(35)SIGNIFICANCE OF TRANS FATTY ACIDS IN CANCERHITOSHI OHMORI, KIYOMU FUJII and HlROKI KUNIY ASU
Department of Molecular Pathology, Nara Medical University, Kashihara, japan

Received September 28, 2015

Abstract: Trans fatty acids (TFAs) are a recent focus of health problems. TFA is a definitive
risk factor for cardiovascular diseases and the death. TF A is also possible risk factor for
Alzheimer's disease, obesity, diabetes, fatty liver, and ovulation infertility. The relationshipbetween TFA and carcinogenic risk is controversial; however, TFA is reported to increase therisk of breast cancer and prostate cancer. Elaidic acid (EA), a trans form of oleic acid, enhances
cancer cell growth, invasion, and anti-apoptotic survival. In animal models, EA promotes tumor
growth and metastasis to the lung, liver, and peritoneum. EA induces sternness in cancer
cells through transactivation of EFGR via SRC from GPR40/120 as receptors in EA-integrated
cholesterol rafts. Activated EGFR relays the signals to activate canonical and non-canonical wnt
pathways and to inactivate notchl pathways. EA also increases miR-494, which inhibits celldifferentiation through decrease of target genes. Continuous EA feeding with dosage alteration
increased cancer cell sternness. EA diminishes the efficiency of 5-fluorouracil by increasing
residual cancer stem cells. These findings suggest that TF A is a relevant cancer promoting
factor. The decision to remove TFA from foods made by the FDA might have an impact on
cancer clinics.

Key words : trans fatty acid, elaidic acid, conjugated linoleic acid, linoleic acid, colorectal cancer

Trans fatty acid
Unsaturated fatty acids generally have cis configurations, which are opposed to transconfigurations 1l. Trans fatty acids (TFAs) are uncommon in nature and usually generated inindustrial processes. TF As are provided with trans configurations by hydrogenation, which
depends mainly on oil temperature, hydrogen pressure, stirring speed, reaction time, and thecatalyst type and concentration 1l. TFAs are widely used in margarine and snack foods, and to
shorten the frying of fast foods.
The health problem evoked by TFAs are a focus of public interest as well as basic or clinicalresearch. An increase of 2% in the daily energy through TFA is associated with a 23% increasein cardiovascular risk of myocardial infarction and chronic heart disease death 2' 3). The totality

(36)Hitoshi OHMORI et al.

of analyses supports the proportionality of changes in TF A intake and changes in blood lipids(and therefore, CHD risk) and supports the use of a linear regression model to describe thisrelationship 4).
The American Heart Association recommends limiting trans fats to <1% energy, and
the American Dietetic Association, the Institute of Medicine, US Dietary Guidelines, andthe National Cholesterol Education Project all recommend limiting dietary trans-fat intake
from industrial sources as much as possible 2l. Regulations grounded on maximum limits andmandated labeling can lead to reductions in actual and reported TF As in food and appear toencourage food producers to reformulate products 5). Food and Drug Administration (FDA)
labeling rules had allowed products containing <0.5 g trans fat per serving to claim 0 g transfat 2l. June 17, 2015, the FDA issued a final determination that there is no consensus thatindustrially-produced TF As are generally recognized as safe for any use in human food. Transfat must be removed from prepared foods within three years by June 2018 4).

Cardiovascular disorder and TF A
Monounsaturated fatty acids, on the other hand, have a positive impact on the serum lipid
profile, lead to decreased LDL-oxidation and favorably influence the metabolism of diabetics 6).
Concerning polyunsaturated fatty acids, it is important to increase the supply of n-3 fatty acids(ratio of n-6:n-3: about 5:1) as there is substantial evidence for their protective effects 6).
As mentioned above, trans fatty acids have been identified as an important cause of
cardiovascular disease and the resulting clinical end points such as strokes and heart attacks 7).
Similar to saturated fatty acids, trans fatty acids increase plasma low density lipoprotein (LDL)cholesterol concentrations. In contrast to saturated fatty acids, trans fatty acids do not increasehigh density lipoprotein (HDL)-cholesterol concentrations 8: 9).
TF A may also worsen insulin sensitivity, particularly among individuals predisposed toinsulin resistance; possible effects on weight gain and diabetes incidence require further
confirmation 3l. TFA upregulated the mRNA levels of resistin and downregulated PPARy andlipoprotein lipase (LPL) 10). The alteration in the mRN A levels of PP ARy and resistin could be
associated with insulin resistance in TF A-fed rats.

