Ellison B J, Rubin H
Department of Molecular and Cell Biology, University of California, Berkeley 94720.
Cancer Res. 1992 Feb 1;52(3):667-73.
The NIH 3T3 line of mouse fibroblasts undergoes "spontaneous" transformation in culture, exhibited in the development of foci of transformed cells overgrowing the confluent monolayer. Evidence is provided here to support the proposition that the spontaneous generation of individual transformed variants is a product of epigenetic induction by various types of growth inhibition. Novel transformed variants generally arise after prolonged confluence and cessation of net growth, with these new types of foci appearing during a second round of confluence, although not in the first round. Few or no transformed variants exist in the cultures prior to growth constraint. The susceptibility of NIH 3T3 cells to induction of transformation is itself shown to be subject to epigenetic influence, with capacity for transformation reflecting passage histories. Cell sublines maintained in long-term subconfluent passage that allows unimpeded growth become more refractory with time to spontaneous transformation, while sublines passaged in more growth-restricting conditions maintain their sensitivity. The differing capacities of the sublines are reflected in the degree of growth inhibition required to induce individual events of spontaneous transformation, and in the frequency at which such new variants arise. Thus growth inhibition not only induces individual transforming events, but even increases cell susceptibility to further induction of transformation. These phenomena are consistent with the progressive state selection model of heritable change, which postulates a self-regulating selection of better adapted states from among those made available to a biological system during heterogeneous fluctuations in its total pattern of chemical equilibria.
小鼠成纤维细胞的NIH 3T3细胞系在培养过程中会发生“自发”转化，表现为转化细胞灶的形成，这些灶会在汇合的单层细胞上过度生长。本文提供的证据支持这样一种观点，即单个转化变体的自发产生是由各种类型的生长抑制引起的表观遗传诱导的产物。新的转化变体通常在长时间汇合和净生长停止后出现，这些新类型的灶在第二轮汇合期间出现，尽管在第一轮中没有出现。在生长受限之前，培养物中几乎不存在或不存在转化变体。NIH 3T3细胞对转化诱导的敏感性本身也受到表观遗传的影响，转化能力反映了传代历史。长期在亚汇合传代中维持的细胞亚系，允许不受阻碍地生长，随着时间的推移，对自发转化变得更具抗性，而在更多生长受限条件下传代的亚系则保持其敏感性。亚系的不同能力反映在诱导单个自发转化事件所需的生长抑制程度以及此类新变体出现的频率上。因此，生长抑制不仅诱导单个转化事件，甚至还增加细胞对进一步转化诱导的敏感性。这些现象与可遗传变化的渐进状态选择模型一致，该模型假设在生物系统化学平衡总模式的异质波动期间，从其可用的状态中进行自我调节选择更好适应的状态。
