标题： 分享，但不均等：肿瘤内异质性出现和维持的合理机制 显示英文标题

标题： Share, but unequally: A plausible mechanism for emergence and maintenance of intratumor heterogeneity

摘要： 肿瘤内异质性（ITH），指的是在单个肿瘤中不同细胞亚群共存的现象，是癌症研究中近半个世纪以来的主要难题。对ITH潜在机制的理解不足阻碍了癌症有效治疗的发展。基于最近对胰腺癌的定量实验结果，我们开发了一个针对某种癌症的一般进化模型，考虑了不同细胞群体通过旁分泌或邻分泌因子的相互作用。我们表明，肿瘤中稳定异质状态的出现需要将旁分泌生长因子（“公共资源”）在生产细胞和仅消耗它们的细胞之间不均等分配。我们的模型为最近在胰腺癌中的{\it 体外}实验研究提供了定量解释，其中胰岛素样生长因子（IGF-II）起到了公共资源的作用。计算出的相图随外源性资源和生长因子生产细胞的比例变化而变化，显示只有在外源性IGF-II浓度的一个狭窄范围内，ITH才会持续。值得注意的是，在缺乏外源性IGF-II的恶劣条件下，ITH的维持需要肿瘤细胞亚群之间的合作，而过量的外源性IGF-II则引发竞争。我们的理论也对测量的{\it 体内}胶质母细胞瘤（GBM）肿瘤生长进行了定量解释。GBM肿瘤生长随肿瘤细胞比例的变化预测可接受实验测试。ITH的机制也为设计有效的治疗方案提供了线索。 显示英文摘要

摘要： Intratumor heterogeneity (ITH), referring to coexistence of different cell subpopulations in a single tumor, 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 tumor 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 {\it in vitro} experimental studies in pancreatic cancer in which insulin growth factor (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 tumor 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 {\it in vivo} tumor growth in glioblastoma multiforme (GBM). The predictions for GBM tumor growth as a function of the fraction of tumor cells are amenable to experimental tests. The mechanism for ITH also provides hints for devising efficacious therapies.