Cancer: Reexpression of Procaryotic Replication Units—the "Procaryote Hypothesis" of Oncogenesis

CANCER: REEXPRESSION OF PROCARYOTIC REPUCATION UNITS— THE "PROCARYOTE HYPOTHESIS" OF ONCOGENESIS KLAUS GROSSGEBAUER* Among the many theories of oncogenesis, three possible mechanisms are favored to result in malignant proliferation: (1) cancer develops because of a direct mutation of one or several specific cellular genes, (2) cancer results from activation of preexisting cellular "tumor genes" mediated by the switch-off of cellular control factors, and (3) cancer requires the presence of phylogenetically foreign noncellular (viral) DNA. This material has to be activated or its cellular control has to be altered [1-4]. Thus, the first two cancer theories work with the existence of more or less specific normal cellular genes, whereas the third hypothesis presumes phylogenetically foreign and noncellular, that is, viral, DNA. In recent years, most authors have espoused the second theory of cancer genesis which works with preexisting cellular "tumor genes." According to the Britten-Davidson model of 1969, the high DNA content of the eucaryotic cell cannot only code enzymes or, more generally, proteins, but it may very well have further functions. Furthermore, it is suggested that most of the cellular genes are normally repressed, the majority of diem by the different types ofhistones. These and a number of other arguments lead to the conclusion that the common element in the induction and progression of malignant growth by all types of carcinogens may be the random unmasking or reexpression of embryonic and nonembryonic genes. Carcinogens could act by altering the structure of the chromatin-DNA-protein-RNA complex and thus changing the differentiation state of the cell. Indeed, the abnormal expression of various normal proteins are common in many cancers, and some ofthese have diagnostic values for detection of cancer. The neoplastic state is ?Institute of Medical Microbiology, Free University of Berlin, FB 1, WE 4, Hindenburgdamm 27, 1000 Berlin 45, FRG.© 1983 by The University of Chicago. All rights reserved. 0031-5982/83/2603-0327$01.00 354 J Klaus Grossgebauer · "Procaryote Hypothesis" ofOncogenesis heritable in the same manner as any other differentiated state. On a more general level, it seems possible that both—epigenetic and genetic modifications—can cause cancer and may operate simultaneously. To prove this hypothesis, we should have extensive knowledge about the complex structure of the highly developed eucaryotic genome, its composition, its mode of replication, and the events of its alteration. Unfortunately, many of the details are only poorly understood. Surprisingly, in the vast number of papers concerning different aspects of the mechanisms of the normal and pathological growth of higher eucaryotic cells, one fundamental idea (and its conclusions) has not been exhaustively analyzed: the possibility that replication units of procaryotes and/or their precursors with the unique capacity for autonomous and indefinite replication are essentially involved in the cancerogenesis . In our view, it is possible that these structures (a) were conferred and conserved in the eucaryotic genome, (b) evolved to eucaryotic replication units, and (c) reexpress by cancerogens leading to the procaryotic precursors. This would allow one to conclude that the procaryotic replication units and the hypothetical tumor genes in eucaryotes are identical. Consequendy, the formation of tumor genes did not begin with the existence ofeucaryotic cells. On thecontrary, this process started very much earlier in the course of die evolution of primitive nucleic acid structures possessing the very novel capacity of indefinite self-replication. This event may have taken place during the development ofa genetic code, in the case of pro- and eucaryotes during the development ofa universal genetic code. Therefore, these structures could be the ancestors of the procaryotic replication units, that is, of the tumor genes, because they might be involved in die fundamental process of indefinite cellular self-replication. Briefly, we suggest the following sequence: ,procaryotic replication units? cancerogensI ) evolution ^eucaryotic replication units" It must be assumed that the procaryotic replication units evolved stepwise to eucaryotic forms suitable for new tasks in the mammalian cell. Obviously, their dangerous primitive function for indefinite selfreplication had to be subdued. The exact nature of the evolutionary process and ofany intermediates which may have occurred must remain a matter of speculation (genetic transposition, repression of genetic activity ?). Our hypothesis further suggests that the expansion or any other modification of these "procaryotic...