Department of Regenerative Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America.
PLoS One. 2011;6(9):e24454. doi: 10.1371/journal.pone.0024454. Epub 2011 Sep 9.
Primary glioblastomas are subdivided into several molecular subtypes. There is an ongoing debate over the cell of origin for these tumor types where some suggest a progenitor while others argue for a stem cell origin. Even within the same molecular subgroup, and using lineage tracing in mouse models, different groups have reached different conclusions. We addressed this problem from a combined mathematical modeling and experimental standpoint. We designed a novel mathematical framework to identify the most likely cells of origin of two glioma subtypes. Our mathematical model of the unperturbed in vivo system predicts that if a genetic event contributing to tumor initiation imparts symmetric self-renewing cell division (such as PDGF overexpression), then the cell of origin is a transit amplifier. Otherwise, the initiating mutations arise in stem cells. The mathematical framework was validated with the RCAS/tv-a system of somatic gene transfer in mice. We demonstrated that PDGF-induced gliomas can be derived from GFAP-expressing cells of the subventricular zone or the cortex (reactive astrocytes), thus validating the predictions of our mathematical model. This interdisciplinary approach allowed us to determine the likelihood that individual cell types serve as the cells of origin of gliomas in an unperturbed system.
原发性神经胶质瘤可细分为几种分子亚型。对于这些肿瘤类型的起源细胞存在着持续的争论，一些人认为是祖细胞，而另一些人则认为是干细胞起源。即使在同一分子亚组中，并且在使用小鼠模型进行谱系追踪的情况下，不同的研究小组也得出了不同的结论。我们从综合数学建模和实验的角度来解决这个问题。我们设计了一种新颖的数学框架来确定两种神经胶质瘤亚型最可能的起源细胞。我们未受干扰的体内系统的数学模型预测，如果导致肿瘤起始的遗传事件赋予对称自我更新的细胞分裂（例如 PDGF 过表达），那么起源细胞就是过渡放大器。否则，起始突变发生在干细胞中。该数学框架通过 RCAS/tv-a 系统在小鼠中的体基因转移得到了验证。我们证明了 PDGF 诱导的神经胶质瘤可以来源于侧脑室下区或皮质中的 GFAP 表达细胞（反应性星形胶质细胞），从而验证了我们数学模型的预测。这种跨学科的方法使我们能够确定在未受干扰的系统中，单个细胞类型作为神经胶质瘤起源细胞的可能性。
