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Department of Cell Biology and Human Anatomy, School of Medicine, University of California, Davis, CA 95616-8643
* To whom correspondence should be addressed. E-mail: klerickson{at}ucdavis.edu.
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ABSTRACT |
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 TOP ABSTRACT IntroductionSummary of studies with...Studies in animal modelsStudies in humansStudies with purified isomersMechanisms by which CLA...Effects of CLA isomers...Effects of CLA isomers...LITERATURE CITED |
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Introduction |
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TOPABSTRACTIntroductionSummary of studies with...Studies in animal modelsStudies in humansStudies with purified isomersMechanisms by which CLA...Effects of CLA isomers...Effects of CLA isomers...LITERATURE CITED |
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CLA is a collective term for isomers of LA that have conjugated double bonds. Depending on the position and geometry of the double bonds, several isomers of CLA have been identified (3). Most of the published studies have used a mixture of CLA isomers with 2 major forms, cis9, trans11-CLA (c9, t11-CLA) and trans10, cis12-CLA, (t10, c12-CLA), and a number of minor isomers (i.e. t7, t9-CLA; c9, c11-CLA; t9, t11-CLA; c10, c12-CLA; t10, t12-CLA; t11, t13-CLA; and c11, c13-CLA). Ruminant meat and dairy products are the major dietary sources of c9, t11-CLA and partially hydrogenated oils such as shortenings and margarines are the main sources of t10, c12-CLA as well as other isomers. Although in some early studies CLA intake was estimated to be 1 g/d, a recent report using food duplicate methodology suggests that average intake in the U.S. population is < 500 mg/d (4).
Feeding a mixture of CLA isomers to animals has been reported to alter chemically induced carcinogenesis, glucose and lipid metabolism, diabetes, body composition, and immune cell functions. Several reviews also indicate that feeding a mixture of CLA isomers hindered the growth of numerous types of tumors (5–9). Recently, purified isomers of CLA have become available for research studies. Results based on feeding CLA preparations enriched in individual CLA isomers indicate that the different isomers have distinct effects on tumorigenesis and lipid metabolism. A few of these studies with the isolated isomers may raise concerns regarding their safety. To the best of our knowledge, there is no published review that focused on the role of individual CLA isomers on tumorigenesis. The focus of this review is the effects of individual CLA isomers on the proliferation and apoptosis of tumor cells both in vivo and in vitro; potential mechanisms that may be involved were also addressed. We included only those studies that examined the effects of purified individual CLA isomers on tumorigenesis, those that compared the effects of the purified isomers with each other, or with those of a mixture of CLA isomers. The literature reviewed here was published between 1999 and 2007. Initially, we summarize results from studies with CLA mixtures without referring to the original references.
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Summary of studies with mixtures of CLA isomers |
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TOPABSTRACTIntroductionSummary of studies with...Studies in animal modelsStudies in humansStudies with purified isomersMechanisms by which CLA...Effects of CLA isomers...Effects of CLA isomers...LITERATURE CITED |
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Studies in animal models |
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TOPABSTRACTIntroductionSummary of studies with...Studies in animal modelsStudies in humansStudies with purified isomersMechanisms by which CLA...Effects of CLA isomers...Effects of CLA isomers...LITERATURE CITED |
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Dietary CLA, 1% (wt:wt), fed for 30 wk significantly decreased incidence of colon cancer induced by 1,2-dimethylhydrazine in 6-wk-old rats (12). Another study compared the effects of diets containing CLA or LA, 3.3% (wt:wt), on the development of pancreatic tumors induced by N-nitrosobis-2-oxopropylamine and their resultant hepatic metastasis in male Syrian hamsters. The number of pancreatic tumors did not differ when CLA- and LA-fed groups were compared; however, hepatic metastasis was significantly greater in the CLA group than in the LA group (13). Different types of tumors from various organs probably respond differently to CLA treatments. Additional details regarding the studies with a mixture of CLA isomers can be found in the reviews cited above.
