Introduction: Colorectal cancer is one of the most frequent cancers in our country as well as in most of the occidental societies. Environmental factors play a crucial role on its development. Nutrients and in concrete fat seems to be one of the most determinant components. Although relatively high fat diets are consumed in Greenland, Finland and some Mediterranean areas, colorectal cancer incidence remains relatively low there. An important difference between these regions and the rest of the western countries is the much higher consumption of fish and fish oil (rich in the n-3 fatty acids eicosapentaenoic, C20:5 and docosahexaenoic, C22:6) in the case of the Northern countries, and fish and olive oil (containing mostly oleic acid, C18:1, n-9) down in the Mediterranean basin. The hypothesis of our study was if «fish oil and olive oil are able to modulate the colorectal cancer development». Aims: The objectives of this study were to evaluate the mechanisms implicated in the modulation of cancer by these oils and determine the implications of its fatty acids. Results: In order to answer the objectives mentioned above we followed two study strategies. First, we performed: in vitro studies using adenocarcinoma cell lines, Caco-2 and Ht-29. The other one is the study of the effects of several nutrients in an animal model of carcinogenesis induction . Fish oil and olive oil induced the differentiation of Caco-2 cells. As a result of this differentiation, the cells began to express Sucrase-Isomaltase and Dipeptydilpeptidase IV enzymes. Homeostasis regulation of colonic tissue depends on a tightly relationship between cell proliferation and cell loss, through apoptosis. With [3H] thymidine incorporation studies, we demonstrated that fish oil has an important inhibitor effect on the proliferation of Caco-2 and HT-29 cells. It seems that this effect is caused by EPA i DHA (n-3 fatty acids present in fish oil). The most important effect on the development of colorectal cancer by fish oil and olive oil is the induction of apoptosis. To determine the Apoptotic index we evaluated cell morphologic changes by DAPI staining. Fish oil, olive oil, as well as DHA, EPA and oleic acid are able to increase apoptosis in a significant manner. These effects are related to a very fast inhibition of the expression of COX-2. Antipoptotic Bcl-2 protein expression decreases after Cox-2 expression inhibition, suggesting that these two genes are implicated in the antineoplastic effects. On the other hand, we demonstrated a clear implication of the proapoptotic protein BAX, because when an inhibitor of BAX was added, apoptosis significantly decreased. Fish oil and olive oil have an important protective effect in the induction of colorectal carcinogenesis in animals which received an azoximethane treatment. Animals fed with fish oil and olive oil as a principal source of fatty acids in its diet, showed a higher apoptotic index. On the other hand, fish oil may have a preventive effect due to an acceleration of the turnover of colonic epithelia through the induction of apoptosis of these cells. Conclusions: Fish oil can modulate the development of colorectal cancer in cellular differentiation, proliferation and apoptosis processes. Fish oil could have a preventive effect on the development of colorectal cancer modifying the regeneration of normal colonic epithelial. Olive oil could modulate the development of colorectal cancer although not having effects in all of the studied mechanisms.
|Date of Award||16 Mar 2006|
|Supervisor||Miquel Àngel Gassull Duró (Director), Rosa Miró Ametller (Tutor) & Xavier Llor Farre (Director)|