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Bassett Research Institute, Cooperstown, NY 13326
3To whom correspondence should be addressed. E-mail: lensauermt{at}aol.com.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • MCF-7 human breast cancer • eicosapentaenoic acid • fatty acid transport • 13-hydroxyoctadecadienoic acid • ERK1/2
The growth of transplantable rodent mammary tumors is stimulated by diets enriched in linoleic acid (LA)4 (1–3), an (n-6) fatty acid (FA), and suppressed by diets containing (n-3) FAs (3–5). Similar positive and negative growth responses were observed in human breast cancer xenografts in immunodeficient rodents fed diets enriched in either LA (6) or (n-3) FAs (7,8), respectively. Studies designed to investigate these dissimilar tumor growth effects indicated that (n-6) and (n-3) PUFAs compete during metabolism in normal tissues (9,10) and in tumors (11). Competition from (n-3) FAs may suppress the formation of growth-promoting eicosanoids from arachidonic acid (AA) and/or may form lipid mediators from (n-3) FAs with lower growth-promoting activities (4–7,9,10,12). Evidence that prostaglandins may not play a prominent role was provided by the finding that tumor growth inhibition by (n-3) FAs is independent of prostaglandin synthesis (13). Recent results suggest that the growth-inhibiting effects of (n-3) FAs may be dependent on specific signal transduction pathways in both rodent (14–16) and human tumors (13,17,18). It is not yet clear whether these signaling pathways are interconnected or whether (n-3) FAs might activate a common early signal. To examine the latter question we studied signaling events caused by plasma (n-3) FFAs in solid tissue-isolated rat hepatoma 7288CTC in vivo and during perfusion in situ. The results demonstrated that 
-linolenic, stearidonic, eicosapentaenoic (EPA), or docosahexaenoic acid caused a rapid suppression of tumor uptake of plasma SFAs, monounsaturated FAs, and (n-6) PUFAs (11,14). The inhibition of LA uptake decreased the rate of tumor conversion of LA to the mitogen, 13-hydroxyoctadecadienoic acid (13-HODE) (19), and the incorporation of [3H]thymidine into tumor DNA (11,14,19). Each of these inhibitions was reversed by the addition of either 8-bromoadenosine-cAMP (8-Br-cAMP) or pertussis toxin (PTX) to the (n-3) FFA–containing arterial blood (14). We hypothesized that a first action of (n-3) FFAs in hepatoma 7288CTC was mediated by a putative inhibitory G protein–coupled (n-3) FFA receptor (GPC FFAR). Two types of G protein–coupled receptors (GPCRs), GPR 40 (20–24) and GPR 120 (25), that are activated by FFAs were identified recently in rodent and human cell lines, including MCF-7 human breast cancer cells (23,24). Both GPR 40 and GPR 120 were activated by long-chain FFAs, including (n-3) FFAs. Activation of GPR 40 was reported to be partially PTX-sensitive (20–23). In this report, we examined the effects of EPA on FA uptake, metabolism of LA to 13-HODE, and cell proliferation in tissue-isolated MCF-7 human breast cancer xenografts in nude rats during perfusion in situ.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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107 cells/mouse). Xenografts from the nude mice were removed and sectioned into 3-mm cubes. Tissue-isolated tumors were grown in adult female ovariectomized homozygous inbred nude rats (RH-rnu, Harlan Sprague Dawley) that had been treated with 90-d release pellets containing 5 mg estradiol by implanting a tumor cube on a vascular stalk formed from the truncated left inferior superficial epigastric artery and vein, as previously described (11,14,26–28). Growth of the implant occurred at a rate of 0.1–0.2 g/d. MCF-7 xenografts propagated in this manner were verified histopathogically as being poorly differentiated, grade III, infiltrating ductal carcinomas of the breast. Immunohistochemical staining of cell nuclei in tissue sections (IMPATH) revealed that these xenografts were 80% estrogen receptor and 10% progesterone receptor positive.