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Studies in humans |
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TOPABSTRACTIntroductionSummary of studies with...Studies in animal modelsStudies in humansStudies with purified isomersMechanisms by which CLA...Effects of CLA isomers...Effects of CLA isomers...LITERATURE CITED |
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CLA levels in the serum and breast adipose tissue were used to analyze the relationship between breast cancer and CLA (15,16). In a study of postmenopausal women, the levels of serum and dietary CLA were significantly lower in breast cancer patients than in control subjects (15). In contrast, CLA concentrations in breast adipose tissue were not directly correlated in women with and without breast cancer (16). Thus, a limited number of studies do not allow us to establish whether CLA can provide any protection in humans against cancer of any site.
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Studies with purified isomers |
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TOPABSTRACTIntroductionSummary of studies with...Studies in animal modelsStudies in humansStudies with purified isomersMechanisms by which CLA...Effects of CLA isomers...Effects of CLA isomers...LITERATURE CITED |
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35% at 6 wk and decreased the number of mammary tumors by 40% at 24 wk after MNU treatment (19). The authors concluded that c9, t11- and t10, c12- CLA isomers were equally effective in reducing MNU-induced tumorigenesis. Rats fed diets with sunflower oil containing c9, t11-CLA or a mixture decreased tumor incidence by 45% (20). Neither of the CLA-containing diets altered the time required to detect palpable tumors (latency). Results from these rat studies showed that c9, t11- and t10, c12-CLA were as effective as the CLA mixture in reducing mammary tumors induced by MNU.
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The effects of 2 purified CLA isomers on the development of intestinal tumors were compared in Min mice (23). These mice have a mutation of the APC gene that leads to neoplasia at multiple sites of both the small and large intestine. In contrast to the tumor development in this mouse model, most human intestinal tumors occur in the large intestine. In this study, Min mice were fed either a diet with sunflower and rapeseed oils or a diet also containing 1% c9, t11-CLA or t10, c12-CLA (23). The total number of adenomas did not differ among the 3 dietary groups, but the sizes of the adenomas were significantly greater in the distal part of small intestine in mice fed the diet containing t10, c12-CLA compared with the control group. Tumor size and numbers in the c9, t11-CLA group did not differ from the control group. These results suggested that t10, c12-CLA may act as a growth promoter in small intestine carcinogenesis. Those results are in contrast to reports citing a reduction in the number of tumors of several digestive organs after feeding a mixture of CLA isomers (6,8). In another study (24), FVB/J female mice with altered erbB2 gene expression in mammary epithelium were fed diets with or without 0.5% c9, t11-CLA or t10, c12-CLA until the tumor diameter reached 20 mm. When CLA feeding of the genetically modified mice started at weaning, t10, c12-CLA accelerated mammary tumor development and decreased the median time required for tumor development compared with the c9, t11-CLA and control groups. Results were similar when feeding the experimental diets started after puberty. In the control wild-type mice, the number of terminal end buds increased by 30-fold after feeding the t10, c12-CLA-containing diet. Collectively, the results from this 1 study (24) demonstrated that t10, c12-CLA accelerated mammary tumor development, whereas the c9, t11-CLA isomer had no effect. In the aggregate of all murine tumor types studied in vivo with purified CLA isomers, t10, c12-CLA reduced tumorigenesis in 6 types and increased tumorigenesis in 2. The c9, t11-CLA isomer reduced tumorigenesis in 6 studies but had no effect in 2 others. However, summarizing the effects of dietary CLA over several tumor types from multiple sites may not be appropriate, because different mechanisms can be associated with tumorigenesis of different tumor types and different stages of tumor progression, especially when the methods for tumor induction are quite different. Sufficient studies with appropriate animal models that parallel human pathogenesis need to be completed before definitive conclusions can be extrapolated to human malignancy.
In vitro studies with purified isomers of CLA. Reports that investigated the effects of individual CLA isomers on the growth, viability, or apoptosis of tumor cell lines were summarized (Table 2). Most of these studies focused on tumor cell lines derived from mammary gland, prostate, and digestive tract or their metastasis and used c9, t11-CLA and t10, c12-CLA isomers; the CLA concentrations used ranged from 1 to 200 µmol/L with treatments lasting 2–11 d.
