Rubin H
Department of Molecular and Cell Biology, University of California, Berkeley 94720-3206.
Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6619-23. doi: 10.1073/pnas.91.14.6619.
Foulds introduced six rules of tumor progression based on his observations of spontaneous mammary cancer in mice and generalized them to all forms of neoplasia [Foulds, L. (1954) Cancer Res. 14, 327-339 and Foulds, L. (1969) Neoplastic Development (Academic, New York), Vol. 1, preface and pp. 72-74.] Rules III, IV, and V are considered controversial, and research in animals seems inadequate to resolve the controversies. A subline of NIH 3T3 cells undergoes progressive transformation to produce foci of increasing population density when repeatedly constrained by sequential rounds of growth to and maintenance at confluence. Analysis of the results provides a cellular basis for rules III, IV, and V. Rule III states that progression is independent of the growth of the tumor and occurs in tumors that are arrested. Cell culture shows that progression is actually favored by constraint of growth, a result inconsistent with a major role for point mutations in progression. Indeed, there is a suggestion that the transformation may arise from chromatin changes preceding apoptosis. Rule IV states that progression can be gradual or abrupt but the latter conclusion has been frequently criticized. Cell culture exhibits both forms of progression but, in particular, eliminates the doubt about the abrupt form. Rule V, which is in a sense an extension of rule IV, states that progression follows one of alternative paths of development. The results in culture indicate that every independent transforming event gives rise to foci of unique morphology. Thus, even for the single characteristic of transformed focus morphology, many alternative paths to neoplasia are available to cells. In addition to clarifying the rules of progression, a method is described for pinpointing the time of the occurrence of events that are only expressed as dense foci after a variable lag time. The results in culture reinforce Foulds' conclusion that neoplastic development is primarily an epigenetically driven process and identify some of the cellular interactions that underlie that process.
福尔兹基于对小鼠自发性乳腺癌的观察，提出了六条肿瘤进展规则，并将其推广到所有形式的肿瘤形成[福尔兹，L.（1954年）《癌症研究》14卷，327 - 339页；福尔兹，L.（1969年）《肿瘤发展》（学术出版社，纽约），第1卷，前言及72 - 74页]。规则三、四和五存在争议，动物研究似乎不足以解决这些争议。当NIH 3T3细胞亚系在连续多轮生长至汇合并维持汇合状态时反复受到限制，会经历渐进性转化，产生细胞密度不断增加的集落。对结果的分析为规则三、四和五提供了细胞基础。规则三指出，进展与肿瘤生长无关，发生在停滞的肿瘤中。细胞培养表明，生长受限实际上有利于进展，这一结果与进展中单个点突变起主要作用不一致。实际上，有迹象表明转化可能源于凋亡前的染色质变化。规则四指出，进展可以是渐进的或突然的，但后一种结论经常受到批评。细胞培养显示了这两种进展形式，但特别消除了对突然形式的疑问。规则五在某种意义上是规则四的延伸，指出进展遵循一条或多条替代的发展路径。培养结果表明，每个独立的转化事件都会产生具有独特形态的集落。因此，即使对于转化集落形态这一单一特征，细胞也有许多通往肿瘤形成的替代路径。除了阐明进展规则外，还描述了一种方法，用于确定那些在可变延迟时间后才表现为密集集落的事件的发生时间。培养结果强化了福尔兹的结论，即肿瘤发展主要是一个由表观遗传驱动的过程，并确定了该过程背后的一些细胞相互作用。
