linoleic-acid and Neoplasm-Metastasis

Large scale human epidemiological studies indicate that high intakes of linoleic acid protect against the development of cancer. One mechanism may be the generation of 13-HODE from linoleic acid. 13-HODE prevents cell adhesion to endothelial cells and can inhibit cancer metastasis. 13-HODE synthesis is enhanced by cyclic AMP. Gamma-linolenic acid, a desaturated metabolite of linoleic acid, causes substantial stimulation of 13-HODE synthesis. A fall in gamma-linolenic acid synthesis with age may be related to the age-related fall in 13-HODE formation.

Topics: Animals; Anticarcinogenic Agents; Cell Adhesion; Cyclic AMP; Endothelium, Vascular; gamma-Linolenic Acid; Humans; Linoleic Acid; Linoleic Acids; Neoplasm Metastasis

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Ipomoea; Linoleic Acid; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; NF-kappa B; Plant Extracts; Proto-Oncogene Proteins c-akt; Sitosterols

The potential effects of 2 types of fatty acids on colorectal cancer (CRC) were assessed using cancer stromal cells. Linoleic acid (LA; C-18, n-6 unsaturated fatty acid) and elaidic acid (EA; C-18, trans acid), both known to affect colon carcinogenesis and cancer progression, were administered by gavage to BALB/c mice, which were inoculated with CT26 syngeneic colon cancer cells in the back. Both EA and LA treatments enhanced tumor growth and metastasis. EA and LA also increased the number of CD133-positive stromal cells in the tumor capsule. Importantly, those cancer cells at the tumor periphery, physically attached to CD133-positive stromal cells, also expressed CD133. These findings suggest that EA and LA might induce stemness in cancer cells through physical association and promote cancer metastasis.

Topics: AC133 Antigen; Animals; Carcinogenesis; Carrier Proteins; Cell Line, Tumor; Cell Movement; Colonic Neoplasms; Disease Models, Animal; Fatty Acids; GTP-Binding Proteins; Isografts; Linoleic Acid; Male; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Nuclear Proteins; Oleic Acid; Oleic Acids; RNA-Binding Proteins; Stromal Cells

The aim of this study was to determine whether α-linolenic acid (ALA ω-3 fatty acid) enriched diet affects growth parameters when applied to a syngeneic model of mammary carcinoma.. BALB/c mice were divided and fed with: 1) a chia oil diet, rich in ALA or 2) a corn oil diet, rich in linoleic acid (LA ω-6 fatty acid). Mice were subcutaneously inoculated with a tumor cell line LM3, derived from a murine mammary adenocarcinoma.. After 35 days, tumor incidence, weight, volume and metastasis number were lower in the ALA-fed mice, while tumor latency time was higher, and the release of pro-tumor metabolites derived from ω-6 fatty acids decreased in the tumor. Compared to the control group, a lower number of mitosis, a higher number of apoptotic bodies and higher T-lymphocyte infiltration were consistently observed in the ALA group. An ALA-rich diet decreased the estrogen receptor (ER) α expression, a recognized breast cancer promotor while showing an opposite effect on ERβ in tumor lysates.. These data support the anticancer effect of an ALA-enriched diet, which might be used as a dietary strategy in breast cancer prevention.

Topics: alpha-Linolenic Acid; Animals; Apoptosis; Cell Line, Tumor; Corn Oil; Diet; Estrogen Receptor alpha; Estrogen Receptor beta; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Linoleic Acid; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplasm Transplantation; Plant Oils; T-Lymphocytes

