作为分支克隆进化和干细胞范式的替代方案。

肿瘤内分子癌细胞异质性通常归因于随机突变的积累，这些突变偶尔会产生更合适的表型。该模型建立在“突变选择”范式之上，在这种范式中，突变驱动更健康的癌细胞，而不受环境条件的影响。另一种模型假定时空变化（例如，血流异质性）通过选择适应每个不同环境的癌细胞来驱动物种形成。在这里，空间遗传变异是肿瘤内进化的结果而不是原因。在自然界中，空间异质性环境经常通过迁移耦合。根据生态模型，我们将相邻的灌注良好和灌注不良的肿瘤区域分别调查为“源”和“汇”栖息地。源栖息地承载能力高，导致移民多于移民。汇栖息地可能支持少量（“软汇”）或没有（“硬汇”）当地人口。在生态上，汇栖息地会导致源栖息地种群规模的减少，例如，血管周围的癌细胞密度可能低于预期。从进化上讲，汇栖息地可以施加有利于与源栖息地不同的特征的选择压力，例如，血管附近的癌细胞可能不太适合该栖息地。软下沉有利于在环境之间移动但在某些情况下可以的多才多艺的癌细胞类型 产生物种形成事件，形成源和汇栖息地专家，导致相隔小距离的癌细胞发生显着的分子变异。最后，血液供应有限的水槽栖息地可能会接受降低浓度的全身药物治疗；局部缺氧和酸中毒可能进一步降低药效，使细胞在治疗中存活并产生耐药性。在这种情况下，汇转变为耐药癌细胞的来源栖息地，导致治疗失败和肿瘤进展。我们注意到这些动态将导致分子特性的空间变化，作为传统分支进化模型的替代方案，并将导致细胞迁移以及目前由干细胞范式描述的癌细胞表型和增殖的变化。