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The t10, c12-CLA isomer inhibited cell growth of colon, colorectal, and gastric cancer cell lines in all studies when assessed, whereas c9, t11-CLA inhibited cell growth in only a fraction (Table 2); t10, c12-CLA was more growth inhibitory than c9, t11-CLA in most of the studies. The c9, t11-CLA isomer was more potent than t10, c12-CLA in inhibiting the growth of colon cell lines (28,29). Most of the studies that did not detect inhibition of cell growth by c9, t11-CLA used a concentration of <50 µmol/L; however, 200 µmol/L failed to inhibit growth of HT-29 cells in 1 study (28). In addition, 50 and 100 µmol/L c9, t11-CLA inhibited the growth of HT-29 cells when the cells were cultured for 11 d (29) compared with 3 d (25). At 100 µmol/L, c9, t11-CLA inhibited the growth of the human gastric adenocarcinoma cell line, SGC-7901 and 50 µmol/L did not (30). Culture conditions including the concentration of CLA, duration of the treatment, and tumor type as well as the cell lines used seem to determine whether CLA isomers would affect cell growth.
In most studies with prostate cell lines, both isomers inhibited cell growth, with effects of t10, c12-CLA greater than c9, t11-CLA (27,29,31,32). In contrast, growth of a rat hepatoma cell line, dRLh-84, was inhibited by 10 µmol/L t10, c12-CLA or a mixture of CLA isomers, whereas c9, t12-CLA stimulated cell growth (33). This is the only study in which c9, t11-CLA stimulated tumor cell growth, suggesting something unique to this cell line or to the culture conditions used.
Summary of in vivo and in vitro studies. Overall, the growth inhibitory effects of c9, t11-CLA and t10, c12-CLA varied with the model used. MNU-induced mammary tumors were reduced by both isomers in rats and mice and t10, c12-CLA increased mammary tumorigenesis in 1 study and decreased it in 2 studies. Small intestine tumors were increased in 1 study and c9, t11-CLA had no effect in some of those studies. The c9, t11-CLA isomer did not inhibit the growth of mammary and colon tumor cell lines but did inhibit growth in prostate tumor cell lines and increased the growth of a hepatoma cell line. The t10, c12-CLA isomer inhibited growth of all the cell lines tested, including breast, colon, and prostate tumors. Results from 2 studies indicated that c9, t11-CLA was even more potent in inhibiting cell growth than t10, c12-CLA. Although results appear to be divergent, even tumors from a similar anatomical site may vary in their response to different chemotherapeutic agents and, thus, it could be expected that they would also differ in their response to lipids.
It can be difficult to extrapolate concentrations used in vitro to doses or dietary concentrations in vivo; the studies above tend to use pharmacological concentrations of CLA isomers. Additional studies are needed with appropriate animal models that represent the stages of human cancers to test the efficacy and safety of different CLA isomers. Most human tumors are not chemically induced, whereas transplanted cells grow as an expansive mass generally with a central necrotic core. Neither model resembles primary human tumors. To interpret the results in a meaningful manner it will also be important to use models where a number of the regulatory pathways and molecular signatures are characterized. An appropriate animal model for human breast cancer may be the mouse mammary intraepithelial neoplastic outgrowth, which has been shown to nearly recapitulate human ductal carcinoma in situ (34,35). With this model, investigators could assess the effects of CLA isomers not only on tumor growth and metastasis but also on transition of preneoplastic lesions to full malignancy. Because these issues need to be addressed, clear conclusions about CLA isomers and alterations of tumorigenesis and applicability to humans are difficult to make at this time.
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Mechanisms by which CLA isomers may inhibit tumor growth |
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TOPABSTRACTIntroductionSummary of studies with...Studies in animal modelsStudies in humansStudies with purified isomersMechanisms by which CLA...Effects of CLA isomers...Effects of CLA isomers...LITERATURE CITED |
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Recent studies have examined the effects of separate CLA isomers on gene expression in mouse liver and adipose tissue. Feeding t10, c12-CLA for 8 wk caused a >1-fold increase in the expression of 278 genes and a decrease in 121 genes in mouse liver, whereas c9, t11-CLA increased the expression of only 22 genes and decreased that of 9 genes (40). In another study, feeding t10, c12-CLA for 14 d caused a >1-fold increase in the expression of 125 genes in adipose tissue (41). Because of those differences between the 2 CLA isomers, it is more appropriate to study their health effects individually rather than as a mixture. Here, we will discuss only the mechanisms investigated using purified isomers. A diagram of possible effects are summarized in Figure 1.
