Regulation of the cellular, molecular and morphological determinants of colonic precancerous stages by dietary lipids
Good, Carolyn Kathleen
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The main objectives of the present dissertation were: (a) to evaluate the effect of dietary lipid composition on the stepwise process of colon carcinogenesis; and (b) to assess the effects of dietary lipid composition on specific cellular and molecular events associated with cell growth and transformation. These objectives are based on the hypotheses that specific dietary lipids will elicit different effects on the growth of preneoplastic colonic lesions, depending on their stage of development. Furthermore, this effect is mediated via their alteration of the expression of specific proteins involved in cell growth and transformation. A series of studies was conducted to investigate these hypotheses. Briefly, F344 rats were injected with azoxymethane to initiate the carcinogenic process. Intervention with diets containing beef tallow, fish oil, corn oil or corn oil + piroxicam (a cyclooxygenase inhibitor), was begun 12-16 weeks after the final carcinogen injection. At timed intervals (6-8 and 12-16 weeks), animals were terminated and their colons assessed for preneoplastic aberrant crypt foci (ACF) and tumors. Quantification of morphological determinants of carcinogenesis revealed that dietary lipids differ from each other in their ability to affect the growth of preneoplastic lesions at various stages of development. A diet high in fish o l was unable to retard the appearance of advanced ACF and large tumors. The piroxicam-treated group exerted a potent inhibitory effect on tumorigenesis compared to the other diet groups ('P' <= 0.05). Molecular analysis of tissues was performed by reverse transcription polymerase chain reaction for the expression of cyclooxygenase (COX1 and COX2), transforming growth factor-_ (TGF-_), epidermal growth factor receptor (EGFR) and extracellular-signal regulated kinase-1 (ERK-1). Expression of these target genes in normal colonic mucosa generally differed from tumors. Tumors from different groups exhibited similar morphology, yet displayed molecular heterogeneity depending on the diet treatment. Tumors able to overcome the inhibitory effects of piroxicam had increased mRNA expression of EGFR ('P' <= 0.05). These findings strengthen the contention that tumors emerge from their progenitor lesions as a result of sequential clonal selection, expansion and adaptation to their biological environment.