SPONTANEOUS TRANSFORMATION AND PROGRESSION IN CELL LINES

肿瘤细胞的异质性似乎是研究的主要障碍 成功治疗癌症。 对于理解也很重要 细胞自主生长（包括转移）的进展。 的 造成异质性的变异率的最高估计 每 10 5 个细胞发生一次可遗传的改变 部门。 在过去的一年里，我们能够在其中分离出五个克隆 Balb/3T3 细胞的后代，该细胞刚刚经历了自发性 变换并表征它们的特性。 我们发现每个 这些克隆可以通过形态与其他克隆区分开来， 琼脂中的集落形成效率 (CFEag) 和肿瘤形成率 裸鼠。 这一发现的意义在于，培养的细胞是如此 转化后不久就不稳定，基本上每个细胞都可能不同 在一个或多个特征上与其他人不同，即存在一个真正的 激进的异质性。 我们还研究了进一步的演变 五个克隆群体中这些特性在一段时间内的变化 6个月期间并得出结论，导致的变化类型 克隆之间最初的差异也可能是造成这种情况的原因 类似于肿瘤进展的持续变化。 由于这个频率 变异的类型非常高，并且涉及到多个属性 定量但不协调的方式，它不太可能是由 传统的基因突变。相反，它可能是一种表观遗传 事件。 这种类型的变化也可能在我们的第二专业中发挥作用 发现，转化细胞的某些特性发生了改变 在裸鼠肿瘤形成过程中以及当肿瘤细胞被再次 有文化的。 前者与普遍接受的观点相矛盾，即细胞 通过裸鼠传代不会改变。 我们发现我们的例子， 期间经常观察到 CFEag 下降超过 100 倍 肿瘤形成。 一些肿瘤细胞恢复了原来的高 CFEag 在文化中反复传代后，但其他人则不然。 也就是说，有一个 反应的异质性，一些变化是稳定的，另一些变化是不稳定的。 迄今为止的证据表明肿瘤发生过程中细胞的变化 形成和随后的培养本质上基本上是后生的， 其类型与上述转化后发生的类似。 研究结果有望为理解起源和 癌症的进展。 (J)

Heterogeneity of cells in tumors appears to be a major obstacle in the successful treatment of cancer. It is also of importance in understanding the progression of cells to autonomous growth including metastasis. The highest estimates of the rate of variation responsible for heterogeneity have been on the order of one heritable alteration per 105 cell divisions. In the past year we were able to isolate five clones among the progeny of a Balb/3T3 cell which had just undergone spontaneous transformation and to characterize their properties. We found that each of the clones could be distinguished from the others by morphology, colony-forming efficiency in agar (CFEag), and rate of tumor formation in nude mice. The implication of this finding is that cultured cells are so unstable soon after transformation that essentially every cell may differ from the others in one or more characteristics, i.e., that there is a truly radical heterogeneity. We have also studied the evolution of further changes in these properties among the five clonal populations over a 6-month period and conclude that the type of variation which led to the initial differences among the clones could also be responsible for continuing change akin to tumor progression. Since the frequency of this type of variation is very high and involves several properties in a quantitative but uncoordinated way, it is unlikely to be caused by conventional genetic mutations. Rather, it is likely to be an epigenetic event. This type of variation is also likely to play a role in our second major finding, which is that some properties of transformed cells are altered during tumor formation in the nude mouse and again when the tumor cells are cultured. The former contradicts the generally accepted view that cells are not changed by passage through nude mice. We find our example, that a decrease in CFEag of more than 100-fold, is frequently observed during tumor formation. Cells from some tumors regain their original high CFEag after repeated passaging in culture but others do not. That is, there is a heterogeneity of response, some changes being stable and others unstable. The evidence to date indicates the alterations in cells during tumor formation and subsequent cultivation are basically epigenetic in nature and similar in type to those described above which occur after transformation. The results promise to provide new ground for understanding the origin and progression of cancer. (J)