Enzymes and histological differentiation of tumours

The study of enzymes in tumours has been one of the central themes of cancer research for many years. This interest stems from the early discoveries of Warburg (1930) that many kinds of tumours appear to have a specific form of metabolism. Since the ultimate control of metabolism in tissues depends upon the levels of enzyme activity, it was logical to search for possible changes in tumour enzyme content as the primary cause of the alteration in tumour metabolism. A vast literature now exists on the enzymology of many kinds of spontaneous and transplantable tumours of animals (particularly rodents) and of man (Greenstein, 1954; Greenstein, 1956; Aisenberg, 1961; Busch and Starbuck, 1964; Pitot, 1966; Knox, 1967; Shonk and Boxer, 1967; Wenner, 1967). One of the most frequently observed differences between a tumour and its homologous normal tissue has been the reduction or loss of enzyme activity or of the responsiveness of an enzyme to its normal regulatory mechanisms. Demonstration of the loss of enzymes and other proteins in tumours led to formulation of the deletion hypothesis of cancer (Miller and Miller, 1947; Potter, 1958) although this concept can no longer be considered tenable. However, until recently, despite this intensive interest in tumour enzyme activity, it has been difficult to relate the significance of any enzyme changes demonstrated to the histological differentiation of tumours. The principal cause of this has been that in most previous studies efforts were largely directed towards establishing differences in selected enzyme activity between fully established tumours and their homologous normal tissues. Thus, tumours at one stage of histological development only were examined in most cases and any possible differences in enzyme content which might be related to structural variations within a single histogenetic tumour class were not considered. Furthermore, in many studies the choice of enzymes examined was determined on a more or less random rather than on a systematic basis. Sometimes it reflected attempts to establish possible differences in activity of enzymes for diagnostic purposes. More commonly, however, it depended upon the special interests and expertise of the individual investigator or was determined by the reliability of the available analytical methods at the time. Therefore, until fairly recently, any meaningful correlation of enzyme activity with the structural differentiation of tumours has virtually been impossible. However, in the past several years emphasis has shifted towards a more systematic analysis of related groups of enzymes in histologically graded series of tumours derived from a single organ or tissue. The concentration upon tumours of a single homogeneous cell type, which show varying degrees of histological differentiation, is based on the assumption that tumours most closely resembling their homologous normal tissues of origin are most likely to show the deviation from normal which has the greatest relevance to neoplasia (Farber, 1968). The most thoroughly studied tumour system developed to exploit this concept has been derived from the rat liver. In this paper the results of some of these studies will be used to illustrate how the pattern of enzyme and metabolic activity in hepatomas can be related to the extent of their structural differentiation. The implications of these findings for current understanding of the fundamental metabolic changes associated with neoplasia will be discussed.