Raynor Anna, Jantscheff Peter, Ross Thomas, Schlesinger Martin, Wilde Maurice, Haasis Sina, Dreckmann Tim, Bendas Gerd, Massing Ulrich
Department of Lipids & Liposomes, Tumor Biology Center, Clinical Research, Breisacher Str. 117, 79106, Freiburg, Germany.
ProQinase GmbH, Breisacher Str. 117, 79106, Freiburg, Germany.
Lipids Health Dis. 2015 Jul 11;14:69. doi: 10.1186/s12944-015-0070-x.
BACKGROUND: Metastasis is the leading cause of mortality in malignant diseases. Patients with metastasis often show reduced Lysophosphatidylcholine (LysoPC) plasma levels and treatment of metastatic tumour cells with saturated LysoPC species reduced their metastatic potential in vivo in mouse experiments. To provide a first insight into the interplay of tumour cells and LysoPC, the interactions of ten solid epithelial tumour cell lines and six leukaemic cell lines with saturated and mono-unsaturated LysoPC species were explored. METHODS: LysoPC metabolism by the different tumour cells was investigated by a combination of cell culture assays, GC and MS techniques. Functional consequences of changed membrane properties were followed microscopically by detecting lateral lipid diffusion or cellular migration. Experimental metastasis studies in mice were performed after pretreatment of B16.F10 melanoma cells with LysoPC and FFA, respectively. RESULTS: In contrast to the leukaemic cells, all solid tumour cells show a very fast extracellular degradation of the LysoPC species to free fatty acids (FFA) and glycerophosphocholine. We provide evidence that the formerly LysoPC bound FFA were rapidly incorporated into the cellular phospholipids, thereby changing the FA-compositions accordingly. A massive increase of the neutral lipid amount was observed, inducing the formation of lipid droplets. Saturated LysoPC and to a lesser extent also mono-unsaturated LysoPC increased the cell membrane rigidity, which is assumed to alter cellular functions involved in metastasis. According to that, saturated and mono-unsaturated LysoPC as well as the respective FFA reduced the metastatic potential of B16.F10 cells in mice. Application of high doses of liposomes mainly consisting of saturated PC was shown to be a suitable way to strongly increase the plasma level of saturated LysoPC in mice. CONCLUSION: These data show that solid tumours display a high activity to hydrolyse LysoPC followed by a very rapid uptake of the resulting FFA; a mechanistic model is provided. In contrast to the physiological mix of LysoPC species, saturated and mono-unsaturated LysoPC alone apparently attenuate the metastatic activity of tumours and the artificial increase of saturated and mono-unsaturated LysoPC in plasma appears as novel therapeutic approach to interfere with metastasis.
背景：转移是恶性疾病死亡的主要原因。发生转移的患者通常血浆溶血磷脂酰胆碱（LysoPC）水平降低，并且在小鼠实验中，用饱和LysoPC处理转移性肿瘤细胞可降低其体内转移潜能。为了初步了解肿瘤细胞与LysoPC之间的相互作用，研究了十种实体上皮肿瘤细胞系和六种白血病细胞系与饱和及单不饱和LysoPC的相互作用。 方法：通过细胞培养试验、气相色谱和质谱技术相结合的方法，研究不同肿瘤细胞的LysoPC代谢。通过检测侧向脂质扩散或细胞迁移，在显微镜下观察膜性质改变的功能后果。分别用LysoPC和游离脂肪酸（FFA）预处理B16.F10黑色素瘤细胞后，在小鼠体内进行实验性转移研究。 结果：与白血病细胞不同，所有实体肿瘤细胞均显示出LysoPC迅速在细胞外降解为游离脂肪酸（FFA）和甘油磷酸胆碱。我们提供的证据表明，先前与LysoPC结合的FFA迅速掺入细胞磷脂中，从而相应地改变了脂肪酸组成。观察到中性脂质数量大量增加，诱导了脂滴的形成。饱和LysoPC以及程度稍轻的单不饱和LysoPC增加了细胞膜的刚性，这被认为会改变与转移有关的细胞功能。据此，饱和和单不饱和LysoPC以及相应的FFA降低了B16.F10细胞在小鼠体内的转移潜能。结果表明，应用高剂量主要由饱和磷脂酰胆碱组成的脂质体是大幅提高小鼠血浆中饱和LysoPC水平的合适方法。 结论：这些数据表明，实体瘤具有很高的水解LysoPC活性，随后会迅速摄取产生的FFA；并提供了一个机制模型。与LysoPC种类的生理混合物不同，单独的饱和和单不饱和LysoPC显然会减弱肿瘤的转移活性，血浆中饱和和单不饱和LysoPC的人为增加似乎是一种干扰转移的新治疗方法。
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