Carcinogenesis and TF A
Literature has proved a direct connection between trans fatty acids and not only
cardiovascular diseases but also breast cancer, nonaggressive prostate cancer, ovulatory
infertility, Alzheimer's disease, diabetes, fatty liver, obesity and allergy 3: 11-17). However, innumerous experimental models and human studies, there is insufficient and inconsistentevidence linking specific TF A isomers to cancers of the prostate, colon and breast 18). The
significant changes in TF A intakes between then and the end of follow-up in 1994 limit thereliability of this observation. There is insufficient evidence to allow any differentiation between
the effects of TF As of animal or vegetable origin on cancer risk 19). In an animal model, 25% EA
diet does not enhance colon carcinogenesis in F344 female rats induced by azoxymethan 20).

SIGNIFICANCE OF TRANS FATTY ACIDS IN CANCER(37)

Cancer progression and EA
Elaidic acid (EA; Cl8:1 1::. 9, trans) is a trans form of oleic acid (OA; Cl8:1 1::. 9, cis), andconstitutes the largest quantity in dietary TF As. In a previous study, Ehrlich ascites tumors in
EA-fed mice showed higher proliferative activity than those in OA-fed mice and this shortened
the survival rate of mice by 45% at maximum 21). EA tends to be more incorporated into Ehrlich
ascites tumor cells and less oxidized than OA 22).
EA increases cell growth, invasion and anti-apoptotic survival in colorectal cancer (CRC)
cells 23). In mouse models, EA enhances tumor growth and metastasis of CRC cells to the lung,
liver, and peritoneum at more pronounced levels than OA treatment 23). The same amount ofperitoneal metastasis occurred with lxl03 cells unber EA treatment as with lxl05 cells under
OA treatment 23). These results suggest that EA might induce sternness of the CRC cells.

Cancer stem cell and EA
Recent studies have focused on the sternness of the cancer cells in the responsibility for
carcinogenis and metastasis 24). Dysregulation of normal stem cells produces transformed stem
cells, which are the tumor-initiating cells or cancer stem cells CSCs 25' 26). In the CSC model, only
CSCs can propagate tumors at carcinogenesis and cancer metastasis 27). Activation of the signal
pathways of wnt, hedgehog, and notch is deeply associated with cancer stem cell dysregulation
27-31 ). The diversity of normal stem cells is reflected in CSCs, generating heterogeneity andplasticity of the progeny 32). Thus, CSCs are an essential therapeutic target, however, theconventional anti-cancer therapies are not effective against CSCs 33' 34). The study of substances
affecting CSCs might provide some novel valuable information on handling CSCs. In the present
study, the pro-tumoral effect of EA is studied with a focus on cancer stem cell modification.
EA increases sphere formation of CRCs, which possess high sternness 23' 35). EA treatment
induces greater expression of nucleostemin in a monolayer culture and CD133 in sphere assays
in comparison with OA treatment 23). Spheres of EA-treated CRCs show larger size and higher
proliferative activity than OA-treated cell spheres 23). The increase of sternness caused by EA
provides resistance to 5-fluorouracil treatment 36).

Receptor, intracellular signal of EA
G-protein coupled receptors (GPRs) are known as receptors of long chain fatty acids. GPR40
and GPR120 in particular function as receptors for unsaturated long-chain free fatty acids, such
as OA or LA 37). Binding of EA to GPR40 and 120 is confirmed by surface protein internalization
assay; however, knockdown of these two receptors does not abrogate completely the increased
proliferative activity of spheres 23). EA might possess another receptor for the function.
EA is involved into triglycerides, cholesterol esters, and phospholipids as well as otherlong chain fatty acids, such as OA, LA 38). However, EA shows low affinity to intestinal lymph
triglyceride in comparison with OA 39). EA is incorporated into the plasma membrane as well as(38)Hitoshi OHMORI et al.

incorporated into triglyceride 401 • EA in the plasma membrane is integrated in the cholesterol
raft, which involves EGFR and GPR40/120. The transactivation of EGFR from GPR40/120
occurrs through Src activation 231 • Crosstalk between GPCR and EGFR is reported to activate
phospholipases C, D, and A2, which subsequently activates PKC/PKD, Raf/MEK/ERK, and
AktlmTOR/p70S6K 411 .
EGFR signaling upregulates nucleostemin and snail, and downregulates notchl andE-cadherin in CT26 cells carrying wild type APC. In contrast, the signal upregulates
nucleostemin, wnt5a and CD44, and downregulates notchl in APC null HT29 cells 231 • Thus
EA provides enhancement of proliferative stem activity and epithelial-mesenchymal transition
phenotype. These effects are closely linked to the prominent metastatic potential of EA-treatedcancer cells.

