New Theory of Carcinogenesis


Tissue organization field theory soto sonnenschein
Carcinogenesis at tissue level of organization

The Zeitgeist of the last fifty years has been that the answer to most biological questions is inevitably found at the lowest level of biological organization. This approach has been extremely productive when applied to phenomena that were found a posteriori to occur at that lower level of organization. One example of this success is sickle cell anemia, where the properties of the mutated hemoglobin molecule adequately explain the signs and symptoms of the disease (the phenotype). To the contrary, the equally well characterized mutations that “cause” the metabolic Lesh-Nyhan syndrome (attributed to a mutation in the hypoxanthine phosphoribosyl transferase gene) and the neuroblastomas in the lgl-2 Drosophila mutants have not shed light on the respective resulting phenotypes; the respective mutated proteins are indirectly responsible for the phenotypes.

The somatic mutation theory of carcinogenesis has been the dominant force driving cancer research during the twentieth century. This theory places carcinogenesis at the cellular level of biological organization. Its basic premises are: 1) cancer is a defect of the control of cell proliferation and 2) the default state of metazoan cells is quiescence. These two premises are contradicted by evidence. Supporters of the theory have dealt with these by incorporating an ever increasing number of ad hoc explanations.

We propose an alternative theory, the tissue organization field theory of carcinogenesis and neoplasia. Its basic premises are: 1) proliferation and motility are the default states of all cells, and 2) carcinogenesis and neoplasia are defects of tissue architecture. Carcinogens act initially by disrupting the normal interactions that take place among cells in the parenchyma and stroma of an organ (the equivalent of the “morphogenetic fields” of developing organisms). In the mammary gland, our experimental model, the stroma appears to be the primary target of carcinogens. Carcinogenesis and neoplasia involve emergent (supracellular) phenomena.

carcinogens target stroma
In the premises of TOFT, carcinogens target the stroma to induce tumor formation

The tissue organization field theory views teratology and carcinogenesis as two related processes in which the tissue architecture is disrupted. While teratogens disrupt embryonic or fetal development, carcinogens act, instead, across all phases of development, including the in ovo and in utero stages, as well as during infancy, puberty, adulthood and finally, aging. From this perspective, carcinogens need not be mutagens. This disruption results in a lessening of the cells’ ability to “read” their positional and historical background. Hence, the tissue’s appearance changes. For example, it may become hyperplastic (it undergoes excessive proliferation), or dysplastic (it resembles normal tissue, but the arrangement of cells in the epithelium looks disturbed, cell sizes vary more than in the normal tissue, cell layers are less neatly arranged, etc). The tissue may also undergo metaplasia, that is, it would resemble a different organ than the one in which it originated (i.e., a simple columnar epithelium would become squamous stratified epithelium). Finally, the epithelium develops a carcinoma in situ.

We hypothesize that the alterations of the reciprocal interactions between stroma and parenchyma resulting from exposure to carcinogens would finally render the epithelial cells unable to restrain their built-in, constitutive properties to proliferate and to become motile. This novel theory incorporates the notion that neoplastic cells may behave like “normal” cells when placed within normal tissues. This latter development implies that a new set of therapeutic points of intervention may become available, and consequently, a more rational alternative approach to the use of unspecific chemotherapeutic agents may be offered to cancer patients.

Using a theory-neutral design, we tested three competing hypotheses, namely, 1) that the primary target of carcinogens is the stroma, 2) that the primary target is the epithelium, and 3) that both epithelium and stroma need to be exposed to the carcinogen. We observed that the recombination of stroma exposed to a carcinogen with normal epithelial cells resulted in neoplasms. The reverse combination did not. This observation implies that the stroma, rather than individual cells in the epithelium, is the target of the carcinogen. These results also suggested that the neoplastic phenotype is contextual and hence, potentially reversible. We explored this hypothesis and found that mammary neoplastic cells isolated from tumors could be normalized when recombined with stroma of normal mature hosts.

NMU stroma tumor
Tumors only develop in NMU-treated stroma (Maffini et al 2004)

Recommended Readings – 

Maffini MV, Soto AM, Calabro JM, et al. 2004. The stroma as the crucial target in rat mammary gland carcinogenesis. J cell Sci 117:1495-502.

Sonnenschein C, Soto AM. 2013. The aging of the Hallmarks of Cancer reviews: a critique. J Biosci 38(3):651-63.

Soto AM, Sonnenschein C. 2011. The tissue organization field theory of cancer: a testable replacement for the somatic mutation theory. BioEssays 33:332-340.

Sonnenschein C, Soto AM. 2004. The somatic mutation theory of cancer: growing problems with the paradigm? BioEssays 26:1097-107.

Sonnenschein C, Soto AM. 2008. Theories of carcinogenesis: an emerging perspective. Semin Cancer Biol 18:372-7.

Baker SG. 2015. A cancer theory kerfuffle can lead to new lines of research. J Natl Cancer Inst 107(2).

Hanahan D. 2014. Rethinking the war on cancer. Lancet 383(9916):558-63.

Weinberg RA. 2014. Coming full circle- from endless complexity to simplicity and back again. Cell 157(1): 267-71.