29 May


As noted in this chapter, the development of our understanding of the cell and molecular biology of the neoplastic process has closely paralleled advances in our understanding  of the cell and molecular biology of normal cells. In retrospect, initially naïve concepts of the biochemistry of neoplasia were based on the assumption that a single biochemical abnormality could explain the neoplastic phenotype. As knowledge of the natural history of neoplastic development and of cel- lular and molecular biology advanced, such a concept was no longer tenable. However, today the pendulum has swung entirely in the opposite direction, in that the complexity of the cell and the molecular biology of the neoplasia are becoming more obvious, and there is no evidence of a ubiquitous, single defect resulting in this disease. Rather, it is apparent that the vast majority of the phenotypic and genotypic alterations seen in neoplasia—i.e.,  cells in the stage of progres- sion—are a direct result of the primary characteristic of this stage, evolving karyotypic instabil- ity (Chapter 9).

In Table 15.13 may be seen a summary of our knowledge to date of a number of processes and functions in the cell and molecular biology of preneoplasia and neoplasia. Although the ta- ble indicates that in virtually every instance of neoplasia the cell and molecular process stated is defective, it is important to note that there is no single component of any of these processes that is ubiquitously abnormal in all neoplasms. However, the majority of neoplasms exhibit at least one defective process in each of those listed. This is indicated by ++++. In all other instances, there are examples of neoplasms that do not exhibit abnormalities in the process listed. In view- ing the listing in preneoplasia, it is noted that the majority show either no or a few examples of abnormalities  in the process listed. Furthermore,  such as in signal transduction,  the processes occurring in the preneoplastic cell are essentially normal but hyperexpressed  as a result of the chronic administration of the promoting agent. Removal of the promoting agent will, of course, result in loss of cell viability (Chapter 7). The three exceptions to this generalization  are seen with DNA methylation,  apoptosis mechanisms,  and the expression of mutant proteins. In this last instance, by our definition of initiation, one should expect that every initiated cell will have mutations in various genes and thus express mutant proteins, although examples of this are not nearly so extensive as that in neoplasia. Abnormalities in apoptosis—i.e., inhibition of this pro- cess—are characteristic of the action of promoting agents, but such an effect is lost in the ab- sence of these agents in preneoplastic  tissue. The increase or changes in DNA methylation in preneoplasia are likely ubiquitous to all preneoplastic cells, although only certain examples have been tendered (Table 15.8), but in virtually every carefully studied case such abnormalities are noted. Alterations in DNA methylation  may be the basis for the transition from promotion to progression and, at least initially, for the development of karyotypic instability in progression. However, at our present state of knowledge, this is clearly a tenuous statement, and it may be that further information will bring a variety of other mechanisms to the fore as candidates for the basis of the cellular and molecular biology of neoplasia. A comparison of the cellular and mo-

lecular biology of preneoplasia with that of neoplasia does, however, emphasize the importance of an understanding of the molecular transition between these two stages as critical to our under- standing of the ultimate formation of the cancer cell.

It should be noted here, however, that alterations in a number of the cell and molecular processes that are seen in neoplasia—i.e.  the stage of progression—contribute  significantly  to the evolving karyotypic instability characteristic of this stage. This includes alterations in com- ponents of the transcription  mechanism,  cell cycle, DNA methylation,  telomerase, and the al- tered or eliminated function of specific tumor suppressor genes such as p53. This would suggest that the basis for the karyotypic instability in neoplastic cells develops from a large number of molecular alterations in the cell. The natural history of the stage of progression is thus likely to result from the successive  alteration of individual mechanisms,  each of which by itself could lead to genomic instability.  Such a scenario may make it very difficult to design therapeutic modalities that are able to correct or interdict the evolution of karyotypic instability of the neo- plastic cell.

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