Abstract
Axon guidance molecules play an important role in regulating proper neuronal networking during neuronal development. They also have non-neuronal properties, which include angiogenesis, inflammation, and tumor development. Semaphorin 3F (SEMA3F), a member of the class 3 semaphorins, was initially identified as an axon guidance factor, that repels axons and collapses growth cones. However, SEMA3F has similar effects on endothelial cells (ECs) and tumor cells. In this review, we discuss the novel molecular mechanisms underlying SEMA3F activity in vascular and tumor biology. Recent evidence suggests that SEMA3F functions as a PI3K-Akt-mTOR inhibitor in mammalian cells, including T cells, ECs, and tumor cells. Therefore, SEMA3F may have broad therapeutic implications. We also discuss the key role of axon guidance molecules as regulators of the tumor microenvironment. Netrin-1, a chemoattractant factor in the neuronal system, promotes tumor progression by enhancing angiogenesis and metastasis. Moreover, our recent studies demonstrate that netrin-1/neogenin interactions augment CD4+ T cell chemokinesis and elicit pro-inflammatory responses, suggesting that netrin-1 plays a key role in modulating the function of a tumor and its surrounding cells in the tumor microenvironment. Overall, this review focuses on SEMA3F and netrin-1 signaling mechanisms to understand the diverse biological functions of axon guidance molecules.
Highlights
The neuronal network is established precisely during development for normal functioning of the neuronal system
CatB activation is crucial for enhancing tumor cell invasiveness and angiogenesis
Targeting mediators such as netrin-1 and CatB could be candidates for brain cancer therapy
Summary
The neuronal network is established precisely during development for normal functioning of the neuronal system. Consistent with our results, SEMA3F downