Investigation of the multistep process of colon carcinogenesis as affected by dietary fat and energy
Lasko, Catherine Michelle
The main objective of this dissertation was to explore the role of dietary fat and energy restriction (ER) on the multistep process of colon carcinogenesis and to investigate the cellular and molecular features of the morphological determinants of various preneoplastic and neoplastic states. It was hypothesized that ER and fat would exert different effects on the growth of preneoplastic lesions depending on their phenotypic features and that their growth modulating abilities would be mediated via alteration of biochemical events known to be involved in cell growth and differentiation. A series of studies was conducted in male F344 rats to investigate the effects of ER (20%) in low (LF) and high fat (HF) corn oil diets on the number and growth characteristics of aberrant crypt foci (A F), microadenomas and adenocarcinomas representing early, intermediate, and late stages of colon carcinogenesis respectively. Changes in dietary fat during the early stages exerted measurable responses on ACF development more rapidly than ER. Feeding a low fat diet during the early time point soon after initiation of colon carcinogenesis permitted the modulation of ACF, microadenomas and tumors by changes in fat and energy during the intermediate stages of carcinogenesis. Upon exposure of the animals to high fat diets during the early time point, a more stringent and growth conducive environment for modulation of ACF, it was demonstrated that ER in conjunction with LF retarded the appearance of macroscopic lesions. The enzymes protein kinase C and tyrosine kinases did not exhibit specific or consistent changes that were attributable to ER or fat associated growth responses. Employing the techniques of reverse transcription polymerase chain reaction, biological difference were demonstrated among the morphological determinants of the multistep process of colon carcinogenesis. The findings of the present research demonstrated that biological responses elicited by ER and fat are separable and that the amenability of the disease process to a growth modulatory environment depends on its biological state.