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

Would it be productive to reconcile the SMT and the TOFT?

Metaphors and images have been used in order to shed light on the subject of explaining cancer.

The SMT centers on “one renegade cell,” and views cancer as a cell-based disease involving

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unregulated cell proliferation [55]. The TOFT, instead, focuses on a “society of cells” and

views cancer as a problem of tissue organization [39]. Hence, as hinted above, explanations of

the process of carcinogenesis by these two theories belong to distinct levels of biological

complexity and, therefore, are incompatible, as are their philosophical stances (reductionism

versus organicism, see below).

The above-referred incompatibilities do not rule out, however, that the data gathered from

experiments based on the SMT might be interpreted either in the context of the TOFT, or even

to refute the arguments of the SMT. For instance, the polyps in humans hemizygous for a

defective adenomatous polyposis coli (APC) gene, the dysplasias appearing prior to neoplasia

in retinoblastoma, the lethal giant larva mutant in Drosophila and the other conditions briefly

referred to above are all anomalies of normal tissue organization. In the case of inactivated

APC, one may even suggest an explanation, since the APC protein binds to β-catenin, which

in turn binds to cell adhesion molecules (cadherins) [56]. APC also binds to the human

homologue of Drosophila discs large (hDdl), which is also involved in cell-to-cell adhesion

through septate junctions [57]. Deletions of this gene result in the loosening of cell-cell

contacts, abnormal morphology of the imaginal discs, and neoplastic development [58]. From

the TOFT perspective, one would study how alterations in APC, catenins, cadherins and hDdl

affect the development of the intestinal crypt and give rise to polyps. Instead, the SMT-based

research effort centers on the role of β-catenin as a transcription factor and looks at the

transcriptional machinery in the epithelial cell nucleus in search of alleged alterations on the

control of cell proliferation, the cell cycle and/or apoptosis. In fact, evidence collected while

using the human APC mutants and the experimental Min mouse model suggests, instead, that

no alteration in the control of cell proliferation in the intestinal epithelium is apparent; what

appears consistently is an alteration in the splitting of the crypts (crypt fission) in the intestines

of these carriers, i.e., an altered three-dimensional intestinal tissue-specific malformation that

seems to be at the core of adenoma enlargement [59].

In the last decade, as already documented above, a substantial number of scientists have moved

from a hard-core SMT stance to acknowledge a decisive role for a tissue component in

carcinogenesis. This resulted in a narrative of the carcinogenic process that invokes the role of

the ‘microenvironment’ but is still dominated by a genetic deterministic rhetoric. From this

perspective, stromal alterations would result in genomic instability of the epithelial cells [10].

This interpretation entails a causal sequence whereby overexpression of matrix

metalloproteinases generates free radicals that would mutate epithelial cells, and these mutated

cells will then develop into a cancer. Thus, according to this particular hybrid view, the role

of the tissue environment would be to generate reactive chemicals that will mutate the DNA

of epithelial cells. However, this attempt to reconcile the two theories does not provide any

explanatory advantage over the “classical” SMT.

Recently, another hypothetical contribution aimed at explaining carcinogenesis has been

presented whereby the core causal element of the SMT, i.e. somatic mutations, is criticized but

not dismissed [53]. In fact, as referred to above, the causal role of mutations on the epithelial

cells in the carcinogenic process is now transferred as well to the cellular components of the

nearby stroma. This variant of the SMT (“a different two-hit model”) does not differ much

from those alternatives sharing with all the others the implicit premise that quiescence is the

default state of cells in metazoa, a notion that lacks evolutionary relevance [16,18].

Additionally, it was proposed that matrix metalloproteinases play a decisive role in

carcinogenesis by “activating” growth factors and cell surface receptors and by facilitating

paracrine signaling pathways, among other possible routes [60,61]. In this reassessment, cancer

would still remain a problem of control of cell proliferation, A stealth implication of this

increasingly popular view of melding the SMT with tissue-based theories is that this would

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cover all possible outcomes preventing a resolution of the question… how is cancer explained?

In other words, no hypothesis would be tested because no hypothesis could be rejected.