Abstract
It is commonly assumed that somatic evolution drives themulti-step process that produces metastatic cancer. But it is difficultto reconcile the inexorable progression towards metastasis in virtuallyall carcinomas and the associated complex change of cancer cellphenotype, characterized by an epithelial-to-mesenchymal transition, withthe random nature of gene mutations. Given their irreversible nature, itis also difficult to explain why certain metastatic carcinomas canreform normal tissue boundaries and remain dormant for years at distantsites. Here we propose an encompassing conceptual framework based onsystem-level dynamics of gene regulatory networks that may helpreconcile these inconsistencies. The concepts of gene expression statespace and attractors are introduced which provide a mathematical andmolecular basis for an “epigenetic landscape”. We then describe howcancer cells are trapped in “embryonic attractors” because ofdistortions of this landscape caused by mutational rewiring of theregulatory network. The implications of this concept for a newintegrative understanding of tumor formation and metastatic progressionare discussed. This formal framework of cancer progression unitesmainstream genetic determinism with alternative ideas that emphasizenon-genetic influences, including chronic growth stimulation,extracellular matrix remodeling, alteration of cell mechanics anddisruption of tissue architecture.