The tissue organization field theory of cancer: a testable replacement for the somatic mutation theory

Abstract

The somatic mutation theory (SMT) of cancer has been and remains the prevalent theory attempting to explain how neoplasms arise and progress. This theory proposes that cancer is a clonal, cell-based disease, and implicitly assumes that quiescence is the default state of cells in multicellular organisms. The SMT has not been rigorously tested, and several lines of evidence raise questions that are not addressed by this theory. Herein, we propose experimental strategies that may validate the SMT. We also call attention to an alternative theory of carcinogenesis, the tissue organization field theory (TOFT), which posits that cancer is a tissue-based disease and that proliferation is the default state of all cells. Based on epistemological and experimental evidence, we argue that the TOFT compellingly explains carcinogenesis, while placing it within an evolutionarily relevant context.

Figure 1

Carcinogenesis according to the TOFT. A single or multiple carcinogenic exposure acts disturbing the reciprocal biophysical and biomechanical communication between the parenchyma and the mesenchyme/stroma in a given morphogenic field. This results in miscues that manifest morphologically in both the stroma and the epithelium. The proliferation and motility restraints imposed by normal tissue architecture loosen and as a consequence, hyperplasia of the epithelium may occur. Further alteration of the reciprocal interactions between tissue compartments will induce metaplasia, dysplasia, and carcinoma. The stroma also may show alterations (desmoplasia, inflammatory cells).

Figure 2

Testing the SMT. The DNA of one single cell needs to be extracted and its sequence checked to verify that no mutations are present. Next, the DNA should be mutated at specific sites, sequenced again to verify that only the intended mutations are present, and then introduced into an enucleated cell. After verification that the DNA organizes properly into chromatin, the cell should be transplanted into an immuno-tolerant mouse. This mouse should be checked to determine whether an organ-specific tumor arises and that all the cells in such a tumor carry the mutations originally introduced into the original founder cell’s DNA.

Figure 3

Testing the TOFT. The epithelium and stroma are detached from each other and separately exposed to a short-lived chemical carcinogen. After the carcinogen is thoroughly washed out, the epithelium and stroma are recombined in a 2 by 2 protocol (vehicle-exposed epithelium with vehicle-exposed stroma, vehicle exposed epithelium with carcinogen-exposed stroma, carcinogen-exposed epithelium with vehicle-exposed stroma, and carcinogen-exposed epithelium with carcinogen-exposed stroma).