Dietary (n-6)-polyunsaturated fatty acids influence cancer development, but the mechanisms have not been well characterised in gastric carcinoma.. We used two in vivo models to investigate the effects of these common dietary components on tumour metastasis. In a model of experimental metastasis, immunocompromised mice were fed diets containing linoleic acid (LA) at 2% (LLA), 8% (HLA) or 12% (VHLA) by weight and inoculated intraperitoneally (i.p.) with human gastric carcinoma cells (OCUM-2MD3). To model spontaneous metastasis, OCUM-2MD3 tumours were grafted onto the stomach walls of mice fed with the different diets. In in vitro assays, we investigated invasion and ERK phosphorylation of OCUM-2MD3 cells in the presence or absence of LA. Finally, we tested whether a cyclooxygenase (COX) inhibitor, indomethacin, could block peritoneal metastasis in vivo.. Both the HLA and VHLA groups showed increased incidence of tumour nodules (LA: 53%; HLA: 89%; VHLA: 100%; P<0.03); the VHLA group also displayed increased numbers of tumour nodules and higher total volume relative to LLA group in experimental metastasis model. Both liver invasion (78%) and metastasis to the peritoneal cavity (67%) were more frequent in VHLA group compared with the LLA group (22% and 11%, respectively; P<0.03) in spontaneous metastasis model. We also found that the invasive ability of these cells is greatly enhanced when exposed to LA in vitro. Linoleic acid also increased invasion of other scirrhous gastric carcinoma cells, OCUM-12, NUGC3 and MKN-45. Linoleic acid effect on OCUM-2MD3 cells seems to be dependent on phosphorylation of ERK. The data suggest that invasion and phosphorylation of ERK were dependent on COX. Indomethacin decreased the number of tumours and total tumour volume in both LLA and VHLA groups. Finally, COX-1, which is known to be an important enzyme in the generation of bioactive metabolites from dietary fatty acids, appears to be responsible for the increased metastatic behaviour of OCUM-2MD3 cells in the mouse model.. Dietary LA stimulates invasion and peritoneal metastasis of gastric carcinoma cells through COX-catalysed metabolism and activation of ERK, steps that compose pathway potentially amenable to therapeutic intervention.

Topics: Animals; Carcinoma; Cell Movement; Dietary Fats, Unsaturated; Dose-Response Relationship, Drug; Female; Humans; Linoleic Acid; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Stomach Neoplasms; Transplantation, Heterologous; Tumor Cells, Cultured

Stearate is an 18-carbon saturated fatty acid found in many foods in the western diet, including beef and chocolate. Stearate has been shown to have anti-cancer properties during early stages of neoplastic progression. However, previous studies have not investigated the effect of dietary stearate on breast cancer metastasis. In this study, we present evidence that exogenously supplied dietary stearate dramatically reduces the size of tumors that formed from injected human breast cancer cells within the mammary fat pads of athymic nude mice by approximately 50% and partially inhibits breast cancer cell metastasis burden in the lungs in this mouse model system. This metastatic inhibition appears to be independent of primary tumor size, as stearate fed animals that had primary tumors comparable in size to littermates fed either a safflower oil enriched diet or a low fat diet had reduced lung metastasis. Also stearate fed mice sub-groups had different primary tumor sizes but no difference in metastasis. This anti-metastasis effect may be due, at least in part, to the ability of stearate to induce apoptosis in these human breast cancer cells. Overall, this study suggests the possibility of dietary manipulation with selected long-chain saturated fatty acids such as stearate as a potential adjuvant therapeutic strategy for breast cancer patients wishing to maximize the suppression of metastatic disease.

Topics: Animal Feed; Animals; Breast Neoplasms; Cell Line, Tumor; Dietary Fats; Disease Progression; Female; Humans; Linoleic Acid; Lung; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Stearates

Recently, there has been a great interest in the effects of different types of n-6 polyunsaturated acids (n-6 PUFAs) upon the immune system and cancer development. However, the effects of n-6 PUFAs are still controversial and as yet undefined. The present study aimed to investigate the anti-tumor effects of n-6 PUFAs against EL4 thymoma and the associated immune mechanisms. To this, sesame oil, a vegetable oil enriched with n-6 PUFAs, or free linoleic acid (LA) were administered intraperitoneally into C57BL/6 mice before and after challenge with EL4 lymphoma cells. Treatment with either sesame oil or LA attenuated the growth and metastasis of EL4 lymphoma. The anti-tumor effect of LA was superior to that of sesame oil, and associated with an increase in the survival rate of the tumor-bearing mice. In addition, both sesame oil and LA showed dose-dependent anti-lymphoma growth in vitro. Treatment with LA generated significant increases in the anti-lymphoma cytolytic and cytostatic activities of T cells and macrophages, respectively, and enhanced production of IL-2 and IFN-gamma while decreased production of IL-4, IL-6 and IL-10. In summation, the results suggest that n-6 PUFAs, represented by LA, can attenuate EL4 lymphoma growth and metastasis through enhancing the specific and non-specific anti-tumor cytolytic activities and production of TH1 cytokines. These findings might be of great importance for a proper design of systemic nourishment with PUFAs emulsions for cancer patients.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cytokines; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Unsaturated; Female; Linoleic Acid; Liver Neoplasms; Macrophages; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Sesame Oil; Spleen; Stimulation, Chemical; T-Lymphocytes, Cytotoxic; Th1 Cells; Thymoma; Thymus Neoplasms

