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

About “causes” and “explanations” in cancer

The lack of precision in the use of the words “cause” and “explanation” has been a source of

confusion in the field of carcinogenesis. More to the point, there is general agreement about

which external agents cause cancer. These “cancer agents” can be neutralized either by

preventing exposure (reducing or abolishing tobacco smoking, providing asbestos-free

environments, etc) or by treatment of the condition to which the cancer process has been linked

[antibiotics for bacterial [25] or parasitic infections [26], antibodies in the form of vaccines for

viral infections [27] (Figure 1). In any case, it is clear that the above-referred interventions are

not “cancer cures.”

There are competing interpretations, however, about how to link these diverse agents to an

explanation of why and how the cancer phenotype arises. To this end, we will compare and

contrast the SMT, which is cell-based, and the TOFT, which is tissue-based. There are various

theories straddling these two levels [28,29]; however, they will not be discussed here as the

issue we are addressing does not require their analysis.

Proponents of the SMT claim that those widely dissimilar agents would somehow cause either

the propagation of already mutated cells or generate mutations in genes that either directly or

indirectly mediate the control of the proliferation of cells that would eventually become

neoplastic. Hence, the cause of cancer would be DNA mutations, and the explanation of the

cancer phenotype becomes altered control of cell proliferation, or of the cell cycle. From this

perspective, both the cancer cause and its explanation reside at the subcellular and cellular

levels of biological organization (Figure 1).

Alternatively, the TOFT proposes that carcinogenic agents generate a disruption in the

reciprocal interactions between cells that maintain tissue organization, tissue repair and local

homeostasis. In these altered microenvironments, the negative controls exerted by tissue

organization are relaxed; hence, the parenchymal cells would be allowed to exercise their

constitutive ability to proliferate and migrate. The explanation of the cancer phenotype offered

by the TOFT is that these alterations generate an abnormal tissue architecture that would deviate

from normalcy as the tissue homeostasis becomes increasingly disrupted. From the TOFT

perspective, both the cancer cause and its explanation reside at the tissue level of biological

organization (Figure 1).

In a brief reference to the hereditary tumors, both the SMT and the TOFT share the notion that

they are caused by germplasm DNA mutations. However, while the SMT seeks to explain how

these mutations alter the proliferation of the cells that express the mutated gene, the TOFT

seeks to explain how these mutated genes would generate an altered histogenesis and

organogenesis. In the context of the TOFT, the mutated gene would code for a protein(s) that

would play important roles in regulating the normal formation of morphogenetic fields in which

those tumors appear. For this reason, we have called these tumors “inborn errors of

development”. The prototypic example of this type of neoplasm is the lethal giant larva 2

(lgl2) tumor in Drosophila [30]. In humans, these types of tumors include retinoblastomas,

Wilms' tumors, the BRCA1 and 2-linked breast and ovarian tumors and a few others.

Sonnenschein and Soto

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

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Another significant subject in this panoply of issues related to carcinogenesis is the one dealing

with tumor susceptibility [31]. We will not address this issue at this time.