Higher plasma levels of lysophosphatidylcholine 18:0 are related to a lower risk of common cancers in a prospective metabolomics study

Since the metabolite levels in our study were measured in blood samples taken years before diagnosis, the present associations between lysoPC and PC ae C30:0 concentrations with the risk of cancer may represent general metabolic alterations fostering the development and growth of cancer cells. In contrast to the relationship between PC ae C30:0 and cancer risk that has not been described in the literature, our findings of associations between lysoPC levels and cancer risk are consistent with results of three case-control studies, in which lower blood concentrations of lysoPCs in patients with breast, prostate and colorectal cancer were found, as compared to controls [16–18].

While a potential shift between lysoPC levels from blood to tumor tissue indicates a higher consumption of lysoPCs by cancer cells, specific signaling properties of lysoPCs in cancer remain to be established [19]. Alternatively, lysoPCs may act as carriers of fatty acids, and extracellular hydrolization of lysoPC a C18:0 and lysoPC a C18:1, followed by a rapid uptake of the respective fatty acids, i.e. stearic (18:0) and oleic acid (18:1), appears to be a characteristic of solid tumors in mice [20]. This is in line with epidemiologic observations of inverse associations between stearic acid levels and breast [21], prostate [3], and colorectal cancer risk [4]. However, it appears spurious why lysoPC a C16:0, lysoPC a C18:1, and lysoPC a C20:4 concentrations also showed inverse associations with cancer risk in our study, whereas circulating palmitic (16:0), oleic (18:1), and arachidonic acid (20:4)—that were not covered by our assay—were not related to cancer risk in previous epidemiological studies.

Possibly, other degradation products of lysoPCs than fatty acids drive tumorigenesis. Extracellular lysoPCs are converted into lysophosphatidic acid (LPA), which induces tumor growth, by autotaxin (ATX), a secreted lysophospholipase D. Overexpression of ATX and LPA receptors has been proposed to be a common feature of several cancers, and both ATX and LPA receptor knockout mice show lower cancer risk [22–24]. Moreover, lysophosphatidylcholine acyltransferase 1 (LPCAT1), which converts lysoPCs into PCs is overexpressed in several cancers, and increased incorporation of PCs into cell membranes may facilitate proliferation, adhesion, and motility of cancer cells [25–27].

Less is known about the role of PC ae C30:0 in carcinogenesis. Elevated PC ae C30:0 concentrations were detected in plasma of patients with ovarian endometriosis [28]. Even though PC levels were inversely associated with prostate cancer risk in one previous study [3] and have been found to be higher in cancer cells than in non-malignant cells [29–31], a distinct biological function of PC ae C30:0 has not been described and ours was the first prospective study on PC ae C30:0 and cancer to our knowledge.

Levels of lysoPCs and PC ae C30:0 were not related to background factors such as BMI, physical activity, or smoking in our study. While PC ae C30:0 has not been shown to be associated with chronic diseases in previous studies, it may seem noteworthy that lysoPC a C18:2 has been proposed to be a potential pre-diagnostic biomarker of diabetes [32]. At the same time, associations between lysoPC a C18:0 and diabetes risk have not been observed in previous studies [32, 33], and potential mediation of associations between lysoPCs and cancer risk by a pre-diabetic state does therefore not appear to be a valid explanation for the present findings.

A limitation of our study is that only a single blood sample was available; however, reasonable mid-term reliability of metabolite levels over time has been demonstrated in reproducibility studies [34–37]. While we cannot provide data on the stability of the analyzed metabolites in long-term storage at ?196 °C, it has been shown that freeze-and-thaw cycles do not substantially affect most metabolites covered by the kit we used [38, 39]. Longer exposure to room temperature, which may indeed lead to an increase of lysoPC levels [38], was avoided in our study, and the plasma samples of case patients and non-cases used for the present metabolomics project have been stored and prepared under exactly the same conditions. Many of the metabolites measured in our project are not part of metabolomics platforms previously used in other studies, which hampers comparisons across studies and underlines the need for standardization [1]. Undoubtedly, replication of the present associations is needed before metabolites such as lysoPC a C18:0 or PC ae C30:0 may eventually be used as cancer biomarkers. Moreover, our findings require further investigation in mechanistic studies, before more definite conclusions on lysoPCs and PC ae C30:0 in tumorigenesis can be drawn.