Modulation of murine mammary tumor vasculature by dietary n-3 fatty acids in fish oil (original) (raw)
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Journal of Neoplasms
Diets high in unsaturated fatty acids, especially those containing high levels of linoleic acid, e.g., corn oil, enhance mammary gland tumorigenesis in experimental animals. In contrast, diets high in long-chain polyunsaturated fatty acids such as eicosapentaenoic (EPA) and docosahexaenoic (DHA), e.g. menhaden oil, appear to have a suppressive effect on this tumorigenic process. Many mechanisms have been proposed to explain the tumor inhibitory action exerted by menhaden oil and other fish oils, e.g., differences in prostaglandin metabolism, energy efficiency, alterations of the immune system, changes in lipid peroxidation, etc. Fundamental to a mechanistic understanding of this phenomenon, however, is an understanding as to whether or not the tumor inhibitory activities of dietary fish oil is mediated via an inhibition of tumor cell proliferation or mediated via an enhancement of tumor cell loss. Whether the amount of dietary fat or the type of fat effects mammary tumorigenic proce...
Cancer Letters, 1998
It is widely known that dietary lipids can modify the ability of different cancers to grow up and metastasize, especially mammary gland tumors. However, it is still unclear whether n-6 fatty acids behave as tumor promoters in this gland cell population. The effect of different nutritional polyunsaturated fatty acids (PUFAs) on tumor growth parameters of two transplantable murine mammary gland adenocarcinomas of low and high metastatic ability was tested on hosts fed diets with corn oil (CO) rich in 18:2n-6, evening primrose oil (EPO) containing 18:3n-6 (GLA) and a third formula supplemented with olein (O) 18:1n-9, which induces an essential fatty acid deficiency (EFAD). Tumor growth parameters were not adversely affected in the corn oil group with respect to stock-fed controls. Furthermore, metastatic spreading diminished in this group. EPO showed a moderate antitumor activity whereas the n-9-enriched diet showed no clear-cut effects. In both mammary gland tumors, n-6 fatty acid-rich lipids formulae, containing GLA and linoleic acid, were not tumor promoters. On the contrary, both exhibited anticancer activity.
Clinical & Experimental Metastasis
Epidemiological studies show a reduced risk of breast cancer (BC) in women consuming high levels of long-chain (LC) omega-3 (ω-3) fatty acids (FAs) compared with women who consumed low levels. However, the regulatory and mechanistic roles of dietary ω-6 and LC-ω-3 FAs on tumor progression, metastasis and survival are poorly understood. Female BALB/c mice (10-week old) were pair-fed with a diet containing ω-3 or an isocaloric, isolipidic ω-6 diet for 16 weeks prior to the orthotopic implantation of 4T1 mammary tumor cells. Major outcomes studied included: mammary tumor growth, survival analysis, and metastases analyses in multiple organs including pulmonary, hepatic, bone, cardiac, renal, ovarian, and contralateral MG (CMG). The dietary regulation of the tumor microenvironment was evaluated in mice autopsied on day-35 post tumor injection. In mice fed the ω-3 containing diet, there was a significant delay in tumor initiation and prolonged survival relative to the ω-6 diet-fed group. The tumor size on day 35 post tumor injection in the ω-3 group was 50% smaller and the frequencies of pulmonary and bone metastases were significantly lower relative to the ω-6 group. Similarly, the incidence/ frequencies and/or size of cardiac, renal, ovarian metastases were significantly lower in mice fed the ω-3 diet. The analyses of the tumor microenvironment showed that tumors in the ω-3 group had significantly lower numbers of proliferating tumor cells (Ki67 +)/high power field (HPF), and higher numbers of apoptotic tumor cells (TUNEL +)/HPF, lower neo-vascularization (CD31 + vessels/HPF), infiltration by neutrophil elastase + cells, and macrophages (F4/80 +) relative to the tumors from the ω-6 group. Further, in tumors from the ω-3 diet-fed mice, T-cell infiltration was 102% higher resulting in a neutrophil to T-lymphocyte ratio (NLR) that was 76% lower (p < 0.05). Direct correlations were observed between NLR with tumor size and T-cell infiltration with the number of apoptotic tumor cells. qRT-PCR analysis revealed that tumor IL10 mRNA levels were significantly higher (six-fold) in the tumors from mice fed the ω-3 diet and inversely correlated with the tumor size. Our data suggest that dietary LC-ω-3FAs modulates the mammary tumor microenvironment slowing tumor growth, and reducing metastases to both common and less preferential organs resulting in prolonged survival. The surrogate analyses undertaken support a mechanism of action by dietary LC-ω-3FAs that includes, but is not limited to decreased infiltration by myeloid cells (neutrophils and macrophages), an increase in CD3 + lymphocyte infiltration and IL10 associated anti-inflammatory activity.
