Article in Seminars in Cancer Biology · April 2008 doi: 10. 1016/j semcancer

Theories of carcinogenesis

The somatic mutation theory (SMT) has been the prevailing one in cancer research for the last

50 years [2]. It is based on the following premises: 1) cancer is derived from a single somatic

cell that successively has accumulated multiple DNA mutations (monoclonality), 2) those

mutations occur on genes that control cell proliferation and the cell cycle [3] and 3) implicitly,

the default state of cell proliferation in metazoa is quiescence. In 1999, based on our work on

the control of cell proliferation and a comprehensive analysis of the literature, we proposed an

alternative theory, the tissue organization field theory (TOFT). Its premises are significantly

different from those of the SMT, namely, 1) carcinogenesis is a problem of tissue organization,

comparable to organogenesis during early development, and 2) proliferation is the default state

of all cells [4,5]. Each of these premises has precedents made by the German School of

Pathology in the last decades of the 19

th

 century [6,7]. Finally, there are hybrid theories

resulting from the lack of fit between the predictions of the SMT and the increasing number

of experimental observations that cannot be accommodated within a cell-centered approach to

carcinogenesis. This option melds the SMT with the concept that cancer is also due to anomalies

in tissue organization [8-11]. Undoubtedly, only time will provide the necessary, decisive

perspective to validate which of these theories most closely explains carcinogenesis [12].

Meanwhile, we will compare the above-referred competing views from today's perspective,

but before doing this we will briefly elaborate on the premise of the default state of cells since

it represents the sharpest difference among the three theories on the subject.