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

An update on the Somatic Mutation Theory

The main driving force of the SMT program has been its reductionist core. In this tradition, it

is assumed that organismic phenomena can be advantageously reduced to cellular and/or

subcellular ones. Thus, when reducing cancer to a cellular phenomenon, neoplasms become

de facto reduced to a single transformed cell and carcinogenesis becomes equivalent to

enhanced proliferation of cells in a dish. Most of this research has been, and is still, conducted

using 2-dimensional in vitro models, where primary cell cultures and established cell lines are

the representative tools. From this seductive simplicity, whereby a single or a few oncogene

(s) may induce cancer, an increasingly complicated picture has mushroomed into more than

350 oncogenes and tumor suppressor genes identified as putative causes of cancer… and these

numbers are predicted to increase [2]. However, if oncogenes were indeed dominant

determinants, as originally claimed, the need for additional gain-of-function effects attributed

to these mutated genes would appear as redundant and difficult to rationalize [32]. To

accommodate these inconsistencies that would have led to invalidate the SMT, an ad hoc

alternative was proposed whereby oncogenes, in addition to disrupting the proliferation control

of the cells that harbor them would exercise their effects indirectly by affecting tissue

organization [8,33].

Accommodating ad hoc arguments have also surfaced regarding the unfulfilled prediction of

a higher mutation rate and consequent increased cancer incidence due to a mismatch repair

(MMR) deficiency [34]. Kinzler & Vogelstein pondered about this paradox and concluded:

“Why isn't MMR deficiency as carcinogenic as mutagen exposure? One possibility would be

that mutagens are carcinogenic not only because they induce mutations, but also because they

cause substantial cellular death with consequent tissue regeneration.” And, “Thus, it is possible

that the dietary factors which lead to colorectal cancer are not mutagens, but rather irritants

that lead to tissue regeneration.” [35]. Clearly, these explanations highlight processes that take

place at the tissue level of organization such as injury and inflammation, which are central to

the explanation of carcinogenesis by the TOFT. Hence, this rationalization represents another

example of the recent tendency of hybridizing the SMT and the microenvironmental origin of

neoplasias.

A recent addition to the variants of the SMT has been called the clonal genetic model of

cancer [36]. Despite acknowledging the above-mentioned objections to the classical view of

the SMT, mutations in oncogenes and suppressor genes are central to this theoretical variant.

An epigenetic component is here added to those stable genetic mutations which include “global

DNA hypomethylation, hypermethylation and hypomethylation of specific genes, chromatin

alterations and loss of imprinting” which could all “lead to aberrant activation of growth-

promoting genes and aberrant silencing of tumor-suppressor genes.” As in other theoretical

alternatives aimed at overcoming the inadequacy of the original SMT, genetic and

“epigenetic”

1

 changes are mixed and matched following an unpredictable pattern that has to

accommodate increasingly complex experimental or clinical lacks of fit.

As we argue below, carcinogenesis and metastases can be considered as initially limited tissue-

based phenomena. Thus, cellular-based (gene mutations, chromosomal atypias, carbohydrate

metabolism anomalies, nuclear size and shape peculiarities, etc) like organismal-based

1Here, the word epigenetic is narrowly interpreted as changes limited to subcellular alterations of DNA methylation, histone modification,

chromosome structure, loss of imprinting and their combinations.

Sonnenschein and Soto

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Semin Cancer Biol. Author manuscript; available in PMC 2009 October 1.

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manifestations (pain, cachexia, tumors and finally, death) are the consequences of cancer, and,

not its cause.

Still another alternative to the classic SMT has been proposed under the ubiquitous use of the

stem cell concept. This option implies that cancers would appear as a result of gene mutations

on operationally-defined, elusive individual stem cells. This theoretical variant proposes that

the original clonal, mutated cells have innate “immortal” properties [37]. It remains unclear in

what way “stem cells” as putative originators of neoplasms represent either a conceptual or a

pragmatic improvement over the shortcomings of the SMT. In other words, how would a stem

cell-based alternative overcome the criticisms over a cell-centered theory when compared to

any other cell type that populate multicellular organisms.