CARCINOGENESIS 



in cell W, which were directly dependent on the products of the 

 inactivated precursor reactions, are not shown in cells Y and Z. 

 It must be remembered, however, that some specialized systems 

 may be functioning at very low levels. It is obvious that many 

 variations are possible in this schema, but that cell Z represents 

 the ultimate degree of anaplasia. In the benign tumor (cell X) 

 the arrows indicate a reactivation of function S at a. level com- 

 parable to that seen in normal cell C. Such activation is pos- 

 sible because of the reoriented equilibrium of the cellular sys- 

 tems following the loss of one or more of the other functions. 



Some neoplastic cells may lie relatively quiescent for long 

 periods without losing their capacity to be promoted. This is 

 illustrated by epidermal and testicular tumors, which may be 

 promoted with croton oil (9,56,57) and estrogen (23), respec- 

 tively, one year after the initiation of the tumor. Similarly, the 

 hormonally dependent tumors, as studied by Furth (22) and 

 Gardner (24), also require a considerable period for initiation 

 and promotion to the neoplastic state. 



Cells intermediate in malignancy (e.g., cell Y) may suffer 

 a further loss of specialized function and pass to the next lower 

 level. The continued deletion of special characteristics from 

 neoplastic cells through successive cell generations has been 

 clearly demonstrated by various investigators who have studied 

 the genetic factors required for successful transplantation of 

 neoplasms (4,25,27). Such studies demonstrate that tumor 

 cells, once incapable of growth in homologous strains, may 

 after prolonged growth be successfully transplanted to pre- 

 viously resistant hosts. This indicates that the number of 

 histocompatibility genes required for successful transplantation 

 may be progressively reduced in the growing cancer cell (25). 

 This process is probably to be identified with the term progres- 

 sion as used by Foulds for describing the changes of neoplastic 

 cells to the more malignant state (19). Thus, whereas normal 

 cells are genetically stable, instability is common once a per- 

 manent, heritable change has occurred in a cell. 



Cell Z represents the most advanced stage of anaplasia. 



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