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Effects of CLA isomers and eicosanoids |
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TOPABSTRACTIntroductionSummary of studies with...Studies in animal modelsStudies in humansStudies with purified isomersMechanisms by which CLA...Effects of CLA isomers...Effects of CLA isomers...LITERATURE CITED |
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-induced apoptosis in a human prostate cancer cell line (47). In contrast, neither of the 2 CLA isomers inhibited COX-2 messenger RNA (mRNA) expression in a human prostate cancer cell line, PC-3 (32); both isomers inhibited cell growth. Thus, results from most of the studies showed that c9, t11-CLA inhibited COX-2 expression. Growth was inhibited in some studies but not examined in others. Alternatively, t10, c12-CLA reduced COX-2 expression and growth in a small percentage of studies. Collectively, these results suggest that changes in COX-2 expression may mediate the inhibitory effects of c9, t11-CLA and alternative mechanisms may mediate the effects of t10, c12-CLA.
The role of the 5-lipoxygenase (5-LOX) pathway in CLA inhibition of tumor growth has been examined. In PC-3 cells, c9, t11-CLA but not t10, c12-CLA decreased transcripts for 5-LOX (32). In breast cancer cells, the t10, c12-CLA isomer but not c9, t11-CLA decreased cell growth and the production of hydroxyeicosatetraenoic acid (5-HETE) while increasing apoptosis (45,48). The inhibitory effect of t10, c12-CLA was reversed by the addition of 5-HETE (48). The growth inhibitory effect of t10, c12-CLA in the human breast tumor cell line MDA-MB-231 could be reversed by the overexpression of 5-LOX-activating protein (FLAP) (45). These authors concluded that 5-HETE may mediate the effects of t10, c12-CLA on breast tumor cell growth and apoptosis by CLA competition with the AA substrate as well as FLAP but not directly on 5-LOX. The c9, t11-CLA isomer increased production of 8-epi-PGF2 in MCF-7 and SW480 tumor cells, whereas t10, c12-CLA increased it only in MCF-7 cells (42).
CLA isomers may also have their effects on tumorigenesis by altering lipid peroxidation. However, information regarding the effects of individual CLA isomers on lipid peroxidation is limited. Further studies are needed to confirm the role of the 5-LOX pathway and of lipid peroxidation in CLA isomer-specific effects on cell growth.
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Effects of CLA isomers on the expression of genes regulating cell growth and apoptosis |
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TOPABSTRACTIntroductionSummary of studies with...Studies in animal modelsStudies in humansStudies with purified isomersMechanisms by which CLA...Effects of CLA isomers...Effects of CLA isomers...LITERATURE CITED |
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than c9, t11-CLA in human breast cancer cells (47). Also, t10, c12-CLA was more effective in increasing the accumulation of p53 and hypophosphorylated protein. p53 and hypophosphorylated protein are required for the progression of G1 to the S phase and protein tyrosine phosphatase- counterbalances the growth-promoting effects of protein kinases. Two other studies examined the effects of purified c9, t11-CLA alone on the expression of genes regulating cell proliferation. c9, t11-CLA decreased the mRNA for c-myc, cyclin D1, c-jun, and ß-catenin in HT-29 and Caco-2 cells (50); it decreased phosphorylation of ERK, P-38, MAPK, and Akt in a murine skin model (46). Based on the limited number of studies, t10, c12-CLA appears to be more inhibitory of the genes regulating cell cycle and growth than c9, t11-CLA. Apoptosis is executed through a series of biochemical reactions involving numerous apoptotic and survival genes as well as associated cell proteins. Eight publications have reported the effects of individual CLA isomers on cell apoptosis (28–30,32,33,53–55). CLA used in these studies varied from 1 to 200 µmol/L. Results from studies with Caco-2 cells have been inconsistent; t10, c12-CLA increased apoptosis in 1 study (31), while both isomers increased apoptosis in another (28). Results from a study with HT-29 cells showed that 4 µmol/L t10, c12-CLA but not c9, t11-CLA induced apoptosis (53). These investigators attributed increased apoptosis to decreased phosphorylation of ErbB3 and Akt. In PC-3 cells, at least 25 µmol/L t10, c12-CLA increased apoptosis by increasing caspase-3 activity and p21 mRNA but decreased bcl-2 mRNA (29,32). The c9, t11-CLA isomer did not alter the expression of bcl-2 or p21 (32). In HCT-116 cells, 50 µmol/L t10, c12-CLA but not c9, t11-CLA induced apoptosis, which was associated with an increase in the expression of a pro-apoptotic gene, nonsteroidal antiinflammatory drug-activated gene-1, and activating transcription factor-3 (55). In the rat hepatoma cell line dRLH-84, 1 µmol/L t10, c12-CLA but not c9, t11-CLA induced apoptosis by activating caspases-3 and 9 (33). In a human gastric adenocarcinoma cell line, SGC-7901, c9, t11-CLA decreased the expression of bcl-2, c-myc, and Ki 67 and increased Fas (30). Thus, in most of the studies, t10, c12-CLA increased apoptosis by either increasing expression of apoptotic genes or by decreasing expression of antiapoptotic genes or both. c9, t11-CLA did not alter apoptosis in a majority of the studies and increased it in only a fraction. In studies that observed increased apoptosis with c9, t11-CLA, concentration was higher compared with studies that failed to detect an effect. Concentrations ranged from 25 to 200 µmol/L, whereas for studies with negative results the concentrations of this isomer were 1 to 50 µmol/L. These data suggest that pharmacological but not physiological concentrations of c9, t11-CLA induced apoptosis.
Results regarding the antitumorigenic effects of purified c9, t11-CLA and t10, c12-CLA isomers were dependent on the tumor type as well as the organ or cellular site. In the aggregate for all tumors tested, t10, c12-CLA tended to reduce tumorigenesis in a majority of studies but increased it in some. c9, t11-CLA also reduced tumorigenesis in most of the studies and had no effect in others. The amount of CLA used in these studies varied from 0.1 to 1.0 weight % of the diet, which would equate to 5–50 g/d for a 70-kg human. That will only be nutritionally attainable with supplements; the risk-benefit ratio of using CLA as an adjuvant or chemopreventive agent for humans remains to be determined.
c9, t11-CLA did not have any noticeable adverse health effects in human and animal studies and it inhibited tumorigenesis in most of the animal studies where it was assessed. Of note is the recent assessment of minor isomers like t9, t11-CLA that may be more potent than t10, c12-CLA. Studies with mixtures of CLA isomers seem now to lack a scientific basis, because the results reviewed here indicate that different CLA isomers act through different mechanisms and have potentially opposing effects on several metabolic pathways. There is an urgent need to have standardized preparations highly enriched in individual CLA isomers. Controlled studies with purified isomers of CLA need to be conducted to determine which isomer(s) may be responsible for benefits as well as risks to human health (56,57). Studies need to be conducted to determine the minimum concentration of CLA necessary to produce the desired effects. To avoid risks associated with high concentrations and long duration of CLA intake, it will be preferable to conduct initial studies first with nonhuman primates.
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FOOTNOTES |
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2 Author disclosures: N. S. Kelley, N. E. Hubbard, and K. L. Erickson, no conflicts of interest.
3 Abbreviations used: AA, arachidonic acid; BP, benzo[a]pyrene; CLA, conjugated linoleic acid; COX-2, cyclooxygenase-2; ER, estrogen receptor; FLAP, 5-lipoxygtenase activating protein; 5-HETE, hydroxyeicosatetraenoic acid; LA, linoleic acid; 5-LOX, 5-lipoxygenase; MNU, methylnitrosourea; PG, prostaglandin; TPA, 12-O-tetradecanoylphorbol-13-acetate.
Manuscript received 10 August 2007. Initial review completed 17 August 2007. Revision accepted 19 September 2007.
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LITERATURE CITED |
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TOPABSTRACTIntroductionSummary of studies with...Studies in animal modelsStudies in humansStudies with purified isomersMechanisms by which CLA...Effects of CLA isomers...Effects of CLA isomers...LITERATURE CITED |
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1. Ha YL, Grimm NK, Pariza MW. Anticarcinogens from fried ground beef: heat-altered derivatives of linoleic acid. Carcinogenesis. 1987;8:1881–7.
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