Mutator phenotype may be required for multistage carcinogenesis.
Mutator phenotype may be required for multistage carcinogenesis.
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作者：
L. Loeb
越来越多的证据表明，癌症的发生经历了从正常细胞到癌前病变、局部肿瘤、侵袭性肿瘤和转移病变的一系列步骤。Foulds(1)最初分析了肿瘤进展阶段的概念，Nowell(2)提出了基于遗传不稳定性和克隆选择的肿瘤进展模型。在小鼠皮肤中，通过细胞对不同化学物质的反应，已经在手术中描绘了肿瘤进展的各个步骤。已经描述了人类肿瘤的表型变化的进展，其解剖定位使获得连续活组织检查成为可能(2，4)。在人类癌症中已有连续的体细胞染色体异常的报道，包括恶性梅尔瘤(5例)、结肠癌(6例)、胶质瘤(7例)、食管腺癌(8例)和肺小细胞癌(9例)。此外，人类乳腺癌中有多种不同的突变被仔细记录(10)。难题在于人类肿瘤中有太多的突变。从这个角度来看，我会考虑突变率和癌症之间的关系。至少需要两个突变才能解释在某些人类遗传病中观察到的染色体变化(11)。对文献的分析表明，细胞中的自发突变率具有足够的大小，足以解释癌症发生的双突变假说。然而，在许多人类肿瘤中观察到了大量的细胞分裂。体细胞的自发突变率不足以解释这些多重突变。如果肿瘤中的多种突变与癌症有因果关系，而不仅仅是伴随癌症，那么我认为肿瘤进展的早期步骤是诱导突变子表型的步骤。肿瘤中更高的突变率可能是许多癌症特征的多重突变的基础。
There is increasing evidence that the pathogenesis of cancer proceeds by sequential steps from normal cells to premalignant foci to localized tumors to invasive tumors and to metastatic lesions. The concept of stages of tumor progression was initially analyzed by Foulds (1), and a model for tumor progression based on genetic instability and clonal selection has been pro posed by Nowell (2). Individual steps in tumor progression have been operationally delineated in mouse skin by the responses of cells to different chemicals (3). A progression of phenotypic changes has been described in human tumors, the anatomical localization of which has made it feasible to obtain serial biopsies (2, 4). Sequential somatic chromosomal abnormalities have been reported in human cancers including malignant mel anoma (5), colon cancer (6), gliomas (7), adenocarcinoma of the esophagus (8), and small cell carcinomas of the lung (9). In addition, a multiplicity of different mutations has been carefully documented in human breast cancer (10). The dilemma is that there are too many mutations in human tumors. In this perspective, I will consider the relationships between mutation rates and cancer. At least two mutations are required to account for the chromosomal changes observed in certain human inherited diseases (11). An analysis of the literature indicates that the spontaneous mutation rate in cells is of sufficient magnitude to account for a two mutation hypothesis for the initiation of cancer. However, a larger number of mu tations are observed in many human tumors. The spontaneous mutation rate in somatic cells is not sufficient to account for these multiple mutations. If the multiple mutations in tumors are causally associated with and not just an accompaniment of cancer, then I argue that an early step in tumor progression is one that induces a mutator phenotype. An increased mutation rate in tumors could be the basis for the multiple mutations that characterize many cancers.