Brown Joel S, Cunningham Jessica J, Gatenby Robert A
IEEE Trans Biomed Eng. 2017 Mar;64(3):512-518. doi: 10.1109/TBME.2016.2623564. Epub 2016 Nov 1.
Evolution of resistance allows cancer cells to adapt and continue proliferating even when therapy is initially very effective. Most investigations of treatment resistance focus on the adaptive phenotypic properties of individual cells. We propose that the resistance of a single cell to therapy may extend beyond its own phenotypic and molecular properties and be influenced by the phenotypic properties of surrounding cells and variations in cell density. Similar variation exists in population densities of animals living in groups and can significantly affect the outcome of an external threat.
We investigate aggregation effects in cancer therapy using Darwinian models that integrate phenotypic properties of individual cells and common population effects found in nature to simulate the dynamics of resistance and sensitivity in the diverse cellular environments within cancers.
We demonstrate that the density of cancer cell populations can profoundly influence response to chemotherapy independent of the properties of individual cells. Most commonly, these aggregation effects benefit the tumor allowing cells to survive even with phenotypic properties that would render them highly vulnerable to therapy in the absence of population effects.
We demonstrate aggregation effects likely play a significant role in conferring resistance to therapy on tumor cells that would otherwise be sensitive to treatment.
The potential role of aggregation in outcomes from cancer therapy has not been previously investigated. Our results demonstrate these dynamics may play a key role in resistance to therapy and could be used to design evolutionarily-enlightened therapies that exploit aggregation effects to improve treatment outcomes.
耐药性的演变使癌细胞能够适应并继续增殖，即使初始治疗非常有效。大多数关于治疗耐药性的研究都集中在单个细胞的适应性表型特性上。我们提出，单个细胞对治疗的耐药性可能超出其自身的表型和分子特性，并受到周围细胞的表型特性和细胞密度变化的影响。生活在群体中的动物种群密度也存在类似变化，并且会显著影响外部威胁的结果。
我们使用达尔文模型研究癌症治疗中的聚集效应，该模型整合了单个细胞的表型特性和自然界中常见的种群效应，以模拟癌症中不同细胞环境下的耐药性和敏感性动态。
我们证明癌细胞群体的密度可独立于单个细胞的特性而深刻影响对化疗的反应。最常见的是，这些聚集效应使肿瘤受益，即使细胞具有在没有种群效应时使其极易受到治疗影响的表型特性，也能使其存活。
我们证明聚集效应可能在赋予原本对治疗敏感的肿瘤细胞治疗耐药性方面发挥重要作用。
聚集在癌症治疗结果中的潜在作用此前尚未得到研究。我们的结果表明，这些动态可能在治疗耐药性中起关键作用，并可用于设计有进化启发的疗法，利用聚集效应来改善治疗结果。
