Research Papers:

Novel pleiotropic effects of bioactive phospholipids in human lung cancer metastasis

Gabriela Schneider, Zachariah Payne Sellers, Kamila Bujko, Sham S. Kakar, Magda Kucia and Mariusz Z. Ratajczak _

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Oncotarget. 2017; 8:58247-58263. https://doi.org/10.18632/oncotarget.17461

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Gabriela Schneider1, Zachariah Payne Sellers1, Kamila Bujko1, Sham S. Kakar2, Magda Kucia1,3 and Mariusz Z. Ratajczak1,3

1Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA

2Department of Physiology and James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA

3Department of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland

Correspondence to:

Mariusz Z. Ratajczak, email: [email protected]

Gabriela Schneider, email: [email protected]

Keywords: bioactive phospholipids, priming, HGF/SF, lung cancer, metastasis

Received: March 03, 2017     Accepted: April 15, 2017     Published: April 27, 2017


We previously proposed that one of the unwanted side effects of chemotherapy and radiotherapy is the increase in several peptide- and non-peptide based chemoattractants in damaged tissues, leading to induction of a prometastatic microenvironment for remaining cancer cells. Herein, we turned out our attention to a potential role of bioactive phospholipids (BphsLs), such as sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), lysophosphatidylcholine (LPC), and lysophosphatidic acid (LPA) in lung cancer (LC) metastasis. We report that LC cells express several functional BphL receptors (for S1P, LPC, and LPA) as well as several enzymes involved in their metabolism and that BphsLs are potent chemokinetic and adhesion factors for these cells. We also demonstrate for the first time the novel role of C1P as a prometastatic factor in LC cells. In addition to their chemokinetic activities, BphsLs also sensitize or prime the chemotactic responsiveness of LC cells to known prometastatic factors such as hepatocyte growth factor/scatter factor (HGF/SF). Thus, for the first time we demonstrate a prometastatic effect that is based on the priming of a cell’s responsiveness to chemotactic factors by chemokinetic factors. To our surprise, none of the bioactive lipids induced proliferation of LC cells or ameliorated toxic effects of vincristine treatment. Interestingly, BphsLs increase adhesion of LC cells to bone marrow-derived stromal cells and stimulate these cells to release ExNs, which additionally increase LC cell motility. In conclusion, our results show that BphsLs are important modulators of prometastatic environment. Therefore, their inhibitors could be considered as potential anti-metastatic drug candidates to be included as a part of post radio- and/or chemo- therapy treatment.

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