Cancer Stem Cells: A Minor Cancer Subpopulation that Redefines Global Cancer Features.
Cancer Stem Cells: A Minor Cancer Subpopulation that Redefines Global Cancer Features.
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DOI：
10.3389/fonc.2013.00076
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发表时间：
2013
影响因子：
4.7
通讯作者：
Hahnfeldt P
中科院分区：
文献类型：
--
作者：
Enderling H;Hlatky L;Hahnfeldt P
近年来，癌症干细胞（CSC）被假设为在实体瘤中仅包含驱动肿瘤起始、进展和转移的较小亚群;所谓的“癌症干细胞假说”。虽然这是一个关于数字的看似微不足道的陈述，但其中的许多内容都岌岌可危。如果这是真的，那么许多癌细胞群体研究的结论可能会受到挑战，因为它们所依赖的批量测定方法基本上都理所当然地认为群体中的“典型”细胞具有能够使癌症永久存在的细胞的属性，即，a CSC。为了支持CSC假说，通过稀释测定法测量，富集所谓的“肿瘤起始”细胞的群体已证明致瘤性相应增加，尽管关于肿瘤起始细胞在任何给定群体中的贡献分数的估计变化很大。一些人认为这种变异性表明CSC分数可能接近100%，这与CSC假设相反，并且在我们在细胞水平上“重新确认”CSC状态的能力中存在简单的测定依赖性错误率。为了更定量地探讨这一争议，我们开发了一个简单的CSC驱动的肿瘤生长动力学的元胞自动机模型。假设CSC和非干细胞癌细胞（CC）亚群在某种程度上共存，我们评估了环境依赖性CSC对称分裂概率和CC增殖能力对肿瘤进展和形态的影响。我们的模型预测，正如预期的那样，CSC分裂的频率是对称的，高度影响群体中CSC的频率，但继续预测这两个频率可以是广泛的分歧，空间限制将倾向于随着时间的推移增加CSC的分数。此外，肿瘤进展时间显示出对对称CSC分裂频率和CC增殖能力的显著依赖性。总之，这些发现可以解释，在CSC假设，观察到的干细胞分数的广泛变化的措施。特别是，虽然CSC分数的影响（环境可修改的）CSC对称划分概率，前者收敛到统一的后者接近100%，CSC分数变得相当小，即使对称划分概率适度低于100%。在后一种情况下，肿瘤表现出聚集的形态，CSC分数随时间稳步增加;当CC的死亡率较高时，两种计数都更是如此。CSC分数和形态的这种变化不仅与CSC假说一致，而且支持它作为一个预期的动态相互作用的副产品，预测发生在相对较小的CSC群体，其CC对应物和宿主隔室之间。
In recent years cancer stem cells (CSCs) have been hypothesized to comprise only a minor subpopulation in solid tumors that drives tumor initiation, progression, and metastasis; the so-called “cancer stem cell hypothesis.” While a seemingly trivial statement about numbers, much is put at stake. If true, the conclusions of many studies of cancer cell populations could be challenged, as the bulk assay methods upon which they depend have, by, and large, taken for granted the notion that a “typical” cell of the population possesses the attributes of a cell capable of perpetuating the cancer, i.e., a CSC. In support of the CSC hypothesis, populations enriched for so-called “tumor-initiating” cells have demonstrated a corresponding increase in tumorigenicity as measured by dilution assay, although estimates have varied widely as to what the fractional contribution of tumor-initiating cells is in any given population. Some have taken this variability to suggest the CSC fraction may be nearly 100% after all, countering the CSC hypothesis, and that there are simply assay-dependent error rates in our ability to “reconfirm” CSC status at the cell level. To explore this controversy more quantitatively, we developed a simple cellular automaton model of CSC-driven tumor growth dynamics. Assuming CSC and non-stem cancer cells (CC) subpopulations coexist to some degree, we evaluated the impact of an environmentally dependent CSC symmetric division probability and a CC proliferation capacity on tumor progression and morphology. Our model predicts, as expected, that the frequency of CSC divisions that are symmetric highly influences the frequency of CSCs in the population, but goes on to predict the two frequencies can be widely divergent, and that spatial constraints will tend to increase the CSC fraction over time. Further, tumor progression times show a marked dependence on both the frequency of CSC divisions that are symmetric and on the proliferation capacities of CC. Together, these findings can explain, within the CSC hypothesis, the widely varying measures of stem cell fractions observed. In particular, although the CSC fraction is influenced by the (environmentally modifiable) CSC symmetric division probability, with the former converging to unity as the latter nears 100%, the CSC fraction becomes quite small even for symmetric division probabilities modestly lower than 100%. In the latter case, the tumor exhibits a clustered morphology and the CSC fraction steadily increases with time; more so on both counts when the death rate of CCs is higher. Such variations in CSC fraction and morphology are not only consistent with the CSC hypothesis, but lend support to it as one expected byproduct of the dynamical interactions that are predicted to take place among a relatively small CSC population, its CC counterpart, and the host compartment over time.