Tumor-bearing and normal immunodeficient rats and mice were housed in microisolator units (Thoren Caging Systems) at 23°C and 45–50% humidity; lighting was diurnal, 12 h light:12 h dark (lights on 0600 to 1800 h; 300 lx). There were no light leaks in the animal facility during the dark period. All rats (tumor-bearing nude rats and blood donor Sprague-Dawley rats) had free access to water and a laboratory diet (Purina Prolab RMH 1000), which had the following proximate nutrient content: protein, 164 g/kg; carbohydrate, 503 g/kg; fiber, 35 g/kg; fat, 62 g/kg; minerals, 25 g/kg; and 10 vitamins and choline. Analyses of several batches of this diet indicated that the FA content was 42 g/kg, 11.8 g/kg as LA (11). Arachidonic and -linolenic acid contents were too low to be identified. The diet consumed by the nude mice and rats was autoclaved. All procedures for animal use and experimentation followed appropriate protocols of the Institutional Animal Care and Use Committee. The animal facility was approved by the American Association for Accreditation of Laboratory Animal Care and was in accordance with regulations and standards of the USDA, U.S. Department of Health and Human Services, and NIH.
Arterial minus venous difference (A-V) measurements in MCF-7 xenografts.
Experiments were performed when the tissue-isolated MCF-7 xenografts weighed 4–7 g. All experiments were performed between 0800 to 1030 h after a normal nocturnal feeding period when the plasma melatonin level was low (28). Procedures for anesthesia, heparinization, maintenance of body temperature of the host nude rat, and surgical and technical procedures for perfusion in situ of tissue-isolated tumors and measurement and collection of arterial and tumor venous blood samples across the tumor were described in detail (11,14,26–29). Donor blood for perfusion was collected between 0800 to 1000 h from 8 to 10 heparinized male Sprague-Dawley rats (200 to 250 g), chilled in ice, and pumped through a warming device and artificial lung to the tumor as described (29). Arterial and tumor venous blood flow rates were 126 ± 2 and 121 ± 2 µL/min, respectively. Tumor venous blood was collected passively. The pH, PO2 and PCO2 in arterial blood samples were monitored and maintained at 7.4, and 100 and 40 mm Hg, respectively. Three or 4 individual xenografts were perfused consecutively with 1 batch (60 mL) of donor blood. Vascular connections (epigastric artery and vein) between the xenograft and host were ligated after steady-state venous blood flow from the tumor was established.
The purpose of these procedures was to ensure that steady-state rates of tumor FA uptake and metabolism and DNA synthesis were established and to simulate the in vivo condition as closely as possible. Perfusions were generally 150 min in duration and were preceded by a 30-min equilibration period (no sample collection). Arterial and tumor venous samples were collected at 30-min intervals into chilled tubes and stored on ice for FA and 13-HODE analyses. Depending on the experiment, the donor arterial blood was supplemented with EPA (Sigma Chemical), added as the sodium salt, 0.4 to 1.0 mmol/L plasma. These EPA concentrations were selected to provide a maximum inhibition of FA uptake, as judged from previous experiments using rat hepatoma 7288CTC (14). Subsequent additions were 10 µmol/L 8-Br-cAMP (Sigma Chemical), 0.5 mg/L PTX (Sigma Chemical), or 50–80 µmol/L 13-(S)-HODE (Cayman Chemical). Agents introduced into the donor blood reservoir required 15 min to reach the tumor. The incorporation of [3H]thymidine into tumor DNA was measured as previously described (11,14,19,26–28).
Lipid extractions, analyses, and calculations. Total plasma lipids were extracted from duplicate 0.2 mL of arterial or tumor venous plasma and were saponified after the addition of internal standards. FFAs were methylated and assayed by GC as previously described (11,14,19,26–28). Unless otherwise indicated, total FA uptake represents the sum of the 7 major FAs in rat plasma (myristic, palmitic, palmitoleic, stearic, oleic, linoleic, and arachidonic acids). Plasma concentrations of total FAs, LA, and EPA are given as mmol/L ± 1 SD, unless otherwise indicated. A-V measurements were converted to rates of FA supply and uptake as previously described (30) and expressed as nmol/(min · g tumor). 13-HODE was measured by HPLC (19). Repeated analyses indicated that MCF-7 xenografts did not release detectable amounts of hydroxyeicosatetraenoic acid and 5-hydroxyeicosatetraenoic acid was used as an internal standard. 13-HODE release was expressed as pmol/(min · g tumor). Arterial blood does not contain 13-HODE.
