Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer
Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer
复制标题
DOI：
10.1073/pnas.1414653112
复制
发表时间：
2015-02-10
影响因子：
11.1
通讯作者：
Christofori, Gerhard
中科院分区：
文献类型：
--
作者：
Archetti, Marco;Ferraro, Daniela A.;Christofori, Gerhard
通过对癌症基因组测序揭示的广泛的肿瘤内异质性是肿瘤进展、诊断和治疗的重要决定因素。是什么维持了异质性仍然是一个悬而未决的问题，因为肿瘤内的竞争导致了对最适合的亚克隆的强烈选择。癌细胞还通过共享具有旁分泌效应的分子（如生长因子）进行合作，如果亚克隆相互依赖生存，则可以维持异质性。然而，如果亚克隆之间没有严格的相互依赖关系，非生产细胞可以免费搭乘邻近生产细胞产生的生长因子，这是一个在博弈论中被称为“公地悲剧”的集体行动问题，这在微生物细胞群体中已经观察到。在这里，我们报告说，类似的动态发生在癌细胞群。不产生胰岛素样生长因子II（IGF-II）的神经内分泌胰腺癌（胰岛素瘤）细胞在纯培养中生长缓慢，但在混合培养中具有增殖优势，在混合培养中它们可以使用生产细胞提供的IGF-II。我们表明，正如进化博弈论所预测的那样，生产细胞不会灭绝，因为IGF-II作为一种非线性公共产品，产生负频率依赖性选择，导致两种细胞类型稳定共存。因此，即使细胞亚克隆之间没有严格的相互依赖性，也可以维持瘤内细胞异质性。减少肿瘤内可用的生长因子的量可能导致生长减少，然后是新的平衡，这可以解释靶向生长因子的治疗复发。
The extensive intratumor heterogeneity revealed by sequencing cancer genomes is an essential determinant of tumor progression, diagnosis, and treatment. What maintains heterogeneity remains an open question because competition within a tumor leads to a strong selection for the fittest subclone. Cancer cells also cooperate by sharing molecules with paracrine effects, such as growth factors, and heterogeneity can be maintained if subclones depend on each other for survival. Without strict interdependence between subclones, however, nonproducer cells can free-ride on the growth factors produced by neighboring producer cells, a collective action problem known in game theory as the "tragedy of the commons," which has been observed in microbial cell populations. Here, we report that similar dynamics occur in cancer cell populations. Neuroendocrine pancreatic cancer (insulinoma) cells that do not produce insulin-like growth factor II (IGF-II) grow slowly in pure cultures but have a proliferation advantage in mixed cultures, where they can use the IGF-II provided by producer cells. We show that, as predicted by evolutionary game theory, producer cells do not go extinct because IGF-II acts as a nonlinear public good, creating negative frequency-dependent selection that leads to a stable coexistence of the two cell types. Intratumor cell heterogeneity can therefore be maintained even without strict interdependence between cell subclones. Reducing the amount of growth factors available within a tumor may lead to a reduction in growth followed by a new equilibrium, which may explain relapse in therapies that target growth factors.