from the very beginning of transformation. questions, Feng [4] used genetic tools and chemical inhibitors to image cancer and swelling in transparent zebrafish larvae. These authors used a novel model of oncogene-induced transformation that focuses on a human population of very superficial cells (the mucous-producing cells of the skin). These solitary cells, closely related to sebaceous gland mucous cells in mammals and sparse in the epidermis of zebrafish larvae, respond to oncogene manifestation by quick, uncontrolled proliferation [5]. In their earlier study, Feng [3] experienced documented that the ability of transformed cells to attract leukocytes through a H2O2 transmission was beneficial to tumor cells, Methoxy-PEPy given that, in the absence of leukocytes, transformed cells did not proliferate and instead underwent apoptosis. The big query that remained unsolved with this earlier study was the nature of the trophic signal released by leukocytes that permitted growth of the transformed cells. In the new work, the search for the trophic transmission ended with an interesting candidate, the eicosanoid prostaglandin E2 (PGE2), which has been involved in swelling and malignancy (examined in [6]) and has a very long history of helping tumor cells to survive, proliferate and invade [7]. Besides confirming the usual suspect inside a novel model of cancer-induced swelling, the strongest points of the study lie in the use of combined genetic methods and small chemical inhibitors to confirm the involvement of PGE2 and its receptor E-prostanoid 1 (EP1) in the trophic support to transformed cells. The authors use chemical inhibitors and morpholinos to knock down the enzymatic activities generating PGE2 and pinpoint the specific pathway namely microsomal rather than cytoplasmic PGEs used by leukocytes to produce PGE2 in the vicinity of Ras-transformed cells (Number 1A). To conquer the problem of early lethality due to morpholino-mediated ablation of microsomal PGEs, they rescued PGE2 signaling during the 1st 9 hours of development by incubating embryos with the long-acting derivative of PGE2, 16,16-dimethyl-PGE2 (dmPGE2). This trick allowed them to study the effects of eliminating PGE2 when oncogene-transformed cells most needed it, i.e. KLF1 from the very beginning of transformation. Elegant lineage ablation studies and live observations in neutrophil- and macrophage-specific transgenic lines shed light on which of the two leukocyte cell populations contribute trophic Methoxy-PEPy PGE2 to malignancy cells. The solution is definitely that PGE2 is the only trophic signal produced by macrophages, whereas neutrophils contribute additional as yet unknown trophic products. Because of these detailed characterizations of the enzymatic pathway and of the innate immune cell populations involved, the study is likely to provide significant suggestions for improving the search for specific drugs focusing on the inflammationCcancer link. Open in a separate window Number 1 PGE2 produced by leukocytes near malignancy cells functions as a pro-survival transmission through the EP1 receptor. (A) The pathways involved in eicosanoid rate of metabolism in the cytoplasm of a leukocyte approaching a malignancy cell are demonstrated, together with the chemical or genetic (morpholino) inhibitors that block specific enzymes. Methoxy-PEPy (B) Different PGE2 receptors (EP1C4) and their association with specific G-protein subunits lead to the activation of different pathways. Protein kinase A (PKA) activation downstream of EP2 Methoxy-PEPy or EP4 signaling stabilizes -catenin (Wnt) and P-ERK (Ras) signals to increase proliferation. EP1 receptors were also found in a perinuclear compartment, where other, as yet unfamiliar mechanisms may lead to transcriptional and epigenetic changes. Observe text for details and referrals. Several questions are raised by this study and remain unresolved, with the fascinating possibility of using the same or related models to find the answers. First of all, how is usually PGE2, signaling through the EP1 receptor, sustaining malignancy growth? You will find studies reporting a role of PGE2 in promoting Akt phosphorylation in neuroblastoma cells through calcium waves and cyclic AMP (cAMP) production [8] through different PGE2 receptors. The four EP receptors (EP1C4) have multiple localizations (being found in the cell membrane, cytoplasm or nucleus), each related to specific downstream pathways in PGE2 signaling (Physique 1B). Although these receptors are not mutually unique, their Methoxy-PEPy combinatorial expression or activation may lead to different outcomes. The possibility of using an model equipped with a wealth of genetic and chemical biology.