Breast cancer is the most prevalent malignancy worldwide. Beyond genetic factors, dietary components like palmitic acid (PA) and sucrose modulate tumor progression and microenvironment dynamics. However, their combined mechanistic impacts on tumor-stroma crosstalk remain undefined. We investigated how dietary PA and sucrose affect breast cancer growth and the tumor microenvironment using a murine model. Mice received Control, high-PA (HPOD), high-sucrose (HCD), or combined (HPCD) diets. We assessed tumor growth, metabolic parameters, membrane fatty acids, histopathology, proliferative indices, and microenvironment markers (CD8, F4/80, α-SMA, HIF-1α, FASN). In vitro assays evaluated PA and fructose effects on LM3 cells and fibroblasts. HCD and HPCD markedly promoted tumor growth versus Control and HPOD. HPOD increased membrane saturated fatty acids, whereas HCD elevated ω-6 PUFAs. Both HCD and HPCD increased macrophage infiltration (F4/80 +), while HPCD specifically activated cancer-associated fibroblasts (α-SMA). HIF-1α protein increased across all experimental diets without mRNA alterations, suggesting post-transcriptional stabilization. FASN protein upregulation occurred in HCD and HPCD, while Fasn mRNA increased specifically in HCD. In vitro, combining PA and fructose enhanced LM3 cell proliferation and viability while reducing apoptosis. Additionally, this co-treatment specifically increased fibroblast viability. Diets rich in PA and sucrose drive breast cancer progression through distinct mechanisms. Carbohydrates transcriptionally activate FASN-mediated lipogenesis, whereas their combination with PA remodels the tumor microenvironment via CAF activation and HIF-1α post-transcriptional stabilization. These findings highlight specific dietary components as critical variables in cancer progression, offering potential implications for nutritional interventions and targeted therapies.

In the present work, a statistical experiment based on the microscopy X-ray fluorescence technique was developed to evaluate the effect of diets rich in ω-3 and ω-6 polyunsaturated fatty acids on tumour tissues. Relative variations on the local content of P, S, Ca, Fe, Cu and Zn were analysed in the experiment. Neoplastic tissues were obtained from mammary gland adenocarcinomas inoculated in mice belonging to three different dietary groups: normal, rich in ω-3 and in ω-6 polyunsaturated fatty acids. Slices of 30 microns thick sections of these samples were scanned in the air atmosphere in areas of 5 mm × 5 mm with a spatial resolution of 50 microns using synchrotron radiation. Principal component analysis was employed to analyse the correlation between the X-ray fluorescence signals of P, S, Ca, Fe, Cu and Zn. The subsequent application of the K-means clustering was used for the automatic segmentation of the image scans. By comparison with conventional histological analysis, the clusters were positively identified as tumour parenchyma, transition and necrotic region. The calculation of the mean content of P, S, Ca, Fe, Cu, and Zn in these regions showed that dietary polyunsaturated fatty acids modify elemental content of tumour parenchyma, suggesting its involvement in the antitumour effects of chia oil and protumour effects of safflower oil.

AbstractThe hypothesis was that maternal intake of the antioxidant alpha-lipoid acid (ALA), during the developmental period of the hypothalamic orexigenic neurons, causes a permanent beneficial effect in offspring metabolism. Pregnant Wistar rats were fed with standard diet (food) + ALA (0.4% wt/wt) from day 14 of gestation to day 20 of lactation (n = 4) or food (n = 4). At 3 months of age, male offspring born from ALA-fed rats or controls (CT) were randomly assigned to be fed with food + 10% fructose solution in drinking water (F) or food + tap water (C), resulting in four groups: ALAF, ALAC, CTF, and CTC (n = 5/group). Food intake and body weight (BW) were measured twice a week for 31 days. Metabolites’ levels in blood, mRNA expressions of Npy, Agrp (hypothalamus), Fasn, Srebf1, Ppard, and Pparg (liver), and the antioxidant capacity of the liver were determined. Results significance was set at p < 0.05. Average BW gain, daily BW gain, and intraabdominal fat tissue at necropsy were higher in CTF group followed by CTC, ALAF, and ALAC groups. There were no differences between groups in Kcal intake per day. mRNA expressions of hypothalamic and hepatic genes and plasmatic levels of glucose and triglycerides were higher in CTF group followed by ALAF, CTC, and ALAC groups. Fructose intake affected the oxidative capacity of the liver, but this effect was not observed in the ALAF group. In conclusion, maternal ALA intake protected the adult offspring to develop metabolic symptoms associated with high fructose in the drinking water.

Diabetic encephalopathy is a chronic complications of diabetes mellitus that affects the central nervous system. We evaluated the effect of ω3 and ω6 polyunsaturated fatty acids (PUFAs) supplementation plus the antioxidant agent nordihydroguaiaretic acid (NDGA) on the etiopathology of diabetic encephalopathy in eSS rats, a spontaneous model of type 2 diabetes.

Diabetes mellitus tipo 2 y otras patologias relacionadas con un estado proinflamatorio cronico (hipertension arterial, aterosclerosis, enfermedad de Alzheimer y cancer ) se producen en ciertos individuos, debido a la acumulacion de alteraciones en el organismo, a traves del tiempo. El proposito de este proyecto es elaborar indices confiables, clinicos y bioquimicos que podrian servir como marcadores de perturbaciones en el organismo que pueden ser indicadores fiables de la manifestacion clinica de diabetes mellitus tipo 2 y si estos parametros son modificables por habitos dietarios saludables y practica de ejercicios fisicos. Estas medidas simples y economicas podrian ser empleadas efectivamente para evitar o posponer la aparicion de diabetes mellitus tipo 2 en sujetos en riesgo.

The acyl-CoA synthetase 4 (ACSL4) is increased in breast cancer, colon and hepatocellular carcinoma. ACSL4 mainly esterifies arachidonic acid (AA) into arachidonoyl-CoA, reducing free AA intracellular levels, which is in contradiction with the need for AA metabolites in tumorigenesis. Therefore, the causal role of ACSL4 is still not established. This study was undertaken to determine the role of ACSL4 in AA metabolic pathway in breast cancer cells. The first novel finding is that ACSL4 regulates the expression of cyclooxygenase-2 (COX-2) and the production of prostaglandin in MDA-MB-231 cells. We also found that ACSL4 is significantly up-regulated in the highly aggressive MDA-MB-231 breast cancer cells. In terms of its overexpression and inhibition, ACSL4 plays a causal role in the control of the aggressive phenotype. These results were confirmed by the increase in the aggressive behaviour of MCF-7 cells stably transfected with a Tet-off ACSL4 vector. Concomitantly, another significant finding was that intramitochondrial AA levels are significantly higher in the aggressive cells. Thus, the esterification of AA by ACSL4 compartmentalizes the release of AA in mitochondria, a mechanism that serves to drive the specific lipooxygenase metabolization of the fatty acid. To our knowledge, this is the first report that ACSL4 expression controls both lipooxygenase and cyclooxygenase metabolism of AA. Thus, this functional interaction represents an integrated system that regulates the proliferating and metastatic potential of cancer cells. Therefore, the development of combinatory therapies that profit from the ACSL4, lipooxygenase and COX-2 synergistic action may allow for lower medication doses and avoidance of side effects.

Dietary arachidonic acid (AA) and eicosanoids influence neoplastic cell (NC) growth, differentiation and apoptosis. Plasma membrane fatty acid and cyclooxygenase (COX) and lipoxygenase (LOX) products were investigated in lung alveolar carcinoma cells from mice fed on different diets. Two groups were fed on a basic diet plus 6% of: corn oil (rich in 18:2n-6; CO) and on olein oil (rich in 18:1n-9; O), respectively. Control group (C) received commercial diet. NC fatty acids were analyzed by GLC, and apoptosis by flow cytometry and microscopy. In NC from CO group AA levels and LOX metabolites were increased, whereas COX metabolites decreased. NC from CO compared to O group diet showed a higher count of apoptosis and increased LOX:COX ratio. High levels of AA and decreased COX eicosanoids has been involved in anti-tumoral mechanisms by increasing tumor cell apoptosis. Present data emphasizes the implications of the dietary fatty acids on the neoplastic process in this tumoral model.

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.

Involvement of arachidonic acid cyclooxygenase (COX) and lipoxygenase (LOX) metabolites in platelet aggregation and coagulation induced by two varieties of cancer cells of murine transplantable tumors was studied. A lung alveolar carcinoma (LAC) and a fibrosarcoma (FS), induced platelet aggregation and plasma coagulation (P<0.05). Pretreatment of both tumor lines with a COX inhibitor did not block the tumor cell induced platelet aggregation (TCIPA). COX [12(S)-HTT] and LOX [12(S)-HETE], metabolites of washed platelets (WP), alone or co-incubated with LAC or FS cells, were analyzed. We observed higher 12(S)-HETE release with respect to 12(S)HHT when WP were co-incubated with LAC cells. With both neoplastic cell (NC) lines prothrombin time (PT) was shortened. Pretreatment of NC with iodoacetic acid, soybean trypsin inhibitor or Factor X-deficient plasma increased the PT. These results indicate that AA metabolites play a role on the procoagulation and platelet aggregation induced by mesenchymal and epithelial murine cancers.

The addition of neoplastic cells (NC) isolated from murine mammary gland adenocarcinomas having moderate and high metastatic ability on in vitro heparinized mice platelet rich plasma (PRP) induced platelet aggregation. One non-metastatic line did not induce aggregation. The aggregatory effect was not correlated with the metastatic abilities. None of the three types of tumors did cause aggregation on whole blood or PRP of rats. These adenocarcinomas seem to be suitable models to study in vitro the interactions between platelets and tumor cells having metastatic and non-metastatic potentials.

The purpose of the present work was to study the in vitro effects of challenging human whole-blood and platelet-rich plasma (PRP) with neoplastic cells (NC) isolated from a murine mammary gland adenocarcinoma. Viable, but not formalinized, isolated tumoral cells induced platelet aggregation in citrated whole blood. NC did not induce aggregation of PRP samples whereas the NC added to PRP induced aggregation in 33% of volunteers if samples were previously stimulated with a subaggregatory strength of collagen. The results suggest a role for other blood cells since the proaggregatory effect was less evident on PRP. Adenocarcinoma M3 seems to be a suitable model to study in vitro platelet-cell tumor interactions.