The standard, generally accepted, theory of tumorigenesis, says that tumors arise from a succession of driver mutations and clonal expansions. However, this standard theory has difficulty explaining many puzzling phenomena in tumorigenesis including (i) foreign-body tumorigenesis, (ii) transgenic mouse tumors that lack the inducing mutation, the synergistic effects of various carcinogens, (iii) cancer resistance in naked mole rats, (iv) different cancer rates for hereditary conditions with

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... ar DNA repair defects, (v) carcinogenic exposure of stromal cells leading to tumors in epithelial cells, and (vi) the roles of BRCA1 mutations, obesity, asbestos, schistosomiasis, viruses, and smoking in carcinogenesis. The proposed detached pericyte hypothesis provides novel explanations for these phenomena. The detached pericyte hypothesis postulates the following events. A carcinogen or chronic inflammation causes pericytes to detach from blood cell walls, either directly through vascular injury or indirectly through fibrosis followed by collagen contraction and obliteration of capillaries. Some detached pericytes form myofibroblasts which increase fibrosis and alter the extracellular matrix. Other detached pericytes develop into mesenchymal stem cells that adhere to the altered extracellular matrix of the the fibrosis. The altered extracellular matrix disrupts regulatory controls, causing the adjacent mesenchymal stem to develop into tumors. Various lines of evidence support the detached pericyte hypothesis. Further investigations into the detached pericyte hypothesis, ideally in the framework of multiple working hypotheses, would likely accelerate progress in cancer research and prevention.