Page 77 - 20dynamics of cancer

62 CHAPTER 4

Twort and Twort (1928, 1939) described several experimental proto-
cols in which sequential application of different chemicals was much
more carcinogenic than either agent alone. In the early 1940s, several
others, notably Rous and Berenblum, reported similar observations on
the co-carcinogenic interaction between two different treatments when
applied sequentially (MacKenzie and Rous 1940; Berenblum 1941; Rous
and Kidd 1941).
Friedewald and Rous (1944) described the first treatment as an ini-
tiator, because it seemed to initiate the carcinogenic process but was
usually not sufficient by itself to cause cancer. They called the second
treatment a promoter, because it caused progression of previously initi-
ated cells but by itself rarely led to cancer. In a series of papers, Beren-
blum and Shubik (1947b, 1947a, 1949) synthesized the experimental
studies and thinking on co-carcinogenesis into the two-stage theory of
initiation and promotion.
The mechanistic action of initiators and promoters has been widely
debated. In some cases, it was thought that the initiator is mutagenic,
causing latent DNA lesions in some cells, and the promoter is mitogenic,
stimulating cell division and providing favorable conditions for tumor
formation. However, no simple mechanistic explanation fits all cases.
Indeed, many observations from experimental carcinogenesis do not fit
with a simple two-stage explanation (Iversen 1995).
The initial theory provided a useful framework for the early experi-
mental studies, but hardened too much into “two-stage” and “initiator-
promoter” slogans that probably hindered as much as helped to un-
derstand the actual mechanisms of carcinogenesis (Iversen 1995). Re-
cent emphasis has moved closer to the actual molecular mechanisms
involved, aided by the great technical advances now underway. Aspects
of initiation and promotion may play a role, but the older dominance
of the rigid two-stage theory has naturally faded. For our purposes, the
two-stage theory is important because it provided the first evidence and
thinking with regard to multiple stages in cancer progression.

AGE-SPECIFIC INCIDENCE

Two observations about cancer incidence in epithelial tissues have led
to multistage theories. First, cancer incidence often increases rapidly