Abstract
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.
Highlights
Metastasis is responsible for more than 90% of cancer-associated mortality, and the need to prevent metastasis is one of the therapeutic priorities in clinical oncology [1]
We report that lung cancer (LC) cells express several functional BphL receptors as well as several enzymes involved in their metabolism and that bioactive phospholipids (BphsLs) are potent chemokinetic and adhesion factors for these cells
Since the pro-migratory effect of LPC is assigned to lysophosphatidic acid (LPA), which is derived from LPC in an autotaxin (ATX)-dependent manner [20], and since, in addition to “classical” LPA receptors, LPC activates G2A and GPR4 receptors, we evaluated the expression of the mRNAs for ATX, G2A, and GPR4 in human LC cells [21, 22]
Summary
Metastasis is responsible for more than 90% of cancer-associated mortality, and the need to prevent metastasis is one of the therapeutic priorities in clinical oncology [1]. What is not often emphasized, these chemoattractants for LC cells are detected in biological fluids and tissues at much lower concentrations than those employed routinely in assays to assess the migration of LC cells [7,8,9]. This was the reason why we began a search for other more relevant chemoattractants that could induce metastasis of these cells in in vivo situations. Surprisingly the binding receptor/s for a very potent bioactive phospholipid chemotractant - that is C1P, have not been identified yet
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