The role of sphingosine-1 phosphate and ceramide-1 phosphate in trafficking of normal stem cells and cancer cells

Abstract

Introduction A common feature of many types of cells is their responsiveness to chemotactic gradients of factors for which they express the corresponding receptors. The most studied chemoattractants so far are peptide-based growth factors and a family of cytokines endowed with strong chemotactic properties, called chemokines. However, additional evidence has accumulated that, in addition to these peptide-based chemoattractants, an important role in cell migration is played by bioactive lipids. Areas covered Solid evidence has accumulated that two bioactive phosphorylated sphingolipids that are derivatives of sphingolipid metabolism, namely sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), are potent chemoattractants for a variety of cells. In this review, we will discuss the effect of these two phosphorylated sphingolipids on the trafficking of normal and malignant cells, and, in particular, we will focus on their role in trafficking of normal hematopoietic stem/progenitor cells. Unlike other mediators, S1P under steady state conditions maintain a steep gradient between interstitial fluid and peripheral blood and lymph across the endothelial barrier, which is important in the egress of cells from bone marrow. Both S1P and C1P may be upregulated in damaged tissues, which may result in reversal of this gradient. Expert opinion S1P and C1P are important regulators of the trafficking of normal and malignant cells, and modification of their biological effects will have important applications in optimizing stem cell mobilization and homing, tissue organ/regeneration, and preventing cancer metastasis.

Ceramide 1-Phosphate: A Mediator of Inflammatory Responses

“…It was concluded that the C1P receptor could be an important drug target for treatment of illnesses in which macrophage migration is a major cause of pathology, as it occurs in inflammatory responses or tumor metastasis. The chemotactic effects of C1P have been confirmed in different biological systems, including homing of hematopoietic stem/progenitor cells to the bone marrow or multipotent stromal cell and endothelial progenitor cell migration ( (Karapetyan et al 2013;Kim et al 2012;Ratajczak et al 2010). Of interest, it was also observed that S1P and C1P stimulated migration of bone marrow-derived stem cells in patients suffering from acute myocardial infarction.…”

“…CerK has been also implicated in neuroblastoma cell proliferation, suggesting that inhibition of this enzyme may be a possible target for anticancer therapy of human neuroblastoma (Bini et al 2012). On the other hand, C1P has been demonstrated to mediate inflammatory responses (Chalfant and Spiegel 2005;HinkovskaGalcheva et al 2005) and to promote cell migration Granado et al 2009b;Karapetyan et al 2013;Kim et al 2012;Ratajczak et al 2010), an action that is also associated to inflammation. Utilizing a combination of pharmacological and molecular approaches, Barth and co-coworkers demonstrated that in human neuroblastoma cells, CerK activity was strictly required for activation of various oxidoreductases, including reactive oxygen species (ROS) producing NADPH oxidase (NOX), cyclooxygenase (COX), and 5-lipooxygenase (5-LOX), which are enzymes involved in pro-inflammatory processes (Barth et al 2012).…”

Current Developments in Mobilization of Hematopoietic Stem and Progenitor Cells and Their Interaction with Niches in Bone Marrow

“…These include the sphingolipids sphingosine-1-phosphate (S1P) [100,[125][126][127][128] that couple to G protein-coupled sphingosine 1-phosphate receptor 1 (S1P1), and ceramide-1-phosphate (C1P) which acts via an hitherto unknown receptor [127,129]. Moreover, extracellular nucleotides, such as adenosine triphosphate (ATP) or uridine triphosphate (UTP) [130] and divalent cation Ca 2+ and the CaR, and H + [131,132] regulate adhesion molecules on the surface of the HSPCs as well as on certain cells of the stem cell niches.…”

“…Both these mechanisms may desensitize responses to potential homing gradients of these bioactive lipids [129].…”

Sphingosine 1-Phosphate as a Link between Blood Coagulation and Inflammation

“…Extracellular S1P regulates proliferation and migration of divers cell types such as vascular cells but also in several tumor types [21] and is a critical regulator of the physiology of the immune and vascular systems, i.e. regulates lymphocyte egress, angiogenesis and platelet maturation and stem cell functions [25,36,37,38]. In addition, recent studies highlight numerous interactions between blood coagulation and the S1P signaling system [18].…”