A non-genetic basis for cancer progression and metastasis: self-organizing attractors in cell regulatory networks.

It is commonly assumed that somatic evolution drives the multi-step process that produces metastatic cancer. But it is difficult to reconcile the inexorable progression towards metastasis in virtually all carcinomas and the associated complex change of cancer cell phenotype, characterized by an epithelial-to-mesenchymal transition, with the random nature of gene mutations. Given their irreversible nature, it is also difficult to explain why certain metastatic carcinomas can reform normal tissue boundaries and remain dormant for years at distant sites. Here we propose an encompassing conceptual framework based on system-level dynamics of gene regulatory networks that may help reconcile these inconsistencies. The concepts of gene expression state space and attractors are introduced which provide a mathematical and molecular basis for an "epigenetic landscape". We then describe how cancer cells are trapped in "embryonic attractors" because of distortions of this landscape caused by mutational rewiring of the regulatory network. The implications of this concept for a new integrative understanding of tumor formation and metastatic progression are discussed. This formal framework of cancer progression unites mainstream genetic determinism with alternative ideas that emphasize non-genetic influences, including chronic growth stimulation,extracellular matrix remodeling, alteration of cell mechanics and disruption of tissue architecture.