Spatial heterogeneity in drug concentrations can facilitate the emergence of resistance to cancer therapy.
Spatial heterogeneity in drug concentrations can facilitate the emergence of resistance to cancer therapy.
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DOI：
10.1371/journal.pcbi.1004142
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发表时间：
2015-03
影响因子：
4.3
通讯作者：
Bonhoeffer S
中科院分区：
文献类型：
--
作者：
Fu F;Nowak MA;Bonhoeffer S
获得性耐药是癌症治疗成功的主要障碍之一。耐药性的产生通常归因于遗传异质性。然而，无论是在实体瘤内部的微观水平上，还是在转移瘤间的宏观水平上，药物穿透肿瘤微环境的异质性也可能导致获得性耐药。在这里，我们使用数学模型来研究药物异质性对逃避治疗概率和耐药时间的影响。具体来说，我们使用足够有效的治疗方法，以尽可能高的药物浓度抑制室中所有先前存在的遗传变异的生长。为了研究药物异质性、生长速率和耐药进化的共同作用，我们分析了癌细胞在不同药物浓度的多个腔室中生长和在腔室之间有限迁移的多类型随机分支过程。我们发现，耐药性可能首先出现在药物渗透性差的避难所隔室，然后从那里进入药物浓度高的非避难所隔室。此外，我们表明，只有低于阈值的细胞迁移率，空间异质性才会加速耐药性进化，否则，过高的迁移率会阻碍耐药性。我们的研究结果为理解为什么癌症倾向于迅速产生耐药性提供了新的见解，并且细胞迁移和很少药物暴露的避难所的存在对于这一目的至关重要。癌症治疗的失败通常归因于治疗前已存在的耐药突变体的生长，但越来越多的证据表明，肿瘤微环境影响细胞对药物的敏感性，从而介导治疗期间耐药性的演变。在这里，我们考虑了肿瘤微环境的重要方面，包括空间药物梯度和细胞增殖的差异率。我们表明，适应性对空间的依赖以及细胞迁移促进了获得性抗性的出现。我们的分析表明，在高浓度的隔离室中选择的耐药细胞很可能从避难所传播，在那里它们首先获得抗性，然后迁移。结果表明，将靶向治疗与抑制细胞运动的抗转移治疗相结合，以及通过增强药物在所有转移区间的运输和分布，将有助于改善临床结果。
Acquired resistance is one of the major barriers to successful cancer therapy. The development of resistance is commonly attributed to genetic heterogeneity. However, heterogeneity of drug penetration of the tumor microenvironment both on the microscopic level within solid tumors as well as on the macroscopic level across metastases may also contribute to acquired drug resistance. Here we use mathematical models to investigate the effect of drug heterogeneity on the probability of escape from treatment and the time to resistance. Specifically we address scenarios with sufficiently potent therapies that suppress growth of all preexisting genetic variants in the compartment with the highest possible drug concentration. To study the joint effect of drug heterogeneity, growth rate, and evolution of resistance, we analyze a multi-type stochastic branching process describing growth of cancer cells in multiple compartments with different drug concentrations and limited migration between compartments. We show that resistance is likely to arise first in the sanctuary compartment with poor drug penetrations and from there populate non-sanctuary compartments with high drug concentrations. Moreover, we show that only below a threshold rate of cell migration does spatial heterogeneity accelerate resistance evolution, otherwise deterring drug resistance with excessively high migration rates. Our results provide new insights into understanding why cancers tend to quickly become resistant, and that cell migration and the presence of sanctuary sites with little drug exposure are essential to this end. Failure of cancer therapy is commonly attributed to the outgrowth of pre-existing resistant mutants already present prior to treatment, yet there is increasing evidence that the tumor microenvironment influences cell sensitivity to drugs and thus mediates the evolution of resistance during treatment. Here, we take into consideration important aspects of the tumor microenvironment, including spatial drug gradients and differential rates of cell proliferation. We show that the dependence of fitness on space together with cell migration facilitates the emergence of acquired resistance. Our analysis indicates that resistant cells that are selected for in compartments with high concentrations are likely to disseminate from sanctuary sites where they first acquire resistance preceding migration. The results suggest that it would be helpful to improve clinical outcomes by combining targeted therapy with anti-metastatic treatment aimed at constraining cell motility as well as by enhancing drug transportation and distribution throughout all metastatic compartments.
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影响因子：
4.3
作者：
Conway JM;Coombs D
通讯作者：
Coombs D
对抗癌疗法的耐药性的进化。
影响因子：
2
作者：
Foo, Jasmine;Michor, Franziska
通讯作者：
Michor, Franziska
影响因子：
56.9
作者：
Bonhoeffer, S;Chappey, C;Petropoulos, CJ
通讯作者：
Petropoulos, CJ
影响因子：
158.5
作者：
Druker, Brian J.;Guilhot, Francois;Larson, Richard A.
通讯作者：
Larson, Richard A.
DOI：
10.1088/1742-5468/2010/07/p07028
发表时间：
2010-07-01
影响因子：
2.4
作者：
Antal, Tibor;Krapivsky, P. L.
通讯作者：
Krapivsky, P. L.