Recent studies have linked conjugated linoleic acid (CLA) to altered tumorigenesis of several sites. We showed recently that a mixture of CLA isomers was able to significantly decrease mammary tumor metastasis in mice. That effect was seen with as little as 0.1% CLA in the diet. Other studies with dietary CLA have shown that various isomers may have differential effects. The purpose of this work was to assess which individual CLA isomers had similar effects in alteration of mouse mammary tumor metastasis. For that, we fed six 20% (w/w) total fat diets which contained either no CLA, low (0.1%, w/w) or high (0.25%, w/w) levels of cis9,trans11-CLA (c9,t11), trans10,cis12-CLA (t10,c12) or a mixture of the 2 isomers (0.125% of each, w/w) as free fatty acids. Neither the separate isomers nor the mixture had an effect on the latency or growth of primary line 4526 tumors when compared to the group without CLA. However, all diets containing CLA significantly decreased the total tumor burden (volume of tumor, mm(3)) in lungs of mice from both spontaneous metastasis (reduced by 42-73%) as well as implantation and survival of the metastatic cell (reduced by 46-61%) when compared with diets containing no CLA. Diets containing a greater concentration of either c9,t11 or t10,c12 had a significantly greater effect compared to the lower concentrations of the respective isomers when metastatic nodule size and total tumor burden were assessed. The diet containing both isomers decreased total tumor burden similarly to the diets containing the lower concentration of each of the isomers. Thus, the effects of c9,t11 and t10,c12 may not be additive and possibly share similar mechanisms for decreasing metastatic tumor burden in mice transplanted with mammary tumor cells.

Topics: Animals; Female; Linoleic Acid; Lung Neoplasms; Mammary Neoplasms, Animal; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplasm Transplantation; Protein Isoforms

The relationship between 15(S)-HETE and 13(S)-HODE from different human tumor cells exposed to n-6 and n-3 essential fatty acids (EFAs) and E-cadherin expression was studied. Colon cancer cells (HRT-18) exposed to gamma linoleic acid (18:3n-6, GLA) and eicosapentaenoic (20:5n-3, EPA) (50microM) showed an increased expression of E-cadherin. Breast cancer (MCF-7) exposed to EPA showed an increment whereas GLA had no effect on E-cadherin expression. No expression of E-cadherin was observed for urothelial cancer (T-24) after GLA or EPA treatment. Significant levels of 15(S)-HETE and 13(S)-HODE were detected after GLA or EPA treatment for all tumor lines. E-cadherin expression was inversely proportional to the 13(S)-HODE:15(S)-HETE ratio when cells were pretreated with GLA or EPA. Nevertheless, the liberation of these metabolites seems to be independent of the E-cadherin expression. The increase in the13(S)-HODE:15(S)-HETE correlates to a decrease in the expression of E-cadherin. Both factors may play a role in metastasis development.

Topics: Arachidonic Acid; Breast Neoplasms; Cadherins; Cell Differentiation; Colonic Neoplasms; Female; Humans; Hydroxyeicosatetraenoic Acids; Immunohistochemistry; Linoleic Acid; Linoleic Acids; Neoplasm Metastasis; Tumor Cells, Cultured; Urinary Bladder Neoplasms; Urothelium