The 4 major lipid classes (triacylglycerols, phospholipids, FFAs, and cholesterol esters) in control and EPA-treated tumors were extracted from 0.25 mL of 20% homogenates prepared in 0.15 mol/L NaCl containing 2.3 mmol/L BHT and were separated by TLC as previously described (30). Heptadecanoic acid, tripentadecanoin, diheptadecanoyl phosphatidyl choline, and cholesterol heptadecanoate were added as internal standards before extraction. Detection of the lipid classes, elution, saponification, and separation of FAME by GC were as described (30). Contents of total FA, LA, and EPA in the lipid fractions are reported as µmol/g tumor wet weight.
Determination of intratumor cAMP content. MCF-7 human breast cancer xenografts were freeze-clamped in situ at the end of the perfusion (26–29). A portion of the tumor was pulverized under liquid nitrogen and cAMP was analyzed in duplicate 100-mg portions using the Biotrak Enzyme Immunoassay System (RPN 225, Amersham-Pharmacia), as previously described (26,27). Results are reported as nmol/g tumor wet weight.
Western blot measurement of tumor ERK1/2. Cytosol and membrane fractions were isolated from frozen, pulverized tumors as described by Allgeier et al. (31). The homogenizing buffer (2 mL) contained 20 µL Halt Protease Inhibitor Cocktail (Pierce Chemical) and 10 µL Phosphatase Inhibitor Cocktails 1 and 2 (Sigma Chemical). Protein was determined by the Folin-phenol reagent (32). Electrophoresis, transfer to a polyvinylidine difluouride membrane, and immunodetection of total and phosphorylated ERK1/2 were performed as previously described (26,27). The bands were visualized using Storm PhosphoImager and Image Quant software (Amersham-Biosciences).
Statistical analysis. Results from control and treatment groups were expressed as means ± SD. For kinetic studies, control xenografts (1 tumor/rat) were treated with EPA (Fig. 1A) or by consecutive additions of EPA followed by PTX (Fig. 1B). Means from serial samples collected during the control and treatment periods (EPA or EPA + PTX) were evaluated by 1-way repeated-measures ANOVA and were compared using Tukey’s test (33). If the normality test failed, the Friedman repeated-measure ANOVA on Ranks was used. For control and treatment groups composed of different xenografts (Table 1 and Fig. 2) treatment groups were compared with the control group using the 1-way Holm-Sidak ANOVA test if normality and equal variance tests were passed. The Kruskal-Wallis 1-way ANOVA on ranks test was used if the normality tests failed. Multiple comparisons were performed by Dunn’s method (33). Differences between control and treatment groups were considered significant at P < 0.05. All analyses were performed using Sigma Stat 3.0.1 (Jandel Scientific).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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15 min for the reservoir blood to reach the MCF-7 xenografts (29). Thus, the inhibitions of total FA and LA uptake and 13-HODE release caused by EPA (Fig. 1A) started at 78 min. After the addition of PTX, the reversal of the EPA-induced inhibition likely occurred at 101 min (Fig. 1B).
The effects of EPA, EPA + PTX, EPA + 8-Br-cAMP, and EPA + 13-HODE on cAMP content, total FA and LA uptakes, 13-HODE release, incorporation of [3H]thymidine into DNA, and DNA content in MCF-7 human breast cancer xenografts were evaluated among different treatment groups (Table 1). The supply rates of total FA and LA to the tissue-isolated xenografts were 65.1 ± 12.8 and 15.0 ± 3.2 nmol/(min · g) (n = 21), respectively, during perfusion in situ with arterial blood from donor rats fed the laboratory diet. In control xenografts, the rates of total FA and LA uptake were 10.1 and 2.4 nmol/(min · g), respectively, or 16% of the FA supplied in 1 pass of arterial blood. 13-HODE was not present in arterial blood but MCF-7 xenografts released 4–7 pmol/(min · g) of 13-HODE to the tumor venous blood. This rate of 13-HODE release accounted for 0.2% of the LA uptake by the MCF-7 xenografts. Addition of EPA to the arterial blood reduced to 0 the rates of both total FA and LA uptake and 13-HODE release but did not influence either the total FA or LA supply rates (data not shown). EPA addition to the arterial blood also significantly decreased intratumor cAMP content, incorporation of [3H]thymidine into tumor DNA, and tumor DNA content. These effects of EPA were reversed and restored to control values by the addition of either PTX or 8-Br-cAMP to the EPA-containing arterial blood. Addition of exogenous 13-HODE to the EPA-containing arterial blood promoted tumor 13-HODE uptake, nearly doubled the rate of [3H]thymidine incorporation, and increased tumor DNA content, but did not affect the EPA-induced inhibitions of either total FA or LA uptakes (Table 1).