microRNA and EA 421
The expression levels of many micro-RNAs (miRNAs) are altered in EA treated CT26
CRC cells examined by miRNA array 421 • miRNA-494 is one of the increased miRNAs, whosefunction, especially in cancer, has not been elucidated. The effect of the treatment of miR494 inhibitor or miR-494 mimic concurrently with EA on sternness is examined by a sphereassay. Sphere density was increased by EA; however, a strong increase is observed withmimic treatment. Meanwhile, sphere density is decreased by inhibitor treatment. CD133 andNS increased with mimic and EA, whereas the inhibitor treatment abrogated the expressionof CD133 and NS 421 • The target genes of miR-494 contained differentiation factors for cancer
stem cells. The expressions of PP ARy coactivator lA, PTEN, and activin A receptor lC are
reduced by treatment with EA and the mimic, and increased by the inhibitor 421 • Thus, miR-494
expression is suggested to be promoted by EA, to maintain the sternness of cancer stem cells
by suppressing differentiation factors 421 •Continuous feeding of EA diet 431
The effect of intermittent feeding restriction (IFR) is simulating human habits of feeding,which are quite variable both temporally and quantitatively. The effect of IFR and foodcontents on cancer are studied using a mouse model. CT26 CRC cells were inoculated into theback of a syngeneic BALB/c mouse. A 24-hour fast was implemented once a week for 4 weeks.
The effect of oral intake of TF As on tumor stem cells with IFR was examined using the model.
Mice fed with 10% EA diet (EA)+IFR, and a control diet (CD)+IFR are compared with EA
alone or CD alone. The order from highest to lowest in terms of tumor weight and tumor MIBl
index (cell proliferation)is: EA+IFD, CD+IFR, EA, and CD. In EA+IFR, NS-positive tumor cells
are transiently increased on the next day of feeding restriction. After 6 weeks with 12 IFRs,
NS-positive CT26 cells are increased in EA+ IFR in comparison with EA alone. These findings
suggest that alteration of feeding habits might enhance cancer sternness.

SIGNIFICANCE OF TRANS FATTY ACIDS IN CANCER(39)

Ruminant TFA
Recent research has now identified an important cardioprotective role for a sub-categoryof trans fats, the ruminant trans fats 7>. TFAs contained in meat of the ruminant animals orvegetable oils have different features from industrial TF As 44>. However, no relationship isfound between ruminant TFA intake levels of up to 4.2% of daily energy intake and changes
in cardiovascular risk factors such as total-cholesterol: HDL-cholesterol and LDL-cholesterol:
HDL-cholesterol ratios. Moreover, a multivariate regression analysis that included other dietary
variables shows that doses of ruminant TFA did not significantly influence the changes in thelipid ratio 45>.

Conjugated linoleic acid
Conjugated linoleic acid (CLA) is composed of positional- and stereo-isomers ofoctadecadienoate (18:2), which is recognized as one of the ruminant TFAs 44>. The
chemoprotective properties of CLA are reported in experimental cancer models and in vitro
examinations 44' 46>. In contrast, LA has carcinogenic properties. LA, an w-6 polyunsaturated
fatty acid, is a stereoisomer of CLA. COX-2 metabolizes LA to PGE2, which plays roles
in carcinogenesis due to its properties of pro-inflammation, pro-proliferatation, andimmunosuppression 47' 48>. CLA activates PP ARy as a ligand 49' 50>. PP ARy is a nuclear hormone
receptor superfamily of ligand-activated transcription factors, which initiate transcription ofgenes associated with energy homeostasis 51>.
CLA affects the risk of cardiovascular disease (CVD) and cancer more than industrial TFAs
52>. CLA supplementation is associated with a significant decrease in LDL cholesterol, and notassociated significantly with decrease in HDL cholesterol, increase in total cholesterol anddecrease in TAG 53>. Supposed adverse effects such as oxidative stress, insulin resistance,
irritation of the intestinal tract and milk fat depression are also examined. It seems that no
consistent result was observed even in similar studies conducted at different laboratories, thismay be due to variations in age, gender, racial and geographical disparities, coupled with typeand dose of CLA supplemented 54>.
The effect of CLA was examined using gastrointestinal cancer cell lines 55). CLA inhibited cell
growth and invasion of MKN28 and Colo320 cancer cells with an increment in apoptosis. CLA
induced growth inhibition was recovered by knockdown of PPARy in both cell lines. In a nudemouse peritoneal dissemination model, CLA treatment significantly decreases the metastatic
foci of both cells in the peritoneal cavity and the survival rate in mice is significantly recoveredby CLA treatment. CLA treatment provides a decrease in EGFR and TGF- a and an increasein Bax 55> in these cells. The anti-tumoral effect of CLA is confirmed with a syngeneic mouse
peritoneal dissemination model of C57BL6 mice and LL2 cells 56>.

(40)Hitoshi OHMORI et al.

Conclusion
Drawing on the above overview, numerous reports indicate that TF A is a pivotal factor
threatening health, evoking risks for almost all of the lifestyle-related diseases. Cardiovasculardiseases are already recognized as a disease associated with TFAs. Our recent studies showthat TF As are closely associated with cancer promotion through induction of cancer sternness.
Now TFAs are a social problem for regulation, i.e. subject to FDA decision. At the same time,the importance of elucidating the bioactive cancer-related functions of fatty acids is suggested.

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