Discovery of Power-Law Growth in the Self-Renewal of Heterogeneous Glioma Stem Cell Populations.
Discovery of Power-Law Growth in the Self-Renewal of Heterogeneous Glioma Stem Cell Populations.
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DOI：
10.1371/journal.pone.0135760
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Kuroda S
中科院分区：
文献类型：
--
作者：
Sugimori M;Hayakawa Y;Boman BM;Fields JZ;Awaji M;Kozano H;Tamura R;Yamamoto S;Ogata T;Yamada M;Endo S;Kurimoto M;Kuroda S
越来越多的证据表明，癌症干细胞（CSCs）驱动肿瘤发生。这表明csc应该是理想的治疗靶点。然而，由于肿瘤中的CSC群体表现出异质性，目前尚不清楚CSC如何有效靶向。为了研究CSC群体在自我更新过程中保持异质性的机制，我们建立了胶质瘤球（glioma sphere， GS）形成模型，以产生胶质瘤干细胞（glioma stem cells, GSCs）富集的群体。基于克隆进化的概念，我们假设，随着培养的每一次传代，GSs的异质克隆亚系逐渐产生，并显示出增加的增殖能力。为了验证这一假设，我们确定了在每一次传代中，由四种不同的胶质瘤细胞系产生的胶质瘤神经球培养物是否逐渐增殖（即在大球体中富集）。我们没有监测自我更新，而是根据神经球克隆大小（#cells/clone）测量异质性。克隆大小分布的对数-对数图与直线（log（%总数克隆）= k*log(#cells/clone)）很好地拟合（r>0.90），表明系统遵循具有特定程度指数（k = - 1.42）的幂律（y = xk）。对GS总群体进行重复传代，在6代传代中保持相同的幂律（CV = - 1.01 ~ - 1.17）。令人惊讶的是，无论是分离的小亚克隆还是大亚克隆的传代，都产生了完全异质的群体，这些群体保留了原始的幂律依赖的异质性。抗gsc药物替莫唑胺（Temozolomide）是众所周知的多形胶质母细胞瘤（GBM）的标准治疗药物，它抑制了克隆的自我更新，但从未破坏GS群体的幂律行为。尽管上述数据不支持上述假设，但它们确实强烈提示了CSC异质性的新机制。他们指出，幂律生长支配着异质胶质瘤干细胞群体的自我更新。数据总是符合幂律，这表明：(i)克隆大小遵循连续的、非随机的、无标度的层次结构；（ii）反映自组织涌现行为的精确生物学规则支配着神经球的产生。幂律行为和原始的GS异质性在多个通道中保持不变，表明这些规则是不变的。这些自组织机制很可能是肿瘤生长过程中肿瘤异质性的基础。这种幂律行为的发现提供了一种机制，可以用于开发新的、更有效的抗癌药物。
Accumulating evidence indicates that cancer stem cells (CSCs) drive tumorigenesis. This suggests that CSCs should make ideal therapeutic targets. However, because CSC populations in tumors appear heterogeneous, it remains unclear how CSCs might be effectively targeted. To investigate the mechanisms by which CSC populations maintain heterogeneity during self-renewal, we established a glioma sphere (GS) forming model, to generate a population in which glioma stem cells (GSCs) become enriched. We hypothesized, based on the clonal evolution concept, that with each passage in culture, heterogeneous clonal sublines of GSs are generated that progressively show increased proliferative ability. To test this hypothesis, we determined whether, with each passage, glioma neurosphere culture generated from four different glioma cell lines become progressively proliferative (i.e., enriched in large spheres). Rather than monitoring self-renewal, we measured heterogeneity based on neurosphere clone sizes (#cells/clone). Log-log plots of distributions of clone sizes yielded a good fit (r>0.90) to a straight line (log(% total clones) = k*log(#cells/clone)) indicating that the system follows a power-law (y = xk) with a specific degree exponent (k = −1.42). Repeated passaging of the total GS population showed that the same power-law was maintained over six passages (CV = −1.01 to −1.17). Surprisingly, passage of either isolated small or large subclones generated fully heterogeneous populations that retained the original power-law-dependent heterogeneity. The anti-GSC agent Temozolomide, which is well known as a standard therapy for glioblastoma multiforme (GBM), suppressed the self-renewal of clones, but it never disrupted the power-law behavior of a GS population. Although the data above did not support the stated hypothesis, they did strongly suggest a novel mechanism that underlies CSC heterogeneity. They indicate that power-law growth governs the self-renewal of heterogeneous glioma stem cell populations. That the data always fit a power-law suggests that: (i) clone sizes follow continuous, non-random, and scale-free hierarchy; (ii) precise biologic rules that reflect self-organizing emergent behaviors govern the generation of neurospheres. That the power-law behavior and the original GS heterogeneity are maintained over multiple passages indicates that these rules are invariant. These self-organizing mechanisms very likely underlie tumor heterogeneity during tumor growth. Discovery of this power-law behavior provides a mechanism that could be targeted in the development of new, more effective, anti-cancer agents.