Identification of gene expression profiles correlated to tumor progression in a preclinical model of colon carcinogenesis.

The rat azoxymethane (AOM)-induced colon carcinogenesis model provides useful information for understanding human colorectal neoplasia. Here, we used the AOM model to measure the gene expression profiles of biomarkers related to tumor progression. We assessed tumor progression stages by computed tomographic (CT) colonography. Messenger RNAs were isolated from tumors and mucosal samples, and gene expression levels were assessed by real-time quantitative polymerase chain reaction (PCR). We show that early stages of tumor progression are associated with an upregulation of matrix metalloproteinase-7 (MMP-7) and of genes involved in the inflammatory response, including interleukin (IL1beta) and tumor necrosis factor-alpha (TNFalpha). The ratio of B-cell lymphoma/leukemia 2 (Bcl-2)-associated X proteins (Bax) to Bcl-2 transcript (proapototic/antiapoptotic signals) is elevated in early stages of tumor progression (Bax/Bcl-2 >1) and reversed in more advanced stages of tumor development (Bax/Bcl-2 <1). These changes are associated with the reduced expression of TNF-related apoptosis-inducing ligand (TRAIL)-death receptor 5 (DR5) and FAS (also known as CD95) apoptotic receptors. Advanced stages of tumor development are characterized by an increase in MMP-9 expression associated with the upregulation of components of the innate immune system: alpha-defensin 5 (DEF-5) and neutrophil gelatinase-associated lipocalin (NGAL). The identification of specific gene expression profiles that correlate with tumor progression stages, as reported in the present study, may represent an important step in evaluating potential chemopreventive and/or chemotherapeutic agents prior to initiating clinical trials.