The Molecular Correlation Concept of Neoplasia: Recent Advances and New Challenges

Summary

This paper critically evaluates the advances made with the molecular correlation concept as a conceptual and experimental approach in elucidating the biochemical strategy of the cancer cells. New advances made in gaining an insight into the behavior of pyrimidine metabolism are also used to illustrate the method and current status of the molecular correlation concept. Investigation of the hepatomas of different growth rates and comparison with appropriate control systems such as the normal, differentiating and regenerating liver has led to the discovery that in neoplastic cells there is an ordered pattern of enzymatic and metabolic imbalance. We documented in detail the linking of biochemical discriminants with neoplastic transformation and progression in carbohydrate, pentose phosphate, purine, pyrimidine, ornithine and polyamine metabolism and in membrane cAMP systems. We pointed out the importance of selecting for such investigations the analysis of the activity, concentration and isozyme pattern of opposing key enzymes in antagonistic pathways of synthesis and degradation. We demonstrated that the control of gene expression operates through reciprocal regulation of opposing key enzymes in antagonistic and competing metabolic pathways.

Current investigations on the behavior of the opposing key enzymes, thymidine kinase and dihydrothymine dehydrogenase, support our earlier reports on the antagonistic behavior of the opposing pathways of thymidine utilization for synthesis and degradation. Ongoing investigations on the behavior of enzymes involved in uridylate and CTP biosynthesis show that CTP synthetase is the rate-limiting enzyme in the overall pathway culminating in CTP production. The activity of UDP kinase was elevated in all the hepatomas, indicating that the behavior of this enzyme was transformation-linked. The activities of uridine kinase, uracil phosphoribosyl-transferase and CTP synthetase were also significantly increased in all tumors and 6- to 11-fold elevated in the rapidly growing neoplasms. These three enzymes are both transformation- and progression-linked in the hepatoma spectrum. Concurrent with this increased capacity for CTP biosynthesis, the capacity of the degradative pathway was decreased.

From this and earlier work and also from results of other laboratories, we have extensive evidence that the cancer cells through a reprogramming of gene expression exhibit a meaningful and ordered biochemical imbalance that confers selective advantages to the cancer cells. Neoplasms may show random fluctuations in some biochemical parameters; this behavior is apparently coincidental and not related to the core of neoplasia. What is essential about neoplastic transformation and progression is ordered and what is not, is the randomness and diversity. The presence of the operation of an ordered pattern is no longer at issue, but rather the challenge is to discover the molecular mechanisms that can account for the highly integrated, purposeful, ordered, poly-enzyme, multi-pathway alterations.

The metabolic imbalance in the hepatomas is specific to neoplasia and no similar pattern has been observed in fetal, differentiating, regenerating or adult normal liver. The applicability of some aspects of the metabolic imbalance discovered in the hepatoma spectrum has also been shown in kidney and mammary cancer in the rat, lymphomas in the mouse, viral-induced hepatoma in the chicken and most importantly in human primary hepatomas and renal cell carcinomas.

With the progress in elucidation of the biochemical strategy of malignancy, a significant challenge is the application of this knowledge to the design of drug treatment. In this laboratory advances were made in achieving a successful design in tissue culture on the basis of enzyme-pattern-targeted chemotherapy. Such applications of the insight into the enzymic and isozymic pattern of tumors and relevant host tissues should permit the design of more selective chemotherapy and biochemical rescue methods to achieve a successful treatment of neoplastic diseases.

Recipient of USPHS Grants CA-13526 and CA-05034, to whom requests for reprints should be addressed at the Laboratory for Experimental Oncology, Indiana School of Medicine, Indianapolis, Indiana 46202.