Cellular mechanisms of risk and transformation

Our early work using the first array and imaging methods for the quantitative analysis of the expression of 4000 cDNA sequences suggested that modulation of mitochondrial gene expression was a factor in determining whether colonic epithelial cells displayed a differentiated or transformed phenotype. We have since dissected a pathway in which mitochondrial function is a key element in determining the probability of cells undergoing cell-cycle arrest, lineage-specific differentiation, and cell death. Moreover, this pathway is linked to signaling through beta-catenin-Tcf, but in a manner that is independent of effects of the APC gene on beta-catenin-Tcf activity. Utilization of unique mouse genetic models of intestinal tumorigenesis has confirmed that mitochondrial function is an important element in generation of apoptotic cells in the colon in vivo and has demonstrated that modulation of cell death may be involved in intestinal tumor progression rather than initiation. Normal spatial and temporal patterns of cell proliferation, differentiation, and apoptosis in the colonic mucosa are determined by developmentally programmed genetic signals and external signals generated by homo- and heterotypic cell interactions, humoral agents, and lumenal contents. Mitochondrial function may play a pivotal role in integrating these signals and in determining probability of cells entering different maturation pathways. How this is accomplished is under investigation using high-density cDNA microarrays.