The challenge we face today is identification of the mechanisms
through which dietary factors perturb fundamental fatty acid (FA) pathways in cancer cells.
In principle, insight into a lipid model for the cancer entity under assessment is required.
This prompted and investigation into FA role-players that drive cellular over-production
and apoptotic pathways under circumstances where environmental factors impede
essential fatty acid metabolism (EFAM) that contributes to colorectal cancer (CRC).
Ultimately, better understanding of FA metabolic pathways followed under colorectal
pathological conditions can contribute to improved therapies by which growth and
recurrence of this disease may be obviated. PURPOSE OF STUDY: The primary goal of
this study was to construct clinically relevant ex vivo FA profiles from a lipid model for
colorectal adenocarcinoma, not previously reported in the literature. Aims were to identify
prominent FA role-players and to debate their involvement in different signaling pathways.
The final purpose of this study was to present a rationale for adjuvant FA therapies to
improve the management of CRC. MATERIAL AND METHODS: The study group
consisted of CRC biopsies (TNM staging, mostly T2/T3) and normal colorectal mucosal
biopsies, (n8 of each group). Biopsy selection was hampered by difficult circumstances,
since most patients received treatment prior to surgery. All the lipid analyses were
personally conducted at the Biolipid Division of the Department Biochemistry at the
University of the Free State (UFS) as follows: lipids were extracted; total lipids (TLs) were
fractionated into neutral lipids (NLs) and phospholipids (PLs); phosholipid subclasses, i.e.
phosphatidylcholine, (PC), phosphatidylserine (PS), phosphatidylethanolamine (PE) and
phosphatidylinositol (PI), were separated; and fatty acid methyl esters of all the classes
and subclasses were analyzed. Lipid analyses were done according to well established
and internationally accepted gaschromatography (GLC) and thin layer chromatography
(TLC) techniques. Statistical analyses were performed by a biostatistician attached to the
UFS, and p-values and 95% confident intervals (95% CI) for median of differences, as
well as specific ratios were calculated. MAIN RESULTS AND DISCUSSION: The ex vivo
phospholipid FA profile for CRC cells revealed linoleic acid (LA), arachidonic acid (AA),
palmitic acid (PA) and oleic acid (OA) as main role-players involved in CRC. An extensive
literature study revealed that: prolonged inflammatory responses and oxidative events,
marked by the up-regulation of cyclooxygenases (COXs) and inducible nitric oxide
synthase (iNOS), contribute to colorectal carcinogenesis; and prolonged cytokine mediated responses, orchestrated by nuclear factor-kappa Beta (NF-κβ) with consequent
immunodeficiency, are prevalent in CRC patients. Past research revealed without doubt
that high dietary AA intake (meat) and COX-2 metabolism play a pivotal role during
colorectal carcinogenesis. CRC is a stress-related cancer and it is plausible that high iron
intake and lipids contribute to chronic inflammation and radical-mediated cell damage in
this age-related disease. Current research directions in CRC concern LOX metabolism
and peroxisome proliferator activator receptors (PPARs) are receiving much attention,
especially PPARδ/β that was an enigma and elicited controversial debate in adenomas
(polyps) and adenocarcinoma. Taken together at this point in time, the impact of
environmental factors on essential fatty acid metabolism (EFAM) that impede LA
conversion to AA via delta-6 and -5 desaturase (Î6d and Î5d) pathways with up-regulation
of the fatty acid synthase (FAS) and Î9d pathways, and the down-regulation of LA
oxidative metabolism via the 15 LOX-1 pathway with up-regulation of the COX-2 and 15-
LOX-2 pathways of AA, is characteristic of colorectal carcinogenesis. Seen in context, the
lipid findings of this study integrated with evidence-based information in the literature
encompasses the following: excessive dietary linoleic acid (LA) intake that can contribute
to cell proliferation, radical-mediated cell damage, and the production of conjugated
linoleic acid (CLA) in the gut; high dietary AA intake and COX-2 over-expression that play
a pivotal role during carcinogenesis and immune responses with consequent exhaustion
of the AA source; enhanced FAS and Î9d activities that contribute to, respectively,
enhanced palmitic acid (PA) and oleic acid (OA), is prevalent in CRC cells. The high PA
content in CRC cells apparently activates PPARδ/β and thereby suppresses apoptosis, a
crucial factor in the pathobiology of CRC. The link between OA and CRC still needs
proper clarification. It is conceivable that the high saturated fatty acid (SFA) content
observed in CRC cells, exogenous intake with red meat and endogenous production by
enhanced FAS activity, contribute to colorectal carcinogenesis and immunodeficiency in
CRC patients, since it can stimulate COX-2 expression (and PGE2 activity) and downregulate
the Th1 immune pathway that make CRC a Th2 dominant disease. Taken in
consideration that lipid rafts rich in SFAs down-regulate the Th1 cytokine subset,
particularly interleukin-2 (IL-2) that stimulates lymphocyte production, it is plausible that
management of the CRC patient is hampered by immunodeficiency. All the altered cell
signaling pathways in CRC debated in this study served as sound foundation for clinical
intervention with adjuvant FA therapeutic strategies to improve CRC management.
CONCLUSION: The identification of prominent FA role-players in CRC cells that serve as
ligands for specific PPAR family members contributed to the assessment of FA driven
proliferation and apoptotic pathways characteristic of CRC. It is conceivable that enhanced PA (and LA) contributes to PPARδ/β over-expression that can suppress PPARγ
(and PPARα) activity and then tilts the scale in favor of apoptotic resistance and survival
of CRC cells. From an epidemiological viewpoint, excessive iron and SFAs seem to be
important co-factors in the multifactorial etiology of CRC. The biohydroxygenation of LA
to different CLA products in the gut and to what extent harmful CLA products may pose a
danger need to be fully explored, especially since the uptake of beneficial products is
apparently limited. Among current therapeutic options in the field of lipids, concurrent
therapy with a COX-2 inhibitor (Celecoxib) and docosahexaenoic acid (DHA) to improve
membrane fluidity and the impact of drug therapy entered clinical trials and although the
outcome is still awaited, the impact of DHA on lymphocyte production may be a concern.
Based on a mountain of evidence presented in this study, it is suffice to say that there is a
rationale for additional adjuvant FA therapies that can be included in the existing
therapeutic regime for CRC management. Firstly, CLA and EPA therapy for prevention of
polyp recurrence and improvement of immunocompetence in CRC patients and secondly,
GLA and EPA therapy in the management of patients with a history of polyp growths is
proposed.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ufs/oai:etd.uovs.ac.za:etd-10232009-125844 |
| Date | 23 October 2009 |
| Creators | Nel, Amanda |
| Contributors | Prof PN Badenhorst, Prof L Louw |
| Publisher | University of the Free State |
| Source Sets | South African National ETD Portal |
| Language | en-uk |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.uovs.ac.za//theses/available/etd-10232009-125844/restricted/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University Free State or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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