Cancer Stem Cell Tumor Model Reveals Invasive Morphology and Increased Phenotypical Heterogeneity
Cancer Stem Cell Tumor Model Reveals Invasive Morphology and Increased Phenotypical Heterogeneity
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DOI：
10.1158/0008-5472.can-09-3663
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发表时间：
2010-01-01
期刊：
影响因子：
11.2
通讯作者：
Vermeulen, Louis
中科院分区：
文献类型：
--
作者：
Sottoriva, Andrea;Verhoeff, Joost J. C.;Vermeulen, Louis
最近开发的癌症干细胞（CSC）概念为肿瘤生长和进展的各个方面提供了新的线索。在这里，我们提出了一个恶性肿瘤的数学模型，以研究分层组织的癌细胞群如何影响实体恶性肿瘤的基本特性。我们确定，在 CSC 背景下建模的肿瘤更忠实地类似于人类恶性肿瘤并表现出侵袭性行为，而没有 CSC 层次结构的肿瘤则不然。这些发现得到了体外研究的证实。此外，我们提供的证据表明，与随机、非分层肿瘤模型中预测存在的进化动力学相比，CSC 模型伴随着高度改变的进化动力学。我们的主要发现表明，CSC 模型允许显着更高的肿瘤异质性，这可能会影响治疗耐药性。此外，我们表明，未能针对 CSC 群体的治疗不仅无法成功治愈患者，而且还会促进复发肿瘤的恶性特征。这些包括快速扩张、入侵增加和异质性增强。癌症研究； 70(1)； 46-56。 (C)2010 AACR。
The recently developed concept of cancer stem cells (CSC) sheds new light on various aspects of tumor growth and progression. Here, we present a mathematical model of malignancies to investigate how a hierarchical organized cancer cell population affects the fundamental properties of solid malignancies. We establish that tumors modeled in a CSC context more faithfully resemble human malignancies and show invasive behavior, whereas tumors without a CSC hierarchy do not. These findings are corroborated by in vitro studies. In addition, we provide evidence that the CSC model is accompanied by highly altered evolutionary dynamics compared with the ones predicted to exist in a stochastic, nonhierarchical tumor model. Our main findings indicate that the CSC model allows for significantly higher tumor heterogeneity, which may affect therapy resistance. Moreover, we show that therapy which fails to target the CSC population is not only unsuccessful in curing the patient, but also promotes malignant features in the recurring tumor. These include rapid expansion, increased invasion, and enhanced heterogeneity. Cancer Res; 70(1); 46-56. (C)2010 AACR.