On the intrinsic inevitability of cancer: From foetal to fatal attraction

The cracks in the paradigm of oncogenic mutations and somatic evolution as driving force of tumorigenesis, lucidly exposed by the dynamic heterogeneity of cancer stem cells or the diffuse results of cancer genome sequencing projects, indicate the need for a more encompassing theory of cancer that reaches beyond the current proximate explanations based on individual genetic pathways. One such integrative concept, derived from first principles of the dynamics of gene regulatory networks, is that cancerous cell states are attractor states, just like normal cell types are. Here we extend the concept of cancer attractors to illuminate a more profound property of cancer initiation: its inherent inevitability in the light of metazoan evolution. Using Waddington's Epigenetic Landscape as a conceptual aid, for which we present a mathematical and evolutionary foundation, we propose that cancer is intrinsically linked to ontogenesis and phylogenesis. This explanatory rather than enumerating review uses a formal argumentation structure that is atypical in modern experimental biology but may hopefully offer a new coherent perspective to reconcile many conflicts between new findings and the old thinking in the categories of linear oncogenic pathways. (C) 2011 Elsevier Ltd. All rights reserved.