Abstract
BACKGROUND: Cancer is a complex disease that involves a sequence of gene-environment interactions in a progressive process that cannot occur without dysfunction in multiple systems, including DNA repair, apoptotic and immune functions. Epigenetic mechanisms, responding to numerous internal and external cues in a dynamic ongoing exchange, play a key role in mediating environmental influences on gene expression and tumor development. HYPOTHESIS: The hypothesis put forth in this paper addresses the limited success of treatment outcomes in clinical oncology. It states that improvement in treatment efficacy requires a new paradigm that focuses on reversing systemic dysfunction and tailoring treatments to specific stages in the process. It requires moving from a reductionist framework of seeking to destroy aberrant cells and pathways to a transdisciplinary systems biology approach aimed at reversing multiple levels of dysfunction. CONCLUSION: Because there are many biological pathways and multiple epigenetic influences working simultaneously in the expression of cancer phenotypes, studying individual components in isolation does not allow an adequate understanding of phenotypic expression. A systems biology approach using new modeling techniques and nonlinear mathematics is needed to investigate gene-environment interactions and improve treatment efficacy. A broader array of study designs will also be required, including prospective molecular epidemiology, immune competent animal models and in vitro/in vivo translational research that more accurately reflects the complex process of tumor initiation and progression.