Schneider Gabriela, Sellers Zachariah Payne, Bujko Kamila, Kakar Sham S, Kucia Magda, Ratajczak Mariusz Z
Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
Department of Physiology and James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
Oncotarget. 2017 Apr 27;8(35):58247-58263. doi: 10.18632/oncotarget.17461. eCollection 2017 Aug 29.
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.
我们之前提出，化疗和放疗的不良副作用之一是受损组织中几种基于肽和非肽的趋化因子增加，从而导致为残留癌细胞诱导出促转移微环境。在此，我们将注意力转向生物活性磷脂（BphsLs），如1 -磷酸鞘氨醇（S1P）、1 -磷酸神经酰胺（C1P）、溶血磷脂酰胆碱（LPC）和溶血磷脂酸（LPA）在肺癌（LC）转移中的潜在作用。我们报告称，LC细胞表达几种功能性BphL受体（针对S1P、LPC和LPA）以及几种参与其代谢的酶，并且BphsLs是这些细胞强有力的化学动力学和黏附因子。我们还首次证明了C1P作为LC细胞中促转移因子的新作用。除了其化学动力学活性外，BphsLs还使LC细胞对已知的促转移因子如肝细胞生长因子/散射因子（HGF/SF）的趋化反应敏感或引发其反应。因此，我们首次证明了一种基于化学动力学因子引发细胞对趋化因子反应的促转移效应。令我们惊讶的是，没有一种生物活性脂质能诱导LC细胞增殖或改善长春新碱治疗的毒性作用。有趣的是，BphsLs增加了LC细胞与骨髓来源的基质细胞的黏附，并刺激这些细胞释放外泌体（ExNs），这进一步增加了LC细胞的运动性。总之，我们的结果表明BphsLs是促转移环境的重要调节因子。因此，它们的抑制剂可被视为潜在的抗转移药物候选物，作为放疗和/或化疗后治疗的一部分。
