Multistep Carcinogenesis:

The cell’s complex self-regulating machinery means that more then one mutation is often required to produce a malignant, metastasising tumor, such as a carcinoma, derived from epithelial cells. For example, if a cell mutates to produce a growth factor to which it already expresses the receptor (paracrine stimulation), that cell will replicate more frequently but will still be subject to cell cycle checkpoints to promote DNA integrity in its progeny. If an additional mutation overriding a cell cycle checkpoint occurs, that cell and its progeny may go on to accumulate further mutations, some of which may allow it to replicate an unlimited number of times by synthesis of telomerase, or to separate from its matrix and cellular attachments without undergoing apoptosis. As deregulated growth continues, cancer cells become increasingly unable to differentiate, fail to respond to local signals as in the normal tissue, and cease to ensure appropriate chromosomal segregation pre-division, generating the classical malignant pathological appearances of disorganised growth, variable levels of differentiation, and polyploidy. This sequence is illustrated for colon carcinomas in figure 1.18.

Since DNA mutation occur so infrequently, only an occasional cell will go on to acquire a further mutation, but this will be transmitted to the progeny of that cell which, due to their faster replication rates, are likely to constitute an increasing fraction of the tumor. It is likely that the morphological premalignant appearances of cancers reflect the underlying number of mutation, particularly as pathological evidence of increased malignancy can be seen arising within premalignant lesions.