Cancer Letters, 1987
The effect of dietary fat concentration and saturation on cell composition and structure of line 168 mouse mammary tumors in vivo was studied using morphometry and electron microscopy. Both the concentration and saturation of fat fed to mice had a significant influence on the volume ratio of mast cells infiltrating line 168 tumors. Tumors of mice fed diets containing a high concentration (20%) of either safflower oil (SO) or palm oil (PO) had 2-3 times the volume ratio of mast cells than mice fed diets containing a low concentration (5%) of either fat. There were no significant differences among diets with respect to other inflammatory cell populations. Mice fed either one of the high fat diets had tumor cells with inclusions that ultrastructurally, appeared to consist of lipid. Dietary fat, however, had no observable affect on cell junctions or other morphological characteristics. Greater infiltration of mast cells in tumors of mice fed high fat diets and the eventual formation of new blood capillaries may explain the decreased latency of tumor onset and enhanced growth of tumors in mice fed diets with high concentrations of fat.
Lipids in Health and Disease, 2010
Background: Nutritional factors play a major role in cancer initiation and development. Dietary polyunsaturated fatty acids (PUFAs) have the ability to induce modifications in the activity of lipoxygenase (LOX) and cyclooxygenase (COX) enzymes that affect tumour growth. We studied the effect of two diets enriched in 6% Walnut and Peanut oils that are rich in ω-3 and ω9 PUFAs respectively on a murine mammary gland adenocarcinoma as compared with the control (C) that received commercial diet. Results: Peanut oil enriched diet induced an increase in membrane arachidonic acid (AA) content and the cyclooxygenase enzyme derived 12-HHT (p < 0.05) and simultaneously showed decrease in 12-LOX, 15-LOX-2, 15-LOX-1 and PGE activities (p < 0.05) that corresponded to higher apoptosis and lower mitosis seen in this group (p < 0.05). Furthermore, Peanut oil group showed lower T-cell infiltration (p < 0.05), number of metastasis (p < 0.05) and tumour volume (p < 0.05) and longer survival rate compared to other groups.
Cancer Research, 2012
An increased ratio of dietary n-3 relative to n-6 fatty acids has been shown to inhibit the development of mammary cancer in animal models. However, the molecular mechanisms by which n-3 fatty acids affect tumor growth remain unknown. Here, we investigated the effects of varying dietary ratios of n-3:n-6 fatty acids on cell signaling in a rat model of chemically induced mammary carcinoma. Cell proliferation was reduced by 60% in carcinomas from the high n-3:n-6 treatment group compared with the low n-3:n-6 treatment group. These changes were associated with decreased cyclin-D1 and phospho-retinoblastoma protein expression and increased levels of cyclin-dependent kinase inhibitors, CIP1 (p21) and KIP1 (p27). In addition, the apoptotic index was increased in carcinomas from the high n-3:n-6 group and was associated with elevated apoptotic protease-activating factor 1 and a higher ratio of Bax/Bcl-2. Interestingly, changes in protein expression were consistent with reduced inflammation...
The Journal of Nutritional Biochemistry, 2001
The aim of this study was to analyze the effects of a polyunsaturated n-6 high-fat diet on rat DMBA-induced breast cancer at different stages of the carcinogenesis and to investigate if changes in the tumor fatty acid composition are one of the mechanisms by which dietary lipids could exert their effects. 14 fatty acids were evaluated in 6 lipid fractions. The results firstly showed that this high-fat diet stimulated the malignant mammary tumor growth, mainly all in the promotion group. The tumor lipid analysis indicated: 1) that each lipid fraction presented distinct major fatty acids (Ͼ5%) which were not the most abundant in the diet, except in the case of the triacylglicerides, suggesting the different resistance to dietary fatty acid modification of the tumor lipid fractions; 2) a higher arachidonic acid content in the fractions with less linoleic acid, above all in phospholipids, particularly in the phosphatidylethanolamine, indicating a different efficiency of conversion; 3) the three most abundant fatty acids in the dietary lipid (18:2n-6, 18:1n-9 and 16:0) were those which essentially displayed the differences between groups; thus, the high-fat diet changed the tumor lipid profile, increasing the 18:2n-6 relative content and decreasing that of the 18:1n-9; differences were significant in phosphatidylcholine, free fatty acids and triacylglycerides. Any change was obtained in the phosphatidylinositol. The greatest number of differences was found in the promotion group. Taken as a whole, our results suggest the different roles of lipid fractions in breast cancer cells and an association between cancer malignancy and the content of linoleic and oleic acids.
