540 Chemie und zugeordnete Wissenschaften
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The sphingolipid sphingosine-1-phosphate (S1P) promotes tumor development through a variety of mechanisms including promoting proliferation, survival, and migration of cancer cells. Moreover, S1P emerged as an important regulator of tumor microenvironmental cell function by modulating, among other mechanisms, tumor angiogenesis. Therefore, S1P was proposed as a target for anti-tumor therapy. The clinical success of current cancer immunotherapy suggests that future anti-tumor therapy needs to consider its impact on the tumor-associated immune system. Hereby, S1P may have divergent effects. On the one hand, S1P gradients control leukocyte trafficking throughout the body, which is clinically exploited to suppress auto-immune reactions. On the other hand, S1P promotes pro-tumor activation of a diverse range of immune cells. In this review, we summarize the current literature describing the role of S1P in tumor-associated immunity, and we discuss strategies for how to target S1P for anti-tumor therapy without causing immune paralysis.
MicroRNAs have been projected as promising tools for diagnostic and prognostic purposes in cancer. More recently, they have been highlighted as RNA therapeutic targets for cancer therapy. Though miRs perform a generic function of post-transcriptional gene regulation, their utility in RNA therapeutics mostly relies on their biochemical nature and their assembly with other macromolecules. Release of extracellular miRs is broadly categorized into two different compositions, namely exosomal (extracellular vesicles) and non-exosomal. This nature of miRs not only affects the uptake into target cells but also poses a challenge and opportunity for RNA therapeutics in cancer. By virtue of their ability to act as mediators of intercellular communication in the tumor microenvironment, extracellular miRs perform both, depending upon the target cell and target landscape, pro- and anti-tumor functions. Tumor-derived miRs mostly perform pro-tumor functions, whereas host cell- or stroma-derived miRs are involved in anti-tumor activities. This review deals with the recent understanding of exosomal and non-exosomal miRs in the tumor microenvironment, as a tool for pro- and anti-tumor activity and prospective exploit options for cancer therapy.
S1P provokes tumor lymphangiogenesis via macrophage-derived mediators such as IL-1β or lipocalin-2
(2017)
A pleiotropic signaling lipid, sphingosine-1-phosphate (S1P), has been implicated in various pathophysiological processes supporting tumor growth and metastasis. However, there are only a few descriptive studies suggesting a role of S1P in tumor lymphangiogenesis, which is critical for tumor growth and dissemination. Corroborating own data, the literature suggests that apoptotic tumor cell-derived S1P alters the phenotype of tumor-associated macrophages (TAMs) to gain protumor functions. However, mechanistically, the role of TAM-induced lymphangiogenesis has only been poorly described, mostly linked to the production of lymphangiogenic factors such as vascular endothelial growth factor C (VEGF-C) and VEGF-D, or transdifferentiation into lymphatic endothelial cells. Recent findings highlight a rather underappreciated role of S1P in tumor lymphangiogenesis, referring to the production of interleukin-1β (IL-1β) and lipocalin-2 (LCN2) by a tumor-promoting macrophage phenotype. In this review, we aim to provide to the readers with the current understanding of the molecular mechanism how apoptotic cell-derived S1P triggers TAMs to promote lymphangiogenesis.