Rates of EPA supply and uptake in the EPA-treated xenografts (Table 1) were 11.0 ± 2.5 and 3.9 ± 2.1 nmol/(min · g) (n = 17), respectively. Thus, 35% of the EPA supplied in arterial blood was removed during 1 pass through the xenografts. Analyses of these results by linear regression (data not shown) indicated that EPA uptake was directly dependent on EPA supply (R2 = 0.564, P = 0.002). Rates of total FA and LA supply in the control xenograft group (Table 1) were 65.1 ± 13.7 and 15.0 ± 3.2 nmol/(min · g) (n = 17), respectively. Thus, total FA and LA uptakes were 16% of supply, different (P < 0.001) from the 35% EPA uptake.
The effects of an increased arterial blood supply of either LA or AA to MCF-7 xenografts during perfusion in situ were tested in pilot studies. These experiments showed that an increased arterial blood plasma LA concentration (1.2 to 1.9 mmol/L) elevated the rates of LA supply [15.6 to 25.3 nmol/(min · g)] and tumor LA uptake [2.1 to 4.7 nmol/(min · g)]. The rate of 13-HODE release was increased [2.4 to 8.4 pmol/(min · g)] and [3H]thymidine incorporation was nearly doubled (47 to 71 dpm/µg DNA). In contrast, an increase in the plasma AA concentration (1.13 to 1.95 mmol/L) increased the AA rates of supply [16 to 27 nmol/(min · g)] and uptake [1.0 to 3.6 nmol/(min · g)], but did not affect either the rate of tumor 13-HODE release [4.1 to 4.4 pmol/(min · g)] or [3H]thymidine incorporation [47 to 48 dpm/µg]. Thus, although LA, AA, and EPA were each taken up by MCF-7 xenografts, their effects on [3H]thymidine incorporation were remarkably different: LA increased, AA had no effect, and EPA inhibited (Fig. 1 and Table 1). Further studies with LA and AA were not performed.
Effects of EPA and EPA + PTX, 8-Br-cAMP, or 13-HODE on p-ERK1/2/total ERK1/2 ratio. The presence of EPA in the arterial blood significantly decreased phosphorylation of ERK1/2 in MCF-7 xenografts perfused in situ (Fig. 2A). The addition of PTX, 8-Br-cAMP, or 13-HODE restored phosphorylated ERK1/2 (pERK1/2) and the pERK1/2:total ERK1/2 ratio to control levels (Fig. 2B). Expression of pERK1/2 correlated directly with 13-HODE release rates and [3H]thymidine incorporation (Table 1).
Incorporation of EPA into tumor lipids.
