HAROLD P. RUSCH 



from some of these lesions and succumb to others. Some of the 

 initial changes produced by carcinogens may not differ from 

 lesions resulting from other toxic agents ; the chief difference is 

 that carcinogens can also induce heritable alterations. 



While it appears possible that the altered cells f/, V, and W 

 may arise from any one of the stages of normal cells B, C, and 

 D, it is probable that cell U is more likely to arise from cell D 

 than from cell B, and cell W is more apt to arise from cell B 

 than from cell D. Some, but not all, of the pathways from the 

 normal to the defective cells are indicated by arrows made of 

 dash lines. Each set of arrows depicts a series of many cells and 

 stages rather than a single change. The period of transition 

 from the normal cells B, C, and D to the altered ones U, V, 

 and W corresponds to the period of initiation as defined by 

 Rous (21) and others (8). The horizontal lines which break the 

 dash lines indicate the time when the reversible condition passes 

 into an irreversible one. That the process of initiation may be 

 reversible for a period is demonstrated by the fact that certain 

 carcinogens must be administered for a considerable time before 

 neoplasms result (13,58). 



Although each cell represented by U, V, and W has a 

 heritable loss of one specialized function and is therefore capable 

 of giving rise to a neoplasm, the conversion into an autonomous 

 cluster of cells does not always proceed rapidly. The cell still 

 retains some competitive cellular constituents which were a part 

 of the once active special system. Such constituents must dis- 

 appear before the final conversion is complete. The removal of 

 such substances is by a gradual deletion, usually occurring with 

 each cell division and culminating in the change of cells U, V, 

 and W to X, Y, and Z, respectively. This change is depicted by 

 the absence from cells X, Y, and Z of the specialized functions 

 marked with the crosses in cells U, V, and W. The final con- 

 version just described corresponds to the period of promotion as 

 described by Rous (21) and others (8), and the series of changes 

 during this period is shown by the arrows made of the long 

 dash lines. The specialized systems, H in cell V and L and H 



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