Leukotriene synthesis is critical for medulloblastoma progression

Purpose: Here, we examined the role of leukotriene, well-known inflammatory mediators, in the tumorigenesis of hedgehog pathway-associated medulloblastoma (MB), and tested the efficacies of antagonists of leukotriene biosynthesis in MB treatment. Experimental Design: We examined the leukotriene levels in MB cells by ELISA. We next tested whether leukotriene synthesis in MB cells relied on activation of hedgehog pathway, or the presence of hedgehog ligand secreted by astrocytes. We then investigated whether leukotriene mediated hedgehog-induced Nestin expression in tumor cells. The functions of leukotriene in tumor cell proliferation and tumor growth in MB were determined through knocking down 5-lipoxygenase (a critical enzyme for leukotriene synthesis) by shRNAs, or using 5-lipoxygenase deficient mice. Finally, the efficacies of antagonists of leukotriene synthesis in MB treatment were tested in vivo and in vitro. Results: Leukotriene was significantly up-regulated in MB cells. Increased leukotriene synthesis relied on hedgehog ligand secreted by astrocytes, a major component of MB microenvironment. Leukotriene stimulated tumor cells to express Nestin, a cytoskeletal protein essential for MB growth. Genetic blockage of leukotriene synthesis dramatically suppressed MB cell proliferation and tumor growth in vivo. Pharmaceutical inhibition of leukotriene synthesis markedly repressed MB cell proliferation, but had no effect on proliferation of normal neuronal progenitors. Moreover, antagonists of leukotriene synthesis exhibited promising tumor inhibitory efficacies on drug-resistant MB. Conclusions: Our findings reveal a novel signaling pathway that is critical for MB cell proliferation and tumor progression, and that leukotriene biosynthesis represents a promising therapeutic target for MB treatment.