Genetic Convergence and Divergence in Tumor Progression1

An essential defect in tumorigenesis is the imbalance between the tendency of neoplastic cells to divide and spread throughout the body, and the capacity of the organism to regulate and restrain such growth. In principle, two main explanatory strat egies have in recent medical history been followed when at tempting to understand the events of carcinogenesis. In the holistic or integrationist approach, the necessity of viewing the organism as a whole is underscored, and consequently, the emphasis is put on large-scale disturbances (for instance, hu moral factors, field effects, topographical disruptions) as caus ative factors in tumor formation (1-3). The ambition of the reductionist approach, on the other hand, is to dissect accurately the pathogenetic process into component events that at least in principle are simple enough to be comprehended fully within the conceptual framework of biological theory. Since the ascent of cellular pathology 100 years ago, the reductionist position has become more and more cytologistic, and today this view dominates most reasoning about oncogenesis (4, 5). Cancer is seen primarily as a cellular disease, in the sense that inherent derangements in the tumor cells themselves, rather than some kind of systematic failure to provide proper proliferation con trol, are of the essence. Tumor cells beget other tumor cells. An obvious mechanism for the conservation of neoplastic capacity between cell gener ations is via a stable genetic alteration that can be faithfully reproduced and passed on to all progeny. Direct evidence of defective genetic material in neoplastic cells dates back to around the turn of the century, when David von Hansemann observed abnormal nuclei in cancers (6). Theodor Boveri in his "Zur Frage der Entstehung Maligner Tumoren" (7, 8) forged