Rethinking carcinogenesis: The detached pericyte hypothesis.

The limiting step in cancer prevention is a lack of understanding of cancer biology. This limitation is exacerbated by a focus on the dominant somatic mutation theory (that driver mutations cause cancer) with little consideration of alternative theories of carcinogenesis. The recently proposed detached pericyte hypothesis explains many puzzling phenomena in cancer biology for which the somatic mutation theory offers no obvious explanation. These puzzling phenomena include foreign-body tumorigenesis, the link between denervation and cancer, tumors in transgenic mice that lack the inducing mutation, and non-genotoxic carcinogens. The detached pericyte hypothesis postulates that (1) a carcinogen or chronic inflammation causes pericytes to detach from blood cell walls, (2) some detached pericytes develop into myofibroblasts which alter the extracellular matrix (3) some detached pericytes develop into mesenchymal stem cells, (4) some of the mesenchymal stem cells adhere to the altered extracellular matrix (5) the altered extracellular matrix disrupts regulatory controls, causing the adjacent mesenchymal stem cells to develop into tumors. Results from experimental studies support the detached pericyte hypothesis. If the detached pericyte hypothesis is correct, pericytes should play a key role in metastasis - a testable prediction. Recent experimental results confirm this prediction and motivate a proposed experiment to partially test the detached pericyte hypothesis. If the detached pericyte hypothesis is correct, it could lead to new strategies for cancer prevention.