This is the first study to investigate the fatty acid content of skeletal muscle phospholipids in cancer patients. The main goal was to determine associations between fatty acid content and composition in skeletal muscle phospholipids and survival. The most significant finding is that having a lower mean absolute amount of the long chain essential fatty acids, AA, EPA and DHA in skeletal muscle phospholipids, is associated with poor prognosis in cancer patients, with a shortened life expectancy by 200 days (5 months).
In a cohort of patients with depletion of AA, EPA and DHA below a critical level as determined by statistical cut-points, approximately 40% more patients died compared to those with fatty acids above 136.9ng/mg, 7.2ng/mg and 25.2ng/mg, respectively in muscle phospholipids. Notably, only one patient died in the group of patients with AA, EPA and DHA above this critical level but 600 days post-surgery. In contrast, over half of patients died within one year of surgery in the group of patients with AA, EPA and DHA below the critical level. Two studies have previously reported an association between levels of AA, EPA and DHA of plasma phospholipid and survival. Lower content of AA, EPA and DHA were reported in plasma of cancer patients who lived < 238 days as compared to > 238 days, determined to be the median days of survival in that study population 9. Also, longer survival of pancreatic cancer patients has been associated with higher content of EPA and DHA, but not AA, in plasma 16. Lower proportions of AA, EPA and DHA in plasma and erythrocyte phospholipids have been reported in bladder, lung, colorectal and pancreatic cancer as compared to healthy or non-malignant populations 8,9,13,14,16. Here, we demonstrate a reduction in EPA, DHA and AA in muscle and further associate this depletion with truncated survival.
Muscle loss 25,26 and plasma phospholipid fatty acid depletion 9 have each been separately reported to be predictors of survival in cancer. The positive association between skeletal muscle mass and concentration of EPA and DHA in plasma phospholipids has been previously reported 9. Based on this, it was hypothesised that there would be a positive association between essential fatty acids and skeletal muscle index, however, this was not observed.
A strong association is observed between essential fatty acids in phospholipid of muscle. Membrane phospholipid fatty acids regulate the biophysical properties of proteins, provide substrates for second messengers and intracellular signals to alter gene expression. Evidence suggests that EPA and DHA in membrane phospholipids can have a protective effect against cancer through several actions including protein kinase activation, enhancing cell apoptosis and modulating inflammation 27–29. The association between dietary/plasma AA and the risk of cancer is highly controversial 30. AA and its metabolites play role in muscle growth 31. AA is converted into 2 series eicosanoids known as prostaglandins F2alpha (PGF2α) and prostaglandin E2 (PGE2) which activate the major anabolic pathway in muscle, phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signalling pathway and induce myotube hypertrophy 32,33. Suppression of PGF2α in the muscle of experimental models has been shown to inhibit muscle recovery after disuse atrophy 34. EPA and DHA in skeletal muscle membranes have been suggested to influence membrane properties that may influence anabolic signalling, particularly through key regulators of muscle protein synthesis 35, and given the association with survival, these mechanisms are worthy of exploration.
Several limitations of the current study warrant mention. First, dietary records were not available for the patients, therefore, the effect of diet on skeletal muscle composition was not determined. The western diet 36,37 and food choices cancer patients make during their cancer trajectory are comprised of foods that are rich in AA 38,39, therefore, depletion of AA observed is not likely to be related to intake, but rather a change in metabolism of essential fatty acids. Moreover, studies reported alterations in plasma and erythrocyte fatty acid composition in cancer patients compared to healthy controls independent of total calorie and fat intake 12,40. Second, reliability of optimal stratification in small sample size is low 23,41. The thresholds determined in this study should be considered approximate until confirmed in additional studies with larger sample size. While the first and only study to evaluate the PL composition in relation to survival, the sample size as too small to adjust for several well-known prognostic factors, which should be accounted for in future studies.
In conclusion, patients with AA, EPA and DHA amounts in muscle phospholipids that were below a critical level had shorter survival. The present study is a first step in establishing alterations in skeletal muscle fatty acid composition and its association with survival in cancer. This work provides rationale for conducting further studies to examine repletion of bioactive fatty acids in cancer. Further work is needed to investigate mechanisms that can explain the strong associations between essential fatty acids and survival in cancer patients observed in this study.