I examined the effects of carp oil, oleic acid, linoleic acid and linolenic acid on tumor growth and metastasis to the liver in mice implanted intrasplenically with highly metastatic Lewis lung carcinoma (LLC) tumors. Carp oil (0.1 or 0.2 mL per mouse) significantly reduced tumor growth and metastasis to the liver. Carp oil at 100 or 1000 mg/L inhibited the DNA synthesis in LLC cells, the capillary-like tube formation of human dermal microvascular endothelial cells (HMVEC) at 1000 mg/L and the adherence of LLC cells to HMVEC at 10 to 1000 mg/L (in vitro). Carp oil (0.2 mL per mouse) inhibited the angiogenesis induced by Matrigel supplemented with vascular endothelial growth factor (VEGF) and heparin (in vivo). Antitumor and antimetastatic actions of carp oil might be partly attributable to the inhibition of DNA synthesis in LLC cells and angiogenesis through the inhibition of the adherence of LLC cells to the microvascular endothelium. Oleic acid (0.1 or 0.2 mL per mouse) significantly inhibited the metastasis to the liver, but it had no effect on the primary solid-tumor growth. Oleic acid inhibited the angiogenesis in both in vitro and in vivo models. Oleic acid at 1000 micromol/L inhibited the DNA synthesis in LLC cells but did not affect the DNA synthesis in HMVEC. These inhibitory actions of oleic acid may be attributable to the inhibition of angiogenesis induced by the tumor. Linoleic acid and linolenic acid had no effect on tumor growth or metastasis to the liver.

Topics: alpha-Linolenic Acid; Animals; Biocompatible Materials; Blood Cell Count; Body Weight; Carcinoma, Lewis Lung; Carps; Collagen; DNA; Drug Combinations; Energy Intake; Fish Oils; Humans; Laminin; Linoleic Acid; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neovascularization, Pathologic; Oleic Acid; Organ Size; Proteoglycans; Tumor Cells, Cultured

In order to explore the effects of conjugated linoleic acid on tumor metastasis, the proliferation, gap junction intercellular communication (GJIC), adhesion to extracellular matrix, and metastasis cascades of tumor cells were imitated in cell culture. The results showed that 100 and 200 mumol/L conjugated linoleic acid could inhibit the proliferation and the adhesion of tumor cells to extracellular matrix, and could recover its gap junction intercellulor communication.

Topics: Animals; Anticarcinogenic Agents; Dose-Response Relationship, Drug; Linoleic Acid; Melanoma, Experimental; Mice; Neoplasm Metastasis; Tumor Cells, Cultured

Recent studies have shown that conjugated linoleic acid (CLA) can inhibit the initiation and thus, incidence of mammary tumors in rodents. The concentration of CLA required for these effects was as low as 0.1% of the diet, with no increased effects above 1%. To date, there is little evidence that CLA has any effect on growth or metastasis of mammary tumors. In this report, we demonstrate that CLA, at the concentrations used in previous studies, had a significant effect on the latency, metastasis, and pulmonary tumor burden of transplantable murine mammary tumors grown in mice fed 20% fat diets. The latency of tumors from mice fed CLA was significantly increased when compared with the 0% CLA control diet. The volume of pulmonary tumor burden, as a result of spontaneous metastasis, decreased proportionately with increasing concentrations of dietary CLA. With 0.5 and 1% CLA, pulmonary tumor burden was significantly decreased compared to mice treated with the eicosanoid inhibitor, indomethacin and fed diets containing no CLA. Tumors of mice fed as little as 0.1% CLA and as much as 1% had significantly decreased numbers of pulmonary nodules when compared with diets containing no CLA. The decrease in the number of pulmonary nodules by CLA was nearly as effective as indomethacin, a known suppressor of tumor growth and metastasis in this malignant model. These data suggest that effects of CLA on mammary tumorigenesis may go beyond the reported alterations in tumor incidence and effect later stages, especially metastasis.

Topics: Animals; Dietary Fats, Unsaturated; Dose-Response Relationship, Drug; Female; Linoleic Acid; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Time Factors; Tumor Cells, Cultured

Topics: Animals; Carcinoma 256, Walker; Cell Communication; Dietary Fats; Epoprostenol; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Linoleic Acid; Linoleic Acids; Neoplasm Metastasis; Rats; Rats, Wistar; Thrombosis

