Cell damage, aging and transformation: a multilevel analysis of carcinogenesis.

There is a vast scientific literature on cancer which no individual can hope to assimilate. To put it mildly, cancer is an enormously complex biological problem that needs to be considered at multiple levels to achieve reasonable understanding. I describe details of work at the cellular level of "spontaneous" neoplastic transformation in culture to point out parallels with the development of cancer in the organism. One of the most surprising relations is that inhibition of cell growth in a transformation-competent population by long term confluence or acutely lowered serum concentration is a strong enhancer of neoplastic change. The transformation is preceded and accompanied by heritable damage to the entire cell population as expressed among progeny cells in a heterogeneous reduction in growth rate at low density as well as delayed reproductive death in some of the cells. The picture bears resemblance to the relation in vivo between local atrophy in the stomach and prostate and cancer in those organs, as well as the relation between tissue damage and cancer in relatively quiescent organs such as pancreas, urinary bladder, etc. Such damage accumulates with age, as does an increasingly permissive local environment for tumor growth. The most common genetic changes found in tumors are large chromosomal deletions. These are precisely the changes that have been found by somatic cell geneticists to cause heritable reduction in growth rate and delayed reproductive death in mutagen-treated and carcinogen-treated somatic cells. Thus, there is a convergence of findings related to cancer in culture and in the organism. The results in cell culture help to focus attention on proximal mechanisms of malignant cell behavior in the organism. However, they are incomplete without considering fundamental aspects of biological behavior such as Elsasser's first principle of ordered heterogeneity in which there can be regularity in the large where there is heterogeneity in the small. The order that controls heterogeneity is weakened with age and contributes to the origin and progression of disordered growth.