Complex Interplay of Genes Underlies Invasiveness in Fibrosarcoma Progression Model

Sarcomas are a heterogeneous group of mesenchymal tumours, with a great variability in their clinical behaviour. While our knowledge of sarcoma initiation has advanced rapidly in recent years, relatively little is known about mechanisms of sarcoma progression. JUN-murine fibrosarcoma progression series consists of four sarcoma cell lines, JUN-1, JUN-2, JUN-2fos-3, and JUN-3. JUN-1 and -2 were established from a single tumour initiated in a H2K/v-jun transgenic mouse, JUN-3 originates from a different tumour in the same animal, and JUN-2fos-3 results from a targeted in vitro transformation of the JUN-2 cell line. The JUN-1, -2, and -3 cell lines represent a linear progression from the least transformed JUN-2 to the most transformed JUN-3, with regard to all the transformation characteristics studied, while the JUN-2fos-3 cell line exhibits a unique transformation mode, with little deregulation of cell growth and proliferation, but pronounced motility and invasiveness. The invasive sarcoma sublines JUN-2fos-3 and JUN-3 show complex metabolic profiles, with activation of both mitochondrial oxidative phosphorylation and glycolysis and a significant increase in spared respiratory capacity. The specific transcriptomic profile of invasive sublines features very complex biological relationships across the identified genes and proteins, with accentuated autocrine control of motility and angiogenesis. Pharmacologic inhibition of one of the autocrine motility factors identified, Ccl8, significantly diminished both motility and invasiveness of the highly transformed fibrosarcoma cell. This progression series could be greatly valuable for deciphering crucial aspects of sarcoma progression and defining new prognostic markers and potential therapeutic targets.

Paracrine and autocrine control of insulin secretion in human islets: evidence and pending questions

Insulin secretion by β-cells is largely controlled by circulating nutrients, hormones and neurotransmitters. However, recent years have witnessed the multiplication of studies investigating whether local regulation also takes place within pancreatic islets, in which β-cells cohabit with several other cell types. The cell composition and architectural organization of human islets differ from those of rodent islets and are particularly favorable to cellular interactions. An impressive number of hormonal (glucagon, glucagon-like peptide1, somatostatin...) and non-hormonal products (ATP, acetylcholine, gamma-aminobutyric acid, dopamine...) are released by islet cells and have been implicated in a local control of insulin secretion. This review analyzes reports directly testing paracrine and autocrine control of insulin secretion in isolated human islets. Many of these studies were designed on a background of information collected in rodent islets. However, the perspective of the review is not to highlight species similarities or specificities but to contrast established and speculative mechanisms in human islets. It will be shown that the current evidence is convincing only for a minority of candidates for a paracrine function whereas arguments supporting a physiological role of others do not stand up to scrutiny. Several pending questions await further investigation.

Role of GnRH Isoforms in Paracrine/Autocrine Control of Zebrafish (Danio rerio) Spermatogenesis

It is well established that hypothalamic GnRH (gonadotropin-releasing hormone) is one of the key peptides involved in the neuroendocrine control of testicular development and spermatogenesis. However, the role of GnRH as a paracrine regulator of testicular function has not been fully investigated. The present study demonstrates the presence of GnRH and its receptors in the zebrafish (Danio rerio) testis, and provides information on direct action of native GnRH isoforms (GnRH2 and GnRH3) on different stages of spermatogenesis in this model. Both GnRH2 and GnRH3 stimulated basal spermatogenesis by increasing numbers of type Aund spermatogonia, spermatozoa, and testosterone release, and in this study GnRH2 exerted higher relative activity than GnRH3. Next, we evaluated the effects of GnRH isoforms on human chorionic gonadotropin (hCG)- and follicle-stimulating hormone (Fsh)-induced spermatogenesis. The 2 GnRH isoforms were found to have different effects on Fsh- and hCG-induced response depending on the stage of spermatogenesis and concentration of the peptides. The results provide strong support for the hypothesis that locally produced GnRH2 and GnRH3 are important components of the complex multifactorial system that regulates testicular germinal cell development and function in adult zebrafish.

High-endothelial cell-derived S1P regulates dendritic cell localization and vascular integrity in the lymph node

While the sphingosine-1-phosphate (S1P)/sphingosine-1-phosphate receptor-1 (S1PR1) axis is critically important for lymphocyte egress from lymphoid organs, S1PR1-activation also occurs in vascular endothelial cells (ECs), including those of the high-endothelial venules (HEVs) that mediate lymphocyte immigration into lymph nodes (LNs). To understand the functional significance of the S1P/S1PR1-Gi axis in HEVs, we generated Lyve1;Spns2Δ/Δ conditional knockout mice for the S1P-transporter Spinster-homologue-2 (SPNS2), as HEVs express LYVE1 during development. In these mice HEVs appeared apoptotic and were severely impaired in function, morphology and size; leading to markedly hypotrophic peripheral LNs. Dendritic cells (DCs) were unable to interact with HEVs, which was also observed in Cdh5CRE-ERT2;S1pr1Δ/Δ mice and wildtype mice treated with S1PR1-antagonists. Wildtype HEVs treated with S1PR1-antagonists in vitro and Lyve1-deficient HEVs show severely reduced release of the DC-chemoattractant CCL21 in vivo. Together, our results reveal that EC-derived S1P warrants HEV-integrity through autocrine control of S1PR1-Gi signaling, and facilitates concomitant HEV-DC interactions.