The dualistic origin of human tumors.
The dualistic origin of human tumors.
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DOI：
10.1016/j.semcancer.2018.07.004
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发表时间：
2018-12
影响因子：
14.5
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Liu J
生命始于受精卵，受精卵由单倍体精子和卵子融合而成。通过卵裂分裂(核分裂而不增加细胞大小)形成卵裂球是胚胎发育的第一步，在合子形成之后。分裂球负责将父母的基因组重新编程为新的胚胎基因组，以产生多潜能干细胞，然后通过沃丁顿的表观遗传格局进行分化，创造新的生命。在过去的150年里，多位作者提出，肿瘤是由于在沃丁顿的景观中出现了某种程度的发育错误而产生的。最近的发现表明，分化的体细胞可以被重新编程为诱导的多能干细胞，体细胞核移植可以成功克隆动物，这些发现从根本上重塑了我们对肿瘤发展和起源的理解。分化的体细胞是可塑性的，可以被诱导去分化为多能干细胞。在这里，我回顾了体细胞可能有一个以前被忽视的内源性胚胎程序的证据，该程序可以被激活，使体细胞去分化为各种潜能的干细胞，从而启动肿瘤。多倍体巨细胞癌细胞(PGCC)在癌症中一直被观察到，最初被认为是不可分裂的。与此相反，最近的研究结果表明，应激诱导的PGCC通过内复制进行分裂，这可能是卵裂球中卵裂样分裂的模式，并通过一个被称为巨细胞周期的程序化过程导致体细胞去分化，巨细胞周期包括四个不同但重叠的阶段：起始、自我更新、终止和稳定。根据应激的强度和类型，不同程度的去分化会导致不同级别的恶性肿瘤的形成。基于这些结果，我提出了一个统一的二元论模型来论证人类肿瘤的起源。该模型的宗旨包括四点，具体如下。1.肿瘤起源于特定发育层次的干细胞，这可以通过双重起源实现：由两个单倍体配子形成的受精卵在正常发育过程中通过卵裂球脱分化(有性繁殖)，或从受损或老化的成熟体细胞通过类似卵裂球的胚胎程序转化(无性繁殖)。2.肿瘤的发生始于一种干细胞，它将分化与增殖程序分离，从而导致干细胞成熟停滞。3.干细胞停滞的发育等级决定了恶性程度：干细胞停滞的水平越原始，肿瘤恶性的可能性就越大。4.环境因素和固有的遗传或表观遗传改变是促进干细胞停滞和体细胞去分化的危险因素或应激源。然而，它们本身并不是肿瘤发生的驱动力。因此，肿瘤的诞生可以被视为一个三位一体的过程，它来自干细胞，通过卵裂球或类似卵裂球的程序进行去分化，然后沿着沃丁顿的景观分化，并在发育层次上停止。阻断PGCC介导的去分化过程并诱导其分化可能是一种消除肿瘤发生和治疗耐药的新途径。
Life starts with a zygote, which is formed by the fusion of a haploid sperm and egg. The formation of a blastomere by cleavage division (nuclear division without an increase in cell size) is the first step in embryogenesis, after the formation of the zygote. Blastomeres are responsible for reprogramming the parental genome as a new embryonic genome for generation of the pluripotent stem cells which then differentiate by Waddington’s epigenetic landscape to create a new life. Multiple authors over the past 150 years have proposed that tumors arises from development gone awry at a point within Waddington’s landscape. Recent discoveries showing that differentiated somatic cells can be reprogrammed into induced pluripotent stem cells, and that somatic cell nuclear transfer can be used to successfully clone animals, have fundamentally reshaped our understanding of tumor development and origin. Differentiated somatic cells are plastic and can be induced to dedifferentiate into pluripotent stem cells. Here, I review the evidence that suggests somatic cells may have a previously overlooked endogenous embryonic program that can be activated to dedifferentiate somatic cells into stem cells of various potencies for tumor initiation. Polyploid giant cancer cells (PGCCs) have long been observed in cancer and were thought originally to be nondividing. Contrary to this belief, recent findings show that stress-induced PGCCs divide by endoreplication, which may recapitulate the pattern of cleavage-like division in blastomeres and lead to dedifferentiation of somatic cells by a programmed process known as “the giant cell cycle”, which comprise four distinct but overlapping phases: initiation, self-renewal, termination and stability. Depending on the intensity and type of stress, different levels of dedifferentiation result in the formation of tumors of different grades of malignancy. Based on these results, I propose a unified dualistic model to demonstrate the origin of human tumors. The tenet of this model includes four points, as follows. 1. Tumors originate from a stem cell at a specific developmental hierarchy, which can be achieved by dualistic origin: dedifferentiation of the zygote formed by two haploid gametes (sexual reproduction) via the blastomere during normal development, or transformation from damaged or aged mature somatic cells via a blastomere-like embryonic program (asexual reproduction). 2. Initiation of the tumor begins with a stem cell that has uncoupled the differentiation from the proliferation program which results in stem cell maturation arrest. 3. The developmental hierarchy at which stem cells arrest determines the degree of malignancy: the more primitive the level at which stem cells arrest, the greater the likelihood of the tumor being malignant. 4. Environmental factors and intrinsic genetic or epigenetic alterations represent the risk factors or stressors that facilitate stem cell arrest and somatic cell dedifferentiation. However, they, per se, are not the driving force of tumorigenesis. Thus, the birth of a tumor can be viewed as a triad that originates from a stem cell via dedifferentiation through a blastomere or blastomere-like program, which then differentiates along Waddington’s landscape, and arrests at a developmental hierarchy. Blocking the PGCC-mediated dedifferentiation process and inducing their differentiation may represent a novel alternative approach to eliminate the tumor occurrence and therapeutic resistance.
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影响因子：
28.2
作者：
Chaffer CL;Weinberg RA
通讯作者：
Weinberg RA
影响因子：
64.8
作者：
Abad, Maria;Mosteiro, Lluc;Serrano, Manuel
通讯作者：
Serrano, Manuel
DOI：
10.1186/bcr3019
发表时间：
2011-09-27
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Beltran AS;Rivenbark AG;Richardson BT;Yuan X;Quian H;Hunt JP;Zimmerman E;Graves LM;Blancafort P
通讯作者：
Blancafort P
影响因子：
3.9
作者：
Bignold, Leon P.;Coghlan, Brian L. D.;Jersmann, Hubertus Pa.
通讯作者：
Jersmann, Hubertus Pa.
影响因子：
5.9
作者：
Braune EB;Tsoi YL;Phoon YP;Landor S;Silva Cascales H;Ramsköld D;Deng Q;Lindqvist A;Lian X;Sahlgren C;Jin SB;Lendahl U
通讯作者：
Lendahl U