Share, but unequally: a plausible mechanism for emergence and maintenance of intratumour heterogeneity
Share, but unequally: a plausible mechanism for emergence and maintenance of intratumour heterogeneity
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DOI：
10.1098/rsif.2018.0820
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发表时间：
2018-11
影响因子：
3.9
通讯作者：
Xin Li;D. Thirumalai
中科院分区：
文献类型：
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作者：
Xin Li;D. Thirumalai
肿瘤内异质性（ITH）是指单个肿瘤中不同细胞亚群的共存，近半个世纪以来一直是癌症研究中的一个主要难题。缺乏对 ITH 潜在机制的了解阻碍了开发有效癌症疗法的进展。根据最近对胰腺癌的定量实验的结果，我们开发了一种癌症的通用进化模型，通过旁分泌或近分泌因子解释不同细胞群之间的相互作用。我们表明，肿瘤中稳定异质状态的出现需要在产生旁分泌生长因子（公共物品）的细胞和仅消耗它们的细胞之间不平等分配。我们的模型为最近的胰腺癌体外实验研究提供了定量解释，其中胰岛素样生长因子 II (IGF-II) 发挥着公共产品的作用。计算出的相图作为外源资源和生长因子产生细胞分数的函数，表明 ITH 仅在外源 IGF-II 浓度的狭窄范围内持续存在。值得注意的是，ITH的维持需要肿瘤细胞亚群在恶劣条件下的合作，特别是缺乏外源IGF-II，而过量的外源IGF-II会引发竞争。我们的理论还定量地解释了多形性胶质母细胞瘤（GBM）体内测量的肿瘤生长。 GBM 肿瘤生长作为肿瘤细胞比例函数的预测是可以通过实验测试的。 ITH 的机制也为设计有效的疗法提供了线索。
Intratumour heterogeneity (ITH), referring to the coexistence of different cell subpopulations in a single tumour, has been a major puzzle in cancer research for almost half a century. The lack of understanding of the underlying mechanism of ITH hinders progress in developing effective therapies for cancers. Based on the findings in a recent quantitative experiment on pancreatic cancer, we developed a general evolutionary model for one type of cancer, accounting for interactions between different cell populations through paracrine or juxtacrine factors. We show that the emergence of a stable heterogeneous state in a tumour requires an unequal allocation of paracrine growth factors (public goods) between cells that produce them and those that merely consume them. Our model provides a quantitative explanation of recent in vitro experimental studies in pancreatic cancer in which insulin-like growth factor II (IGF-II) plays the role of public goods. The calculated phase diagrams as a function of exogenous resources and fraction of growth factor producing cells show ITH persists only in a narrow range of concentration of exogenous IGF-II. Remarkably, maintenance of ITH requires cooperation among tumour cell subpopulations in harsh conditions, specified by lack of exogenous IGF-II, whereas surplus exogenous IGF-II elicits competition. Our theory also quantitatively accounts for measured in vivo tumour growth in glioblastoma multiforme (GBM). The predictions for GBM tumour growth as a function of the fraction of tumour cells are amenable to experimental tests. The mechanism for ITH also provides hints for devising efficacious therapies.