Models of neoplasia and their diagnostic implications: a historical perspective

In comparison with normal cells, cancer cells have an enhanced ability to trap both nitrogen and energy; an enhanced operation of the glycolytic and direct oxidative pathways, leading to accumulation of lactate and increased production of NADPH; and a greater content of lysosomal hydrolases. These changes represent a reprogramming of gene expression, which, at its most specific, is accompanied by the reappearance in the cell and ultimately in the body fluids of oncodevelopmental proteins not normally found in mature adult tissues. The most florid stage of this reprogramming leads to the metastatic phenotype, which confers upon the cancer cell the ability to stimulate angiogenesis, invade the bloodstream and lymphatic vessel, and arrest and proliferate in distant tissues. The diagnostic implications of these phenotypic changes are illustrated for cancer of the cervix uteri and cancer of the colon. We also review the classical theories of neoplasia, including the cellular anoxia concept of Warburg, the deletion hypothesis of Potter, and various other mechanisms emphasizing genomic derepression and impaired immunity. The critical steps in chemical carcinogenesis are described, and the Vogelstein-Lane model is presented, emphasizing the stepwise and cumulative genomic changes affecting chromosomes 5q, 17p, 18q, and gene amplification of chromosome 12 as well as genomic instability resulting from reduced DNA methylation. The main consequences of these genomic alterations include overexpression or activation of oncogenes such as c-myc and k-ras, together with mutation or functional inactivation of suppressor genes such as p53. Finally, the implications of these findings for diagnosis and management are illustrated by reference to recent investigations in cancers of the breast, colon, and bladder, in which these genomic alterations can be detected by examination of appropriate cellular material and by detection in serum of antibodies to the p53 gene product.