Impact of fatty acid metabolism in breast cancer peritumoral tissue. Clinical and pathogenic aspects

El càncer de pit es el càncer més comú en dones i el segon càncer amb més morts relacionades. Conèixer el comportment de les cèl·lules tumorals en el seu microambient pot obrir noves posibilitats d’estudis i dianes terapèutiques en el futur. En aquesta tesi hem demostrat com factors alliberats pel teixit adipós, entre els quals cal destacar FABP4, potencien els diferents hallmarks del càncer. Tanmateix, hem demostrat que la comunicació és bidireccional entre cadascun dels elements del microambient, i que la transferència de lípids i el seu posterior metabolisme és diferencial entre les línies tumorals, cosa que podria explicar els seus diferents graus de tumorogenicitat. El sistema inmunitari, com element del microambient tumoral es veu modificat, generant un estat pro-inflamatori que es tradueix en el increment del mateix en les pacients de càncer de pit, que a més es veu relacionat positivament amb l’increment de FABP4. En aquest estudi s’ha demostrat que el perfil lipoproteic es veu modificat de forma significativa en aquestes dones, on hi ha un enriquiment de triglicèrids i colesterol a les diferents lipoproteïnes, las quals s’associen positivament amb l’estat pro-inflamatori de les pacients. L’estudi del sèrum per 1H-NMR també ens otorga coneixements sobre les alteraciones del perfil de LMWMs de les pacients, on trobem un increment de determinats aminoàcids en el sèrum de les mateixes. El coneixement de nous biomarcadors pot marcar noves vies diagnòstiques que ajuden a la selecció precoç i per tant en el millor pronòstic d’aquestes pacients.El cáncer de mama es el cáncer más común en mujeres y el segundo con más muertes relacionadas. Conocer el comportamiento de las células tumorales en su microambiente puede abrir nuevas posibilidades de estudios y dianas terapéuticas en un futuro. En esta tesis hemos demostrado como factores liberados por el tejido adiposo, entre los que cabe destacar FABP4 potencian los diferentes hallmarks del cáncer. Así mismo, hemos demostrado que la comunicación es bidireccional entre cada uno de los elementos del microambiente y que la transferencia de lípidos y su posterior metabolismo es diferencial entre las diferentes líneas tumorales, lo cual podría explicar sus diferentes grados de tumorogenicidad. El sistema inmunitario como elemento del microambiente tumoral se ve modificado por el mismo, generando un estado pro-inflamatorio que se traduce en un incremento del mismo en las pacientes de cáncer de mama, el cual se ve relacionado positivamente con el incremento de FABP4 en las mismas. Además, en este estudio se ha demostrado que el perfil lipoproteico se ve significativamente alterado en estas mujeres, donde hay un enriquecimiento de triglicéridos y colesterol en las diferentes lipoproteínas, las cuales también se asocian positivamente con el estado inflamatorio de las pacientes. El estudio del suero por 1H-NMR también nos otorga conocimiento sobre alteraciones en el perfil de LMWMs de las pacientes, donde encontramos un increment de determinados aminoácidos en el suero de las mismas. El conocimiento de nuevos bioamarcadores puede marcar nuevas vías de diagnóstico que ayuden a la detección temprana y por índole en el mejor pronóstico de estas pacienBreast cancer is the most common cancer in women and the second cancer with more related deaths. Knwoledge og the behavior of tumor cells within their microenvironment might open new research possibilities and new therapeutic tarjets in the future. In this doctoral thesis, we have demonstrated how diverse factors that are released by the adipose tissue, especially FABP4, are able to enhance the diverse cancer hallmarks. Moreover, we have demonstrated the birectionallity of the microenvironemnt crosstalk, as well as that the lipid transfer and their metabolism is different in the different submolecular BC types, thus might explain their different malignance grades. Tne immune system, as an element of the tumor microenvironment is altered by this crosstalk, by activating the pro-inflammatory pathways. This is translate to an enhancement of the pro-inflammatory status of BC patients. Interestingly, this status is positively correlated with the increment of FABP4 serum levels in BC patients. Moreover, this study has demonstrated that the liporpotein profile is notably altered in BC patients, where there is a cholesterol and triglycerides enrichement within the different lipoproteins. These changes have been positively correlated with the inflammatory status of our BC patients. The serum LMWMs analysis by 1H-NMR demonstrated that there was a disregulated serum levels of different aminoacids. Knowledge of new biomarks would open new diagnosis methods, that might help in an earliest diagnosis, hence in the BC patients’ prognosis

MCF-7 Drug Resistant Cell Lines Switch Their Lipid Metabolism to Triple Negative Breast Cancer Signature

Obesity and adipose tissue have been closely related to a poor cancer prognosis, especially in prostate and breast cancer patients. The ability of transferring lipids from the adipose tissue to the tumor cells is actively linked to tumor progression. However, different types of breast tumor seem to use these lipids in different ways and metabolize them in different pathways. In this study we have tracked by mass spectrometry how palmitic acid from the adipocytes is released to media being later incorporated in different breast cancer cell lines (MDA-MB-231, SKBR3, BT474, MCF-7 and its resistant MCF-7 EPIR and MCF-7 TAXR). We have observed that different lines metabolize the palmitic acid in a different way and use their carbons in the synthesis of different new lipid families. Furthermore, we have observed that the lipid synthesis pattern varied according to the cell line. Surprisingly, the metabolic pattern of the resistant cells was more related to the TNBC cell line compared to their sensitive cell line MCF-7. These results allow us to determine a specific lipid pattern in different cell lines that later might be used in breast cancer diagnosis and to find a better treatment according to the cancer molecular type

Altered Serum Metabolic Profile Assessed by Advanced 1H-NMR in Breast Cancer Patients

Background: Altered lipid metabolism has been described in some types of cancer. To analyse in depth the metabolic modifications in breast cancer patients, advanced 1H-nuclear magnetic resonance was performed in these patients. The main objective of this paper was to define a specific lipidomic signature for these cancer patients. Materials and methods: Serum from 240 women (171 breast cancer patients and 69 control women) were studied and analysed by nuclear magnetic resonance. Results: Triglyceride-enriched particles, specifically very low-density lipoprotein triglycerides, intermediate-density lipoprotein triglycerides, low-density lipoprotein triglycerides, and high-density lipoprotein triglycerides, were positively associated with breast cancer. Moreover, alanine, tyrosine, and branched amino acids were also associated with increased risk of breast cancer. Conclusions: Breast cancer patients showed a modified metabolome, giving a very interesting tool to draw different radar charts between control women and breast cancer patients. To our knowledge, this is the first time that advanced nuclear magnetic resonance profiling has been used to identify relevant and specifically altered lipid or amino acid metabolites in BC serum samples. The altered metabolic signature could be analysed for early and reliable BC patient diagnosis and prognosis