Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.
Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan.
Cancer Med. 2022 Sep;11(18):3491-3507. doi: 10.1002/cam4.4699. Epub 2022 Mar 22.
Numerous studies have investigated the possible involvement of eicosanoids, lysophospholipids, and sphingolipids in cancer. We considered that comprehensive measurement of these lipid mediators might provide a better understanding of their involvement in the pathogenesis of cancer. In the present study, we attempted to elucidate the modulations of sphingolipids, lysophospholipids, diacyl-phospholipids, eicosanoids, and related mediators in cancer by measuring their levels simultaneously by a liquid chromatography-mass spectrometry method in a mouse model of carcinomatous peritonitis.
We investigated the modulations of these lipids in both ascitic fluid and plasma specimens obtained from Balb/c mice injected intraperitoneally with Colon-26 cells, as well as the modulations of the lipid contents in the cancer cells obtained from the tumor xenografts.
The results were as follows: the levels of sphingosine 1-phosphate were increased, while those of lysophosphatidic acid (LysoPA), especially unsaturated long-chain LysoPA, tended to be increased, in the ascitic fluid. Our findings suggested that ceramides, sphingomyelin, and phosphatidylcholine, their precursors, were supplied by both de novo synthesis and from elsewhere in the body. The levels of lysophosphatidylserine (LysoPS), lysophosphatidylinositol, lysophosphatidylglycerol, and lysophosphatidylethanolamine were also increased in the ascitic fluid, while those of phosphatidylserine (PS), a precursor of LysoPS, were markedly decreased. The levels of arachidonic acid derivatives, especially PGE2-related metabolites, were increased, while the plasma levels of eicosanoids and related mediators were decreased. Comprehensive statistical analyses mainly identified PS in the ascitic fluid and eicosanoids in the plasma as having highly negative predictive values for cancer.
The results proposed many unknown associations of lipid mediators with cancer, underscoring the need for further studies. In particular, the PS/LysoPS pathway could be a novel therapeutic target, and plasma eicosanoids could be useful biomarkers for cancer.
许多研究已经探讨了类二十烷酸、溶血磷脂和神经鞘脂在癌症中的可能作用。我们认为，对这些脂质介质的综合测量可能会更好地了解它们在癌症发病机制中的作用。在本研究中，我们试图通过液相色谱-质谱法同时测量这些脂质在癌性腹膜炎小鼠模型中的水平，以阐明它们在癌症中的调节作用。
我们研究了腹腔液和血浆标本中这些脂质的调节作用，这些标本是从腹腔内注射 Colon-26 细胞的 Balb/c 小鼠中获得的，以及从肿瘤异种移植中获得的癌细胞中的脂质含量调节作用。
结果如下：在腹腔液中，1-磷酸鞘氨醇的水平增加，而溶血磷脂酸（LysoPA），特别是不饱和长链 LysoPA，倾向于增加。我们的研究结果表明，神经酰胺、神经鞘磷脂和磷脂酰胆碱的前体，既可以通过从头合成，也可以从身体其他部位提供。溶血磷脂酰丝氨酸（LysoPS）、溶血磷脂酰肌醇、溶血磷脂酰甘油和溶血磷脂酰乙醇胺的水平也在腹腔液中增加，而 LysoPS 的前体磷脂酰丝氨酸（PS）的水平则显著降低。花生四烯酸衍生物的水平，特别是 PGE2 相关代谢物的水平增加，而血浆中类二十烷酸和相关介质的水平降低。综合统计分析主要确定了腹腔液中的 PS 和血浆中的类二十烷酸及其相关介质对癌症具有高度负预测值。
这些结果提出了许多脂质介质与癌症之间未知的关联，强调了进一步研究的必要性。特别是 PS/LysoPS 途径可能是一个新的治疗靶点，而血浆类二十烷酸可能是癌症有用的生物标志物。
