Colon Cancer Research – Dr Stefan Abel
Dr Stefan Abel
Title of the project
Establishing endpoints to evaluate the modulating effect of specific n-6/n-3 FA ratios on colon cancer development in an animal model and colon cancer in humans.
Highlights of the project
When considering the important role of the lipid metabolism during cancer, the observed effects, i.e. phospholipid PC/PE ratio, cholesterol, fatty acid content and ratios, not only differs between the cancer and the adjacent surrounding tissues but also between rats and humans. In this regard changes in the membranal PC/PE ratio and associated fatty acid (FA) profiles are observed which can be related to the altered growth pattern in the cancerous tissue. In the rat colon polyps, the ratio is mainly affected by changes in the PE concentration, whereas in the human tissue the PC concentration is the main determinant. This indicates that certain lipid parameters can be utilized as biomarkers for altered cell growth and cancer development which can be utilised as biological targets for chemoprevention by dietary interventions.
What has been achieved?
Several diseases, including some cancers, have been associated with changes in the membrane lipid composition. High intakes of n-6 PUFA have been linked to the development of colon cancer in association with low n-3 PUFA intake. Therefore understanding the differences in the lipid profiles between cancer and normal cells in the colon, and dietary modulation may be invaluable in understanding their role in carcinogenesis. The current research was conducted to characterise specific lipid changes associated with cancer development in the colon of the rat and in humans. Changes in the cell membrane lipid composition affect the structural and functional properties of membranes, thereby altering the growth characteristics of cells. Regarding cell structural and function, membrane phospholipid classes (phosphatidylethanolamine, PE and phosphatidylcholine, PC, making up the bulk of cellular membranes) have a characteristic asymmetric phospholipid membrane distribution as indicated by the PC/PE ratio. Membrane disruption, together with altered cholesterol and fatty acid levels, is associated with abnormal cell growth. Alterations in FA levels occur due to various factors such as increased requirement as building blocks for cell membranes, impaired FA elongation and desaturation and substrate requirement for eicosanoid synthesis. Of special importance are the fatty acids C18:2n-6, C20:4n-6, C20:5n-3 and C22:6n-3 in these processes.
Certain lipid biomarkers are altered in carcinogenesis and are similarly affected in human colon cancer tissue and rat colon polyps although alterations manifest differently; i.e changes to the PC/PE ratio, Chol/PL, C20:4n-6 level and the C20:4n-6 PC/PE ratio; total n-6 & n-3 FA membrane concentration and the #6 S/P ratio. When considering these lipid biomarkers, it appears that the PC/PE ratio and associated FA changes are good indicators for rapid cell growth, an important characteristic of cancer cells. With regards to colon cancer, the lipid profile of cancer tissue differs significantly from the surrounding. Alterations in the tissue cholesterol and phospholipid levels, i.e. PC and PE, result in changes in the cholesterol/phospholipid (Chol/PL) and PC/PE ratios, indicators of cell membrane fluidity. Alterations in FA levels is characterised by increased C18:1n-9, a shift in C20:4n-6 content between the phospholipids PC and PE as indicated by a changes in the C20:4n-6 PC/PE ratio and n-6 and n-3 PUFA content. Changes in the level of C20:4n-6 have important implications in cancer development as this FA is the precursor for the hormone-like active metabolites, the E-series of prostaglandins, which are involved in cell growth. Differences in the alterations when comparing animal (rat) to human cancer tissue is possibly related to interspecies differences with regards to growth and cell turnover, which appear to be faster in the animal.
Changes in the PUFA profile, particularly the LC-PUFA and cellular oxidative status, are associated with potentially neoplastic lesions. Cell proliferation and apoptosis appears to be dependent on levels of oxidants/antioxidants in the cell. A reducing environment stimulates proliferation while a shift towards an oxidizing environment initiates apoptosis and necrosis. Therefore the cellular redox environment is an important determinant for the outcome of cell survival. In cancer cells the oxidative status is low creating a protective environment for proliferation. Cancer cells also have a high content of oleic acid (C18:1n-9) which displays antioxidant properties. Therefore, the antioxidant potential of oleic acid (C18:1n-9) is important in contributing towards the low oxidative status in cancer cells and can be regarded as an important biological antioxidant. In this regard LC-PUFA, key substrates for lipid peroxidation, can play a role in the control of cell proliferation by inhibiting cell growth and stimulating or enhancing apoptosis by increased cellular lipid peroxidation.
