Essential fatty acids: molecular and cellular basis of their anti-cancer action and clinical implications

In summary, after a few decades of research, we now have a clearer picture of the role of EFAs in carcinogenesis, invasion and metastasis and cancer treatment. Selective PUFAS, i.e. HUFAs including GLA and DGLA of n-6 series, EPA and DHA of n-3 series have potential anti-cancer effects. It is also known that when considering the effect of fatty acid on cancer, one must take into account of the following points: (i) the type of the fatty acids, (ii) their saturation, desaturation and the degree of desaturation, (iii) ways to deliver fatty acids to cancer cells or host and (iv) tumour/cell type. These are among the most important factors determining the effects of a fatty acid on cancer cells. HUFAs exert cytotoxic effects on cancer cells by inducing both necrosis and apoptosis. They also modify invasion and metastasis related parameters, such as cell adhesion, motility and angiogenesis (Fig. 9). Both in vivo and clinical studies have already shown the beneficial effect of fatty acid administration to tumour-bearing hosts. However, some other fatty acids, such as LA, have been shown to produce opposite effects in tumour cells. There are thus many gaps still needing to be filled concerning the role of EFAs in cancer and several key issues are outlined as follows: 8.1 Cloning of human desaturase. Although numerous studies indicated a deficiency of desaturases, this has so far been carried out using function assays, i.e. by measuring the conversion products. We now need to clone these molecules, which will significantly aid studies on EFAs and cancer and also will be useful in clinical interventions. 8.2. Identification of GLA or LA receptors. Although receptors of a range of eicosanoids have been identified, it was not until recently that presence of receptors which may directly bind EFAs have been identified and termed PPARs [121,122]. However, given the diversified effects of these fatty acids, there arises the possibility that more than one type of receptor mediates the response of these fatty acids in the cell. 8.3 Identification of key metabolites in EFA mediated cell phenomenon. As illustrated in Figs. 1 and 2, a large of number of metabolites are generated from a single fatty acid. The knowledge of the biological effects of these diverse materials are yet to be fully established, although some have already been determined (i.e. 12-HETE and 13-HODE) [306-311]. 8.4. Identification of EFA-specific inducible genes. EFAs seem to participate the regulation of a range of gene related events. What would be interesting to know is which genes may be specifically regulated by EFAs and responsible for the effects exerted by EFA. Future work will have to be sought in this aspect. This may be extended to search for the PPREs [312-314]. 8.5 Key signalling events in EFA mediated cell function. Compelling evidence so far suggest an active and important role of EFA in a number of cell functions, such as cell growth, motility, migration and adhesion. As yet the exact signalling pathway(s) involved in these effects are not fully characterised. Signalling pathways which regulate the growth, apoptosis, motility, migration, adhesion and are less well known in EFA actions, should now be explored. These include BCL family, mitogen-activated protein kinase (MAPK) family, rac/rho family, sub-coat membrane protein family, etc. [315-318]. Some recent studies have already indicated a role for some of these events in EFA mediated cell behaviour [89,283,284,319]. These events may individually participate the regulation of EFA mediated effects in cancer, or be collectively responsible. An understanding of these events in EFA action may provide clues both in the mechanisms and in designing new strategies in the application of EFA in patients with cancer. Research in this important area of cancer and biochemistry has come a long way and is beginning to show the usefulness of certain fatty acids as possible anti- cancer agents. The approach of using EFAs in cancer treatment has pointed to an exiting new direction [56,257]. With the emerging new cellular and molecular explanations concerning their anti-cancer action, one can say with confidence that these essential ingredient in our life will give us new means in the war against cancer.