Napoletani Domenico, Signore Michele, Struppa Daniele C
Institute for Quantum Studies, Chapman University, Orange, CA, 92866, USA.
Department of Hematology, Oncology and Molecular Medicine, Tumor Stem Cell Biobank, Istituto Superiore di Sanita, 00161, Rome, Italy.
F1000Res. 2013 Dec 6;2:268. doi: 10.12688/f1000research.2-268.v1. eCollection 2013.
In this paper we develop a theoretical frame to understand self-regulation of aneuploidy rate in cancer and stem cells. This is accomplished building upon quasispecies theory, by leaving its formal mathematical structure intact, but by drastically changing the meaning of its objects. In particular, we propose a novel definition of chromosomal master sequence, as a sequence of physically distinct whole or fragmented chromosomes, whose length is taken to be the sum of the copy numbers of each whole or fragmented chromosome. This fundamental change in the functional objects of quasispecies theory allows us to show that previously measured aneuploidy rates in cancer populations are already close to a formally derived aneuploid error threshold, and that any value of aneuploidy rate larger than the aneuploid error threshold would lead to a loss of fitness of a tumor population. Finally, we make a phenomenological analysis of existing experimental evidence to argue that single clone cancer cells, derived from an aneuploid cancer subpopulation, are capable of self-regulating their aneuploidy rate and of adapting it to distinct environments, namely primary and metastatic microenvironments. We also discuss the potential origin of this self-regulatory ability in the wider context of developmental and comparative biology and we hypothesize the existence of a diversification factor, i.e. a cellular mechanism that regulates adaptation of aneuploidy rates, active in all embryo, adult and cancer stem cells.
在本文中，我们构建了一个理论框架，以理解癌症和干细胞中非整倍体率的自我调节机制。这一工作是基于准种理论完成的，保留其形式数学结构不变，但彻底改变其研究对象的含义。具体而言，我们提出了一种新的染色体主序列定义，它是由物理上不同的完整或片段化染色体组成的序列，其长度为每个完整或片段化染色体拷贝数之和。准种理论功能对象的这一根本性变化使我们能够证明，先前在癌症群体中测得的非整倍体率已经接近一个形式推导得出的非整倍体错误阈值，并且任何大于该阈值的非整倍体率值都会导致肿瘤群体适应性的丧失。最后，我们对现有实验证据进行了现象学分析，认为源自非整倍体癌症亚群的单克隆癌细胞能够自我调节其非整倍体率，并使其适应不同的环境，即原发性和转移性微环境。我们还在发育生物学和比较生物学的更广泛背景下讨论了这种自我调节能力的潜在起源，并假设存在一种多样化因子，即一种调节非整倍体率适应性的细胞机制，在所有胚胎、成体和癌症干细胞中都起作用。
