The Many Models of Carcinogenesis: En Route to a Unified Theory

There are currently at least ten 'theories' of carcinogenesis, with levels of explanatory power ranging from almost none to moderate. More appropriately referred to as models or hypotheses, these ten theories are: the Egg Cell Genetic Program Hypothesis, the Atavistic Hypothesis, the Quantum Field Stem Cell Differentiation Hypothesis, the Tissue Organization Field Hypothesis, the Cancer Stem Cell Hypothesis, the Bad Luck Hypothesis, the Ground State Hypothesis, the Epigenetic Hypothesis, the Clonal Expansion Hypothesis, and the Somatic Mutation Hypothesis. Experimental support for these models varies from very few to thousands of published studies. Central to all of the models, including those that invoke resurrection of ancestral cell division phenotypes, is alteration of normal genetic programing (gene expression profiles). A large body of experimental work has shown that this altered gene expression during carcinogenesis happens in three primary ways: mutation, epigenetic modification, and metabolic disruption. Collectively, various combinations of these transformation drivers lead to disruption of cell cycle control, DNA damage/apoptosis, electrochemical and water balance, body location constraints, and elimination of anti-tumor immune responses. If one views mutation, gene expression, and epigenetics as aspects of cancer genetics, the existing models can by in large be viewed as mutualistic rather than as adversarial, each contributing to a framework that supports an authentic, though still inchoate, unified theory of carcinogenesis.