Diets rich in linoleic acid (LA) stimulate the metastasis of MDA-MB-435 human breast cancer cells from the mammary fat pads of nude mice. This omega-6 fatty acid is metabolized to various cyclo-oxygenase and lipoxygenase products, several of which have been previously associated with tumor cell invasion and metastasis. We now report that MDA-MB-435 cells secreted increased levels of prostaglandin E2 (PGE2), and 12-hydroxyeicosatetraenoic acid (12-HETE) and 15-HETE when cultured in the presence of 2.7 microM (0.75 micrograms/ml) LA; 5-HETE secretion was unchanged. The 12-lipoxygenase inhibitor esculetin (20 microM) completely blocked the LA-stimulated 12-HETE secretion. Linoleic acid also increased MDA-MB-435 cell invasion in an in vitro assay; this stimulation was abolished by 20 microM esculetin, but was unaffected by piroxicam, a selective cyclooxygenase inhibitor. The effect of LA on invasion was replicated by 0.1 microM 12-HETE, but not by 5-HETE or PGE2; 15-HETE was stimulatory only at a concentration of 1.0 microM. Zymographic and Northern blot analyses showed that these events are accompanied by the induction of 92 kDa isoform type IV collagenase (metalloproteinase-9) enzymic activity and mRNA expression by exogenous LA and 12-HETE, and their suppression by the 12-lipoxygenase inhibitor. These results suggest that the effects of dietary LA on breast cancer cell metastasis in the nude mouse model are due, at least in part, to enhanced 12-HETE biosynthesis, with an associated increase in proteolytic enzyme activity and tumor cell invasiveness.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Breast Neoplasms; Collagenases; Eicosanoids; Gene Expression; Humans; Hydroxyeicosatetraenoic Acids; Linoleic Acid; Linoleic Acids; Lipoxygenase Inhibitors; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasm Metastasis; Piroxicam; RNA, Messenger; Tumor Cells, Cultured; Umbelliferones

Growth and metastasis to the lung of the human breast cancer cell line MDA-MB-435 in nude mice fed a high-fat (20% wt/wt) high-linoleic acid (LA; 12% wt/wt) diet were significantly reduced by the addition of the cyclooxygenase inhibitor indomethacin to the drinking water at a dose of 10 micrograms/ml (approximately 1 mg/kg body wt). No toxicity was observed in these mice; at 20 micrograms/ml indomethacin, gastric ulcerations occurred. After necropsy, tumor eicosanoids were measured by radioimmunoassay in the control and 10 micrograms/ml indomethacin treatment groups. Levels of the cyclooxygenase products prostaglandin (PG) E (PGE), 6-keto-PGF1 alpha, and thromboxane B2 (TxB2) were significantly reduced in indomethacin-treated mice compared with controls; however, the 6-keto-PGF1 alpha-to-TxB2 ratio was significantly increased. Two lipoxygenase products, 5-hydroxyeicosatetraenoic acid (5-HETE) and 15-HETE, were unaffected, but the 12-HETE levels were increased compared with the untreated high-LA-fed group. Metastases to the lungs in mice fed a high-fat low-LA (2% wt/wt) diet were also reduced compared with those in the high-LA-fed control mice, but whereas tumor cyclooxygenase and lipoxygenase product levels were reduced, no change in the 6-keto-PGF1 alpha-to-TxB2 ratio was observed. The use of selective cyclooxygenase inhibitors may prevent LA-mediated progression of breast cancer at several levels of the metastatic cascade, among which may be interference with tumor cell-vascular endothelial cell interaction and with angiogenesis.

Topics: Animals; Breast Neoplasms; Cell Division; Cyclooxygenase Inhibitors; Dietary Fats; Eicosanoids; Female; Humans; Indomethacin; Linoleic Acid; Linoleic Acids; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Tumor Cells, Cultured

This hypothesis proposes that the essential fatty acids (EFAs), linoleic acid (LA) and gamma-linolenic acid (GLA), play important roles in cancer treatment. Oxidation of LA by lipoxidase especially increases tumour cell death, whilst GLA inhibits urokinase-type plasminogen activator (uPA) activity. Increased uPA activity is: firstly, responsible for cancer invasion and metastasis and secondly, responsible for proteolysis of lipoxidase which favours a decrease in cancer cell death. Addition of LA and GLA to available therapeutic regimens may be worth considering in cancer treatment.