Chemoprevention of Breast Cancer by Fish Oil in Preclinical Models: Trials and Tribulations
Cancer Research, 2011
Despite the perception that omega-3 fatty acids (n-3 FA) protect against breast cancer, epidemiologic studies have yielded inconsistent results. Although preclinical data have been, in general, more supportive of a protective effect of n-3 FA on breast cancer, inconsistencies still remain, which preclude definite conclusions or in-depth mechanistic investigations despite 30 years of research in this area. In this review, we discuss key variables that may account for inconsistencies of results across preclinical studies and provide recommendations for future experiments testing the chemopreventive effect of n-3 FAs in breast cancer, as part of a multiagent approach under rigorously controlled conditions. Cancer Res; 71(19); 6091-6. Ó2011 AACR.
Clinical & Translational Oncology, 2002
The dietary fat hypothesis postulates that dietary or exogenously derived fatty acids play an important role in the carcinogenesis, evolution and/or progression of breast cancer. In order to reveal possible underlying mechanisms of this hypothesis, we studied the influence of ω- 3 polyunsaturated fatty acids (PUFAs) -α-linolenic (ALA), eicosapentaenoic (EPA) and docosahexaenoic (DHA)-, ω-6 PUFAs-linoleic (LA), γ-linolenic (GLA) and arachidonic (ARA)- and monounsaturated ω- 9 oleic acid (OA) on the proliferation, adhesion and metastatic potential of human breast cancer cells in culture. GLA and the ω-3 PUFAs, ALA and DHA, inhibited significantly the cell growth of MCF-7 and MDA-MB-231 breast cancer cell lines, while EPA has less marked inhibitory effects. ω-6 PUFAs, LA and ARA, or ω- 9 OA had either no effect or caused a slight increase of proliferation. The attachment of breast cancer cells to the extracellular matrix components (type IV collagen, fibronectin and Matrigel) was significantly inhibited by ω-6 GLA and ω-3 PUFAs ALA, DHA and EPA. At concentrations which had no effect on cell growth over the duration of experiments the ω-6 PUFAs, LA and GLA, and the ω-3 PUFAs, ALA, DHA and EPA, had the ability to inhibit both cellular migration and invasion into type IV collagen and Matrigel. In summary, our findings indicate important differences in the ability of ω-3, ω-6 and ω-9 fatty acids to modulate prolif eration, attachment to extracellular matrix components, mo-tility and invasiveness of human breast carcinoma cells in vitro, with the GLA and all ω-3 PUFAs being the most effective inhibitors. Our data are consistent with the view that the type rather than the amount of dietary fatty acids is be more important in breast cancer development and progression. Los ácidos grasos exógenos o procedentes de la dieta podrían jugar un papel importante en la carcinogénesis, evolución y/o progresión del cáncer de mama. Para estudiar los posibles mecanismos que subyacen a esta hipótesis hemos estudiado en cultivo, la influencia de los ácidos grasos poliinsaturados (PUFAs) ω-3 -α-linolénico (ALA), eicosapentaenoico (EPA) y docosahexaenoico (DHA)-, los PUFAs ω-6 -linoleico (LA), γ-linolénico (GLA) y araquidónico (ARA)- y el ácido graso monoinsaturado ω-9 ácido oleico (OA) en la proliferación, adhesión y potencial metastásico de las células humanas de cáncer de mama. El GLA y los PUFAs ω-3 ALA y DHA inhibieron significativamente el crecimiento de las células de cáncer de mama, mientras que los efectos inhibidores del EPA fueron menos marcados. Los PUFAs ω-6, LA y ARA, o el ω-9 OA no modificaron o produjeron un débil incremento de la proliferación. La adhesión de las células de cáncer de mama a componentes de la matriz extracelular (colágeno tipo IV, fibronectina y Matrigel) fue inhibida significativamente por el ω-6 GLA y por los PUFAs ω-3 ALA, DHA y EPA. A las concentraciones que no afectó el crecimiento celular durante el transcurso de los experimentos, los PUFAs ω-6 LA y GLA y los PUFAs ω-3 ALA, DHA y EPA inhibieron la migración e invasión celulares en el colágeno tipo IV y el Matrigel. En resumen, nuestros resultados indican que existen diferencias importantes en la capacidad de los ácidos grasos ω-3, ω-6 y ω-9 para modular in vitro la proliferación, adhesión a componentes de la matriz extracelular, motilidad e invasividad de las células humanas de cáncer de ma-ma, siendo el GLA y los PUFAs ω-3 los inhibidores más efectivos. Los resultados son consistentes con la opinión de que, más que la cantidad total, es el tipo de ácido graso en la dieta el factor más importante en el desarrollo y progresión del cáncer de mama.