How was this project of value in the struggle against cancer?
Based on the findings from the present investigation, dietary fat intake plays a distinctive role in modifying the lipid composition of cellular membranes. As membrane structure and function are dependent on the lipid composition, diet induced alterations impact significantly on cellular features/characteristics. As a result, cellular functions that diverge from the norm may promote abnormal cellular states, such as the process of carcinogenesis, which may be modulated by specific dietary constituents. The development of colon polyps in the rat cancer model illustrated that a diet high in n-6 PUFA may play an underlying role. This result was conveyed by the significant differences between the lipid profiles of the polyps and surrounding mucosa, which was associated with a particular high n-6 FA diet. An interactive role of SATS, MUFA and C20:4n-6 was highlighted as the main driving force to sustain the altered growth characteristics of the polyps. The dietary FA modulation study indicated that colon mucosa and RBC membranes respond differently to dietary n-6/n-3 FA ratios. This is indicative of differing tissue interactions to dietary modulation, unique to specific tissue compartments. Hence, RBC membrane lipid profiles, which have been widely used as a biomarker for other tissues compartments, are not a true reflection of alterations in the colon.
The development of colon cancer can be associated with alterations in lipid metabolism affecting cell membrane structure and function. This was confirmed as significant differences exist between the lipid profiles of the colon cancer tissue and surrounding in both the rat and humans, although distinct for each species. An interactive role between cholesterol, phospholipids and fatty acids are likely to play an important role in cancer development. In this regard, the oxidative status in a cell also contributes to creating an environment stimulating the growth and development of cancer cells. Changes in the colon
polyp cholesterol, phospholipid and FA biomarkers could therefore provide unique targets for developing strategies in chemoprevention by means of dietary manipulation.
- Schuhr I, Abel S, Gelderblom WCA. The antioxidant effect of oleic acid (18:1n-9) and role in cell survival in carcinogenesis. (In preparation)
- Abrahams C, Abel S, De Kock M, Swanevelder S, Gelderblom WCA. Lipid profile of
colon polyps and surrounding mucosa tissue in rats fed a sunflower oil based diet. (Submitted to LIPIDS)
- Ms I Schuhr, MSc, thesis title: To investigate the anti-oxidant potential of Oleic acid (C18:1n-9) in primary and cancer cells. University of Technology Dresden (TUDresden), Germany.
- Ms C Abrahams, MSc (cum laude), thesis title: The Modulating Effect of Fatty Acids onthe Lipid Profile in Colon Epithelial Mucosa In Vivo. Department of Medical Biosciences, Faculty of Natural Science at the University of the Western Cape, Bellville, South Africa.
- Abel S, Schuhr I, Gelderblom WCA. The antioxidant potential of oleic acid (C18:1n 9)and effect on cell survival in carcinogenesis. 9th International Society for the Study of Fatty Acids and Lipids (ISSFAL) Conference, Maastricht, The Netherlands, 29 May 29 – 2 June 2010.
- Abel S, Abrahams C, Gelderblom WCA. Alterations in PUFA profile and oxidative statusin liver and colon carcinogenesis. 9th International Society for the Study of Fatty Acids and Lipids (ISSFAL) Conference, Maastricht, The Netherlands, 29 May – 2 June 2010.
- Abrahams C, Abel S, De Kock M and Gelderblom WCA. Dietary polyunsaturated fattyacids modulate the lipid profile and oxidative status of rat colon mucosa. 15th World Conference of Food Science and Technology (IUFoST), Cape Town, South Africa, 22 – 26 August 2010.
- Abel S, Schuhr I, Gelderblom WCA. The antioxidant potential of oleic acid in FB1-induced hepatocarcinogenesis. 23rd biannual South African Nutrition Congress, Durban ICC, KwaZulu-Natal, 19-22 September.
- Abrahams C, Abel S, De Kock M, Swanevelder S and Gelderblom WCA. An alteredlipid profile contributes to colon polyp development in rats fed a high fat diet.Medical Research Council’s 4th Research Day, MRC Conference Centre, Tygerberg, South Africa, 14-15 October 2010.