Topics: Antineoplastic Agents, Phytogenic; Cell Death; Fatty Acids, Essential; gamma-Linolenic Acid; Humans; Linoleic Acid; Linoleic Acids; Lipoxygenase; Models, Biological; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Oxidation-Reduction; Plant Oils; Urokinase-Type Plasminogen Activator

Linoleic acid (LA), an omega-6 fatty acid, enhanced the appearance of type IV collagenase activity in culture medium conditioned by the metastatic MDA-MB-435 human breast cancer cell line; this effect was maximal with 0.75 microgram/ml LA. Zymography showed an increase in the gelatinolytic 92 kDa metalloproteinase, a form associated with the metastatic phenotype, during culture in the presence of 0.75 microgram/ml LA. Indomethacin, 20 micrograms/ml, completely suppressed the stimulation of collagenase by LA, suggesting a role for the eicosanoids. The tumor cells expressed mRNA for both the 72 and 92 kDa isoforms of type IV collagenase. Basal levels of the 92 kDa mRNA were much higher; both were up-regulated by LA despite the absence of detectable 72 kDa activity in conditioned medium.

Topics: Breast Neoplasms; Collagenases; Eicosanoids; Extracellular Space; Gene Expression; Humans; Isoenzymes; Linoleic Acid; Linoleic Acids; Matrix Metalloproteinase 9; Neoplasm Metastasis; RNA, Messenger; Stimulation, Chemical; Tumor Cells, Cultured

The purpose of the study was to determine the effect of three different levels of dietary linoleic acid (LA) intake on the growth of MDA-MB-435 human breast cancer cells in the mammary fat pads of nude mice, and their metastasis to the lungs. These diets were isocaloric, and contained different mixtures of safflower (LA-rich) and coconut (saturated fatty acid-rich) oils to provide 23% (w/w) total fat, with 2, 8, and 12% (w/w) LA. A fourth group was fed a low-fat, 5% (w/w) corn oil diet. There were 25 mice in each dietary group. A necropsy, 12 weeks after the tumor cell injections, the primary tumor weights in the 12% LA (4.1 +/- 2.7 g)- and 8% LA (3.5 +/- 1.7 g)-fed groups were significantly greater (P < 0.05) than those fed the 2% LA diet (2.5 +/- 1.5 g); they did not differ significantly from the weights of mammary fat pad tumors in the 5% corn oil-fed mice. The incidence of grossly visible pulmonary metastatic nodules was not significantly different between the 8 and 12% LA-fed mice, but was higher for both groups compared with the 2% LA-fed group (P < 0.05), with a similar trend in comparison with the 5% corn oil group. The mean total calculated volumes of the macroscopic metastases per tumor-bearing mouse were significantly greater in the 8 and 12% LA (157 +/- 250.7 and 99.1 +/- 140.0 mm3, respectively), compared with the 2% LA (23.3 +/- 51.8 mm3)- and 5% corn oil (24.5 +/- 35.1 mm3)-fed mice; all P < 0.05. Micrometastases were observed most frequently in the 5% corn oil and 2% LA dietary groups, but none of the differences were statistically significant. No differences were detected in the concentrations of prostaglandin E, leukotriene B4, or 5-hydroxyeicosatetraenoic acid in tumors from mice fed the four different diets.

Topics: Adipose Tissue; Animals; Breast Neoplasms; Cell Division; Dietary Fats; Female; Humans; Linoleic Acid; Linoleic Acids; Lung Neoplasms; Mammary Glands, Animal; Mice; Mice, Nude; Neoplasm Metastasis; Transplantation, Heterologous; Tumor Cells, Cultured

We have previously shown that a high fat diet (20% w/w) containing 12% linoleic acid (18:2) can significantly increase the metastasis of mammary tumor cells when compared with high fat diets that contain 8% or less 18:2 with a constant level of oleic acid (18:1). This effect may have been due to an alteration of eicosanoid metabolism because the cyclooxygenase inhibitor, indomethacin, abolished the increase. Because 18:1 may interfere with the metabolism of 18:2 to 20:4, we have now tested whether the 18:1 that supplements the 18:2 diet can have an effect on spontaneous or experimental metastasis of the line 4526 murine mammary tumor. For this, six 20% fat diets were formulated with 1%, 6%, and 12% 18:2 and either high or low levels of 18:1. Our results indicate that the amount of select fatty acids other than 18:2 at 12% has no significant effect on mouse growth, tumor growth, or tumor latency. When spontaneous metastatic burden was calculated, no significant differences between mice fed diets containing 1% and 6% 18:2 were observed. However, 4 to 5 times more of a metastatic burden was observed in mice fed diets containing 12% 18:2. No significant differences were observed between high and low 18:1 diets when the 18:2 content was 1 or 12%. However, at 6% 18:2, 18:1 significantly decreased metastatic burden. When experimental metastasis was assessed, relatively low levels of surface lung nodules were observed at 1% and 6% 18:2, but significantly higher levels were observed at 12% 18:2.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Dietary Fats; Fatty Acids; Female; Linoleic Acid; Linoleic Acids; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Oleic Acid; Oleic Acids

