Fatty Acids and Membrane Lipidomics in Oncology: A Cross-Road of Nutritional, Signaling and Metabolic Pathways

Abstract

Fatty acids are closely involved in lipid synthesis and metabolism in cancer. Their amount and composition are dependent on dietary supply and tumor microenviroment. Research in this subject highlighted the crucial event of membrane formation, which is regulated by the fatty acids’ molecular properties. The growing understanding of the pathways that create the fatty acid pool needed for cell replication is the result of lipidomics studies, also envisaging novel fatty acid biosynthesis and fatty acid-mediated signaling. Fatty acid-driven mechanisms and biological effects in cancer onset, growth and metastasis have been elucidated, recognizing the importance of polyunsaturated molecules and the balance between omega-6 and omega-3 families. Saturated and monounsaturated fatty acids are biomarkers in several types of cancer, and their characterization in cell membranes and exosomes is under development for diagnostic purposes. Desaturase enzymatic activity with unprecedented de novo polyunsaturated fatty acid (PUFA) synthesis is considered the recent breakthrough in this scenario. Together with the link between obesity and cancer, fatty acids open interesting perspectives for biomarker discovery and nutritional strategies to control cancer, also in combination with therapies. All these subjects are described using an integrated approach taking into account biochemical, biological and analytical aspects, delineating innovations in cancer prevention, diagnostics and treatments.

GEO data mining and TCGA analysis reveal altered branched chain amino acid metabolism in pancreatic cancer patients

“…BCAA catabolism related genes BCAT1, BCAT2, BCKDHA, BCKDHB, BCKDK, ACADS and ACADSB were found significantly down-regulated in PDAC group ( Figure 2D ). As known, the fatty acid biosynthesis enzymes such as acetyl-CoA carboxylase (ACC), fatty-acid synthase (FASN) and ATP-citrate lyase (ACLY) were reported to be greatly increased in various tumors [ 12 , 21 , 22 ]. Meanwhile, BCAA catabolism was shown to inhibit fatty acid oxidation (FAO) while promoting lipid accumulation [ 23 , 24 ].…”

Altered Levels of Desaturation and ω-6 Fatty Acids in Breast Cancer Patients’ Red Blood Cell Membranes

“…After activation through phospholipase A2 and liberation in the cytoplasm, it produces different metabolites by action of cyclooxygenase (COX) enzymes. For example, prostaglandin H2 is an important mediator of cancer-associated inflammation, response to growth factors, tumor progression, and metastasis [ 9 , 37 , 38 ]. Thus, the higher level of AA RBC from patients compared to controls, which was not seen in a previous study [ 30 ], could be an indicator of an activity of lipid mediators that is necessary to cancer cells.…”

“…On the other hand, polyunsaturated fatty acids (PUFA), distinct in omega-3 (ω-3) and omega-6 (ω-6) fatty acids (FA), are essential for humans, since their precursors (linoleic and alpha-linolenic acids, respectively) must be obtained from the diet. Once the precursors are in the organism, they can be metabolized by enzymatic systems to form other PUFA that have important physiological functions as mediators of several processes, as previously mentioned [ 8 , 9 ]. In cancer, cells adapt their membrane properties to sustain their survival with a variability that depends on the stage and type of cancer [ 10 ].…”

“…RBC can be obtained by non-invasive methods and cheap procedures. Our recent review of the state-of-the-art on fatty acids in oncology [ 9 ] highlighted that the RBC fatty acids are emerging as important biomarkers. In our previous study, we found metabolic changes associated with de novo synthesis of FAs and promoted metabolism of ω-6 FAs in a patient cohort with different cancer types and different chemotherapy treatments.…”

Nuclear Receptor-Mediated Metabolic Reprogramming and the Impact on HR+ Breast Cancer

“…Mechanistically, SCD1 expression is regulated by estrogen and to a lesser extent by insulin growth factor 1 (IGF1) through SREBP1c. In breast cancer, SCD1 expression results in increased cellular MUFA levels which are essential for the full activation of AKT signaling and suppression of AMPK activity, resulting in increased cell survival and evasion of apoptotic signals [ 166 , 167 , 168 , 169 , 170 ].…”