Ko HM, Seo KH, Han SJ, Ahn KY, Choi IH, Koh GY, et al. with platelet activating factor antagonists could be a promising strategy for cancer treatment. synthesis, which is responsible for the functional regulation of plasma membranes 11,12. During inflammation, large amounts of PAF are generated, which occurs through the remodeling pathway, where alkyl-acyl-glycerophosphocholines (GPC) are converted to PAF via the concerted action of phospholipase A2 and PAF-acetyltransferases (LPCATs). In addition to the PAF generated by enzymatic processes, a wide range of oxidized phospholipids that bind to the PAF receptor (PAFR) are generated by oxidative stress 13,14. Because these phospholipids can activate downstream signaling Bay 65-1942 HCl cascades similar to native PAF, we will use the designation PAFR agonists for all these lipids. The receptor that binds PAF is usually a GPCR (G-protein coupled receptor), cloned by Sugimoto et al. 15, and its activation induces different effects depending on the cell type. PAFR was initially described in macrophages, polymorphonuclear leukocytes, and endothelial cells, among others 2-4. This receptor is also expressed in some tumor cells, and PAFR agonists are generated in the tumor microenvironment, where they exert tumor-promoting effects that are dependent on the direct effect on tumor cells or cells from the tumor microenvironment. In this review, we will first discuss the effects of PAF in tumor cells and then the PAF effects on cells from the tumor microenvironment, such as macrophages and endothelial cells. Finally, the effect of PAFR antagonists on cancer treatment and in tumor cell repopulation after radio- and chemotherapy will be addressed. PAFR AND TUMOR CELLS The expression of PAFR is usually elevated in MAG several human tumor lineages [e.g., Kaposi’s sarcoma cells 16, the endometrial cancer cell line HEC-1A 17, epidermoid carcinoma (A431 cells) 18, the stomach cancer cell line JR-St 19, and N1E-115 neuroblastoma cells 20]. High amounts of PAFR transcripts 1 and 2 were found in human hepatocellular carcinoma 21 and gastric adenocarcinoma 22. In tumor cells, PAFR activation through G-proteins and tyrosine kinases is usually transduced to downstream pathways, including NFkB, MAPKs, AKT, PI3 kinase and Src 3,23. Together, these PAFR-activated pathways play a central role in oncogenic processes by inducing tumor cell proliferation. PAF has been reported to promote non-small cell lung cancer (NSCLC) progression and metastasis by initiating a forward feedback loop between PAFR and STAT3 24. PAFR activation also inhibits PTEN activity, leading to phosphorylation of the PI3K and ERK pathways that are critical signals for survival, proliferation and differentiation of tumor cells Bay 65-1942 HCl 25. The role of PAF in tumor cell survival, proliferation and migration was also shown in ovarian cancer. Aponte et al. 26 found increased degrees of PAFR in serous ovarian tumors in comparison to benign and mucinous tumors. The writers demonstrated that in serous ovarian tumor cells, PAF promotes Bay 65-1942 HCl cell proliferation and, in the molecular level, PAFR activation was followed by phosphorylation of EGFR, Src, Paxillin and FAK. A couple of years later on, EGF binding towards the EGF receptor was proven to transactivate PAFR, resulting in cPLA2 PAF and activation production in ovarian tumor cells 27. In another scholarly study, the same writers 28 confirmed that both PAFR and EGFR signaling pathways promote tumor cell success and migration with this tumor type which the combined focusing on of both receptors considerably reduced tumor development and development in nude mice. In major dental squamous cell carcinoma (OSCC), the enzyme in charge of PAF synthesis, LPCAT1, can be overexpressed in comparison to that in regular tissue, and its own silencing reduced tumor cell invasiveness and proliferation 29, indicating that the PAF/PAFR axis is in charge of suffered prosurvival and proliferative signaling in malignant cells. PAF also plays a part in the malignant advancement of esophageal squamous cell carcinoma by Bay 65-1942 HCl stimulating PI3K/AKT activation 30. Blockade from the PAFR pathway inhibits tumor development of breast tumor 25, prostate tumor 31, and Kaposi’s sarcoma 32. These results had been from the inhibition of tumor angiogenesis 33. Co-workers and Bussolati proven that breasts tumor cells (MCF7, T-47D, MDA-MB231) communicate PAFR and make PAF in response to in vitro excitement with VEGF, bFGF, HGF, TNF and thrombin 34, indicating that indicators stated in the tumor microenvironment can induce activation from the PAFR pathway in tumor cells. Furthermore, PAF can activate tumor cells, macrophages and endothelial cells to amplify PAF PAFR and creation manifestation on the membranes in autocrine,.