This study examines whether oleate may influence the linoleate enhanced metastasis of line 4526 murine mammary tumors. In addition, the in vitro proliferative response of line 4526 to oleate and other selected fatty acids was assessed. Initially, the tumor cells were grown in a defined medium supplemented with palmitate, stearate, oleate, linoleate, linolenate or arachidonate. The unsaturated fatty acids stimulated and the saturated fatty acids inhibited proliferation compared to fatty acid-free medium. Next, we examined the effect of oleate on the linoleate enhanced metastasis of 4526 tumors by substituting oleate for saturated fat in isoenergetic diets containing high or low levels of linoleate. Oleate had no effect on metastasis in mice fed the high linoleate diets but it significantly increased metastasis in mice fed the low linoleate diets. Finally, the fatty acid compositions of tumors and mammary fat pads were compared to diet fatty acid compositions and metastatic frequency. Metastasis corresponded more closely to total unsaturated fatty acids than to total polyunsaturated fatty acids or to any individual fatty acid. These studies suggest that both mono- and polyunsaturated fatty acids may stimulate mammary tumor metastasis. However, the influence of dietary oleate probably depends on the level of linoleate and total unsaturated fatty acids in the diet.

Topics: Animals; Body Weight; Cell Division; Dietary Fats, Unsaturated; Dose-Response Relationship, Drug; Fatty Acids; Female; Linoleic Acid; Linoleic Acids; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Oleic Acid; Oleic Acids; Organ Size; Tumor Cells, Cultured

The mechanism(s) by which dietary linoleic acid (18:2n-6) enhances mammary tumor growth and metastasis is not known. Since arachidonic acid (20:4n-6)-derived prostaglandins (PG) may play a role in the metastatic dissemination of tumor cells, the ability of two murine mammary tumor cell lines, 4526 (metastasis positive) and line 168 (spontaneous metastasis negative), to convert 18:2n-6 into prostaglandins was examined. Cells were initially incubated with [14C]18:2n-6 and after 8-24 h the [14C]fatty acids were quantitated by high-performance liquid chromatography following transesterification. [14C]18:2n-6 was metabolized primarily to [14C]dihomogammalinolenic acid (20:3n-6) in line 4526 cells and [14C]20:4n-6 in line 168 cells. Examination of cellular fatty acid levels revealed a 20:3n-6/20:4n-6 ratio of 1.79 +/- 0.36 and 0.20 +/- 0.02 in line 4526 and 168 cells, respectively. These data are consistent with an inherently lower delta 5 desaturase activity in line 4526 relative to 168. To assess the metabolism of 18:2n-6 into eicosanoid products, the cell lines were prelabeled with [14C]18:2n-6 or 0-40 microM nonradiolabeled 18:2n-6 overnight and subsequently stimulated with calcium ionophore A23187 for 1 h. Total PGE production, as determined by radioimmunoassay, was greater in 168 relative to 4526 cells at all 18:2n-6 concentrations. 14C-prostaglandins detected by high-performance liquid chromatography and argentation thin-layer chromatography were: PGF1 alpha and PGE1 (derived from 20:3n-6) and PGF2 alpha and PGE 2 (derived from 20:4n-6) from line 4526; PGE1 and PGE2 from line 168. PGE1/PGE2 ratios were 1.43 +/- 0.07 and 0.23 +/- 0.03 for 4526 and 168 lines, respectively. Neither cell line synthesized lipoxygenase products following [14C]18:2n-6 or [3H]-20:4n-6 incubations under the conditions employed. Additional studies are warranted in order to define the biological properties of 1- and 2-series cyclooxygenase products as they relate to tumor cell metastasis.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Fatty Acids, Unsaturated; Female; Linoleic Acid; Linoleic Acids; Mammary Neoplasms, Experimental; Mice; Neoplasm Metastasis; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Tumor Cells, Cultured