The content of total FA, LA, and EPA in triacylglycerols, phospholipids, cholesterol esters, and FFAs was examined in control and EPA-treated MCF-7 xenografts (Table 2). The FA contents of these lipid classes did not differ in the control or treated tumors, except that EPA was absent in control tumors and present in EPA-treated tumors, predominantly in phospholipids. Rates of total FA, LA, and EPA uptake for the 6 EPA-treated xenografts examined were shown above (Fig. 1A). These tumors were exposed to EPA in the arterial blood (0.98 mmol EPA/L plasma) for the final 72 min of the perfusion. During this period, the xenografts removed 3.5 nmol EPA/(min · g) from the arterial blood and total EPA uptake was 0.252 µmol EPA/g. Analyses of the freeze-clamped EPA-treated xenografts indicated an incorporation of 0.28 µmol EPA/g into the triacylglycerol, phospholipid, and cholesteryl ester fractions. Thus, 110% of the total EPA removed from arterial blood by the xenografts was incorporated into tumor lipids; very little or no EPA was oxidized.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Two possible candidate GPCRs, GPR 40 and GPR120, are known presently. GPR40 is a 7 transmembrane former GPC orphan receptor that was cloned from animal and human genomic DNA (20,21). GPR40 mRNA was expressed in rat (22) and murine pancreas ß cells (20), several human tissues (20), and in MCF-7 cells (23) and other human breast cancer cell lines (24). Cell proliferation induced by LA in MCF-7 cells was reported to be partially sensitive to PTX (23); cell proliferation induced by oleic acid in MDA-MB-231 cells overexpressing GPR40 was decreased when the GPR40 gene was silenced by RNA interference (24). Both GPR40 and GPR120 were shown to be present in STC-1 murine enteroendocrine cells (25). Several FFAs, but in particular -linolenic acid, an (n-3) FA, induced cell survival in serum-starved STC-1 cells. RNA interference experiments suggested that GPR120 and not GPR 40 was responsible for the increased cell survival induced by -linolenic acid (25). When measured in vitro by the mobilization of intracellular calcium stores, >30 compounds including (n-6) and (n-3) FAs, several other natural and synthetic FAs, and thiazolidinedione drugs were identified as ligands for GPR40 in HEK293 cells (21). Activation by multiple FFA ligands does not provide strong support for either GPR40 or GPR120 as the GPCRs responsible for the EPA-induced inhibitions of cell proliferation observed in MCF-7 xenografts (Fig. 1, Table 1) and in rat hepatoma 7288CTC (11,14). Identification of the GPCRs that cause either activation or inhibition of cell proliferation in solid tumors under in vivo conditions may require development of specific antagonists for GPR40, GPR120, and other as yet unidentified GPCRs.
The shutdown of tumor FA uptake after addition of either EPA or t10,c12-CLA to the arterial blood was correlated with a marked decrease in intratumor cAMP content in both MCF-7 xenografts [Table 1 and Table 1 in (26)] and rat hepatoma 7288CTC [Table 1 in (27)]. Replenishment of the intratumor cAMP content by the addition of either PTX or 8-Br-cAMP restored FA uptake despite the continued presence of EPA or t10,c12-CLA in the arterial blood. The changes in intratumor cAMP that are critical to FA uptake may occur in specific locations within the tumor cell. For example, addition of 13-HODE to the arterial blood increased intratumor cAMP in MCF-7 xenografts (26) and in rat hepatoma 7288CTC (27) but did not increase FA uptake already inhibited by t10,c12-CLA. Biochemical mechanisms for FA transport in cells are controversial, particularly concerning the roles played by passive diffusion (36), specific FA transport proteins (37,38), and/or acyl-CoA synthetases (37). No specific requirement for cAMP in FA transport is known. Relations between intratumor cAMP content and regulation of FA transport in tumors are currently under study in our laboratory. In tumors, uptake of FAs, particularly LA, is critical for growth. Definition of the signaling pathways for control of FA uptake in cancer could lead to new approaches for therapeutic intervention and/or chemoprevention.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by AICR Grant 00B037 and NCI Grant R01 CA 76197.
4 Abbreviations used: AA, arachidonic acid; A-V, arterial-venous difference; 8-Br-cAMP, 8-bromoadenosine-cAMP; CLA, conjugated linoleic acid; EPA, eicosapentaenoic acid; ERK 1/2, extracellular signal-regulated kinase p44/p42; FA, fatty acid; FFAR, FFA receptor; GPCR, G protein–coupled receptor; 13-HODE, 13-hydroxyoctadecadienoic acid; LA, linoleic acid; pERK 1/2, phosphorylated ERK 1/2; PTX, pertussis toxin.
Manuscript received 2 March 2005. Initial review completed 20 April 2005. Revision accepted 13 June 2005.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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