Abstract
Early models and observations on the clonal origin of cancer asserted that cancer arises from a sequence of rare mutations that confer the capability to one cell, and its progeny, to grow outside the control of the tissue of origin. More recently, theories for polyclonal tumour evolution and accumulating experimental evidence have challenged this perspective. However, the role and a model for non-cell-autonomous mechanisms during mutationally-driven carcinogenesis, at the best of our knowledge, are not well characterised. Therefore, we developed a simple yet insightful theoretical framework to address the question of how frequent and important non-cell-autonomous mechanisms during the early steps in carcinogenesis might be. We show that the three-dimensional tissue architecture is likely to amplify local non-cell-autonomous mechanisms of carcinogenesis mediated by cooperation of different, non- or partially-transformed mutants. We thus propose that clonal cooperation during the earliest steps in oncogenesis is an under-appreciated process, yet a phenomenon that might be an essential force that shapes tumour evolution.