High levels of dietary linoleic acid (18:2) have been shown to increase the spontaneous metastasis of line 4526 mouse mammary tumors. In this report, the influence of 18:2 on specific events of tumor metastasis, namely, lodgement, proliferation and survival, were studied using spontaneous and experimental metastasis assays with line 4526 cells. A significantly greater number of radiolabeled tumor cells lodged in the lungs of mice fed 4, 8 and 12% 18:2 when compared with mice fed lower levels of 18:2. The effect of dietary 18:2 appeared to be on the host tissue (lungs) and not the tumor cells. Lodgement of tumor cells first cultured in serum of mice fed 18:2 then injected into mice fed 1% 18:2 was not affected. There were no significant differences in the percentage of [3H]thymidine labeled metastatic cells from lungs of mice fed different levels of 18:2. However, the number of surface lung nodules that appeared in mice 21 days after injection of unlabeled line 4526 cells increased in mice fed 8 and 12% 18:2 compared with those fed lower levels of 18:2. Thus, dietary 18:2 may increase metastasis by influencing the lodgement, implantation and survival but not proliferation of line 4526 mouse mammary tumor cells.

Topics: Animals; Cell Adhesion; Cell Division; Cell Line; Cell Survival; Dietary Fats; Female; Linoleic Acid; Linoleic Acids; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplasm Transplantation

The influence of the cyclo-oxygenase inhibitor, indomethacin (IM), on the metastasis, development and prostaglandin E (PGE) levels of line 4526 mammary tumors grown in mice fed high fat (HF, 20%, w/w) diets containing various levels of linoleic acid (18:2) was investigated. Control mice that grew primary tumors and were fed HF diets containing 12% 18:2 (w/w) had 2-3 times the number of lung metastases than mice fed 1%, 4%, or 8% 18:2. Chronic treatment of mice with 10 micrograms/ml IM in drinking water reduced metastasis in 1% and 4% 18:2-fed mice compared to controls and completely inhibited the increased metastasis of mice fed the 12% 18:2 diet. Treatment with IM also increased the latency and decreased the growth rates of primary 4526 tumors of all dietary groups. Treatment of mice with a higher dosage of IM (20 micrograms/ml), decreased tumor metastasis even further compared to controls, but did not decrease tumor growth rate compared to the lower dosage of IM (10 micrograms/ml). Tumor PGE levels, measured by radioimmunoassay (RIA), were decreased by IM treatment. These data provide evidence that arachidonic acid metabolites such as PGE may be involved in the metastasis of 4526 mammary tumors.

Topics: Animals; Drug Interactions; Female; Indomethacin; Linoleic Acid; Linoleic Acids; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplasm Transplantation; Prostaglandins E

The influence of quantitative differences in dietary linoleic acid (18:2) on the metastasis as well as the development of line 4526 mouse mammary tumors was investigated. High fat diets (20%, w/w) that contained either 1, 2, 4, 8, or 12% 18:2 by weight, were prepared by using mixtures of coconut and safflower oil and fed to female BALB/c mice that were subsequently inoculated with 10(4) 4526 tumor cells s.c., either at the lateral abdominal wall (LAW) or in the mammary fat pad (MFP). Latency of LAW tumors was influenced by the level of dietary 18:2, whereas the latency of MFP tumors was not. When metastasis was assessed, mice with MFP tumors fed 1, 2, 4, or 8% 18:2 diets had 62-73% fewer lung surface tumor nodules than similar mice fed 12% 18:2. Mice in all dietary groups with LAW tumors had fewer metastatic lung nodules than mice with MFP tumors; mice with LAW tumors fed diets containing 1, 2, or 4% 18:2 had 52-69% fewer nodules than similar mice fed diets containing 8 or 12% 18:2. There were no significant differences in the rate of increase of body weight or the daily mean tumor volumes when compared with dietary 18:2 level. Fatty acid composition of the tumor, particularly the level of 18:2, was significantly altered by diet. This study demonstrates that while the level of dietary 18:2 does not enhance the growth rate of primary 4526 tumors and does or does not affect the latency depending on the primary site, it does significantly alter the metastasis. These results stress the importance of metastasis assessment in future studies involving dietary fat effects on tumorigenesis.

Topics: Animals; Body Weight; Dietary Fats; Fatty Acids; Female; Linoleic Acid; Linoleic Acids; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplasm Transplantation