Institute for Medical Biomathematics, 10 Te'ena str, P.O.B. 282, 60991 Bene Ataroth, Israel.
J Theor Biol. 2012 Apr 7;298:32-41. doi: 10.1016/j.jtbi.2011.12.016. Epub 2011 Dec 23.
The cancer stem cell (CSC) hypothesis states that only a small fraction of a malignant cell population is responsible for tumor growth and relapse. Understanding the relationships between CSC dynamics and cancer progression may contribute to improvements in cancer treatment. Analysis of a simple discrete mathematical model has suggested that homeostasis in developing tissues is governed by a "quorum sensing" control mechanism, in which stem cells differentiate or proliferate according to feedback they receive from neighboring cell populations. Further analysis of the same model has indicated that excessive stem cell proliferation leading to malignant transformation mainly results from altered sensitivity to such micro-environmental signals. Our aim in this work is to expand the analysis to the dynamics of established populations of cancer cells and to examine possible therapeutic avenues for eliminating CSCs. The proposed model considers two populations of cells: CSCs, which can divide indefinitely, and differentiated cancer cells, which do not divide and have a limited lifespan. We assume that total cell density has negative feedback on CSC proliferation and that high CSC density activates CSC differentiation. We show that neither stimulation of CSC differentiation nor inhibition of CSC proliferation alone is sufficient for complete CSC elimination and cancer cure, since each of these two therapies affects a different subpopulation of CSCs. However, a combination of these two strategies can substantially reduce the population sizes and densities of all types of cancer cells. Therefore, we propose that in clinical trials, CSC differentiation therapy should only be examined in combination with chemotherapy. Our conclusions are corroborated by clinical experience with differentiating agents in acute promyelocytic leukemia and neuroblastoma.
癌症干细胞（CSC）假说认为，恶性细胞群体中只有一小部分负责肿瘤生长和复发。了解 CSC 动力学与癌症进展之间的关系可能有助于改善癌症治疗。对一个简单的离散数学模型的分析表明，发育组织中的内稳态受“群体感应”控制机制的控制，其中干细胞根据它们从相邻细胞群体接收到的反馈信息进行分化或增殖。对同一模型的进一步分析表明，导致恶性转化的过度干细胞增殖主要是由于对这种微环境信号的敏感性改变所致。我们在这项工作中的目的是将分析扩展到已建立的癌细胞群体动力学，并研究消除 CSCs 的可能治疗途径。所提出的模型考虑了两种细胞群体：可以无限分裂的 CSCs 和不分裂且寿命有限的分化癌细胞。我们假设细胞总密度对 CSC 增殖具有负反馈作用，并且高 CSC 密度会激活 CSC 分化。我们表明，单独刺激 CSC 分化或抑制 CSC 增殖都不足以完全消除 CSC 和治愈癌症，因为这两种疗法中的每一种都影响 CSC 的不同亚群。然而，这两种策略的结合可以大大减少所有类型癌细胞的群体大小和密度。因此，我们建议在临床试验中，应仅在与化疗联合的情况下检查 CSC 分化疗法。我们的结论得到了急性早幼粒细胞白血病和神经母细胞瘤中分化剂的临床经验的证实。
