The Tumor Growth Paradox and Immune System-Mediated Selection for Cancer Stem Cells
The Tumor Growth Paradox and Immune System-Mediated Selection for Cancer Stem Cells
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DOI：
10.1007/s11538-012-9798-x
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发表时间：
2013-01-01
影响因子：
3.5
通讯作者：
Hahnfeldt, Philip
中科院分区：
文献类型：
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作者：
Hillen, Thomas;Enderling, Heiko;Hahnfeldt, Philip
癌症干细胞（CSC）驱动肿瘤进展、转移、治疗抗性和复发。了解CSC动力学及其与非干细胞（称为肿瘤细胞，TC）的相互作用仍然很少，理论模型可能有助于阐明它们在癌症进展中的作用。在这里，我们开发了一个数学模型的一个异质群体的CSC和TC研究提出的“肿瘤生长悖论“aEuro“加速肿瘤生长与增加细胞死亡，例如，可以导致免疫反应或细胞毒性治疗。我们发现，如果TC与CSC竞争空间和资源，它们可以阻止CSC分裂并使肿瘤进入休眠状态。相反，如果这种竞争因TC死亡而减少，结果是CSC的释放及其重新增殖，最终导致更大的肿瘤生长。在这里，我们提出了这个肿瘤生长悖论的分析证明。我们展示了模型的数值结果如何进一步了解实体瘤中癌症干细胞的比例如何演变。以免疫系统为例，我们表明，诱导细胞死亡可以导致从次要亚群中选择癌症干细胞，使其成为肿瘤中占主导地位的且渐进的整个细胞类型。
Cancer stem cells (CSCs) drive tumor progression, metastases, treatment resistance, and recurrence. Understanding CSC kinetics and interaction with their nonstem counterparts (called tumor cells, TCs) is still sparse, and theoretical models may help elucidate their role in cancer progression. Here, we develop a mathematical model of a heterogeneous population of CSCs and TCs to investigate the proposed "tumor growth paradox"aEuro"accelerated tumor growth with increased cell death as, for example, can result from the immune response or from cytotoxic treatments. We show that if TCs compete with CSCs for space and resources they can prevent CSC division and drive tumors into dormancy. Conversely, if this competition is reduced by death of TCs, the result is a liberation of CSCs and their renewed proliferation, which ultimately results in larger tumor growth. Here, we present an analytical proof for this tumor growth paradox. We show how numerical results from the model also further our understanding of how the fraction of cancer stem cells in a solid tumor evolves. Using the immune system as an example, we show that induction of cell death can lead to selection of cancer stem cells from a minor subpopulation to become the dominant and asymptotically the entire cell type in tumors.