Aneuploidy precedes and segregates with chemical carcinogenesis

A century ago, Boveri proposed that cancer is caused by aneuploidy, an abno rmal balance of chromosomes, because aneuploidy correlates with cancer and because experimental aneuploidy generates "pathological" phenotypes. Half a century later, when cancers were found to be nonclonal for aneuploidy, but clonal for somatic gene mutations, this hypothesis was abandoned. As a res ult, aneuploidy is now generally viewed as a consequence, and mutated genes as a cause of cancer. However, we have recently proposed a two-stage mecha nism of carcinogenesis that resolves the discrepancy between clonal mutatio n and nonclonal karyotypes. The proposal is as follows: in stage 1, a carci nogen "initiates" carcinogenesis by generating a preneoplastic aneuploidy; in stage 2, aneuploidy causes asymmetric mitosis because it biases balance- sensitive spindle and chromosomal proteins and alters centrosomes both nume rically and structurally tin proportion to the degree of aneuploidy). There fore, the karyotype of an initiated cell evolves autocatalytically, generat ing ever-new chromosome combinations, including neoplastic ones. Accordingl y, the heterogeneous karyotypes of "clonal" cancers are an inevitable conse quence of the karyotypic instability of aneuploid cells. The notorious long latent periods, of months to decades, from carcinogen to carcinogenesis, w ould reflect the low probability of evolving by chance karyotypes that comp ete favorably with normal cells, in principle analagous to natural evolutio n. Here, Mie have confirmed experimentally five predictions of the aneuploi dy hypothesis: (1) the carcinogens dimethylbenzanthracene and cytosine arab inoside induced aneuploidy in a fraction of treated Chinese hamster embryo cells; (2) aneuploidy preceded malignant transformation; (3) transformation of carcinogen-treated cells occurred only months after carcinogen treatmen t, i.e., autocatalytically; (4) preneoplastic aneuploidy segregated with ma lignant transformation in vitro and with 14 of 14 tumors in animals; and (5 ) karyotypes of tumors were heterogeneous. We conclude that, with the carci nogens studied, aneuploidy precedes cancer and is necessary for carcinogene sis. (C) 2000 Elsevier Science Inc. All rights reserved.