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Saturated and mono-unsaturated lysophosphatidylcholine metabolism in tumour cells: a potential therapeutic target for preventing metastases.

Raynor A, Jantscheff P, Ross T, Schlesinger M, Wilde M, Haasis S, Dreckmann T, Bendas G, Massing U - Lipids Health Dis (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Lipids & Liposomes, Tumor Biology Center, Clinical Research, Breisacher Str. 117, 79106, Freiburg, Germany. raynor@tumorbio.uni-freiburg.de.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Proposed uptake/metabolism of LysoPC in tumour cells. The majority of LysoPC is extracellularly degraded to GlyceroPC and FFA by a LysoPC degrading factor. This factor – probably a LysoPLA – is partly released into the supernatant of the tumour cells. The resulting extracellular FFA can subsequently be taken up and incorporated into membrane PL and neutral lipids. Excess of neutral lipids can be stored as LD. Another possible uptake route for LysoPC is its incorporation into the cellular membrane as a whole molecule, where it becomes part of the Lands’ Cycle: the deacylation and reacylation process
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Fig9: Proposed uptake/metabolism of LysoPC in tumour cells. The majority of LysoPC is extracellularly degraded to GlyceroPC and FFA by a LysoPC degrading factor. This factor – probably a LysoPLA – is partly released into the supernatant of the tumour cells. The resulting extracellular FFA can subsequently be taken up and incorporated into membrane PL and neutral lipids. Excess of neutral lipids can be stored as LD. Another possible uptake route for LysoPC is its incorporation into the cellular membrane as a whole molecule, where it becomes part of the Lands’ Cycle: the deacylation and reacylation process

Mentions: Our studies concerning the fate of the extracellular LysoPC and the increase of the LysoPC bound FA in the cellular lipids revealed (i) that incubation with saturated LysoPC species as well as the corresponding FFA results in an almost identical incorporation of the respective FA within the cellular lipids, and (ii) that removal of LysoPC from the cellular supernatant is accompanied by a corresponding increase of extracellular FFA. Obviously, the main mechanism for the cellular uptake of LysoPC bound FA consists of a rapid cleavage of the sn-1-ester bond of LysoPC by a LysoPLA activity followed by the rapid cellular uptake of the resulting FFA, supported by the high FFA gradient between the intracellular and extracellular environment and the rapid transmembrane movement of FFA [21]. High LysoPLA activities have been observed in certain mammalian cells and tissues (e.g. liver, gastric mucosa, kidney, brain, lung, and macrophages) [22, 23]. Data for LysoPLA activities in tumour tissues/cells are not yet available. The proposed LysoPLA activity that we found in tumour cells is at least partly released into the cell culture supernatant, as LysoPC degradation continues when the supernatant is further incubated cell-free. A model summarizing these processes is suggested in Fig. 9.Fig. 9


Saturated and mono-unsaturated lysophosphatidylcholine metabolism in tumour cells: a potential therapeutic target for preventing metastases.

Raynor A, Jantscheff P, Ross T, Schlesinger M, Wilde M, Haasis S, Dreckmann T, Bendas G, Massing U - Lipids Health Dis (2015)

Proposed uptake/metabolism of LysoPC in tumour cells. The majority of LysoPC is extracellularly degraded to GlyceroPC and FFA by a LysoPC degrading factor. This factor – probably a LysoPLA – is partly released into the supernatant of the tumour cells. The resulting extracellular FFA can subsequently be taken up and incorporated into membrane PL and neutral lipids. Excess of neutral lipids can be stored as LD. Another possible uptake route for LysoPC is its incorporation into the cellular membrane as a whole molecule, where it becomes part of the Lands’ Cycle: the deacylation and reacylation process
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4499168&req=5

Fig9: Proposed uptake/metabolism of LysoPC in tumour cells. The majority of LysoPC is extracellularly degraded to GlyceroPC and FFA by a LysoPC degrading factor. This factor – probably a LysoPLA – is partly released into the supernatant of the tumour cells. The resulting extracellular FFA can subsequently be taken up and incorporated into membrane PL and neutral lipids. Excess of neutral lipids can be stored as LD. Another possible uptake route for LysoPC is its incorporation into the cellular membrane as a whole molecule, where it becomes part of the Lands’ Cycle: the deacylation and reacylation process
Mentions: Our studies concerning the fate of the extracellular LysoPC and the increase of the LysoPC bound FA in the cellular lipids revealed (i) that incubation with saturated LysoPC species as well as the corresponding FFA results in an almost identical incorporation of the respective FA within the cellular lipids, and (ii) that removal of LysoPC from the cellular supernatant is accompanied by a corresponding increase of extracellular FFA. Obviously, the main mechanism for the cellular uptake of LysoPC bound FA consists of a rapid cleavage of the sn-1-ester bond of LysoPC by a LysoPLA activity followed by the rapid cellular uptake of the resulting FFA, supported by the high FFA gradient between the intracellular and extracellular environment and the rapid transmembrane movement of FFA [21]. High LysoPLA activities have been observed in certain mammalian cells and tissues (e.g. liver, gastric mucosa, kidney, brain, lung, and macrophages) [22, 23]. Data for LysoPLA activities in tumour tissues/cells are not yet available. The proposed LysoPLA activity that we found in tumour cells is at least partly released into the cell culture supernatant, as LysoPC degradation continues when the supernatant is further incubated cell-free. A model summarizing these processes is suggested in Fig. 9.Fig. 9

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Lipids & Liposomes, Tumor Biology Center, Clinical Research, Breisacher Str. 117, 79106, Freiburg, Germany. raynor@tumorbio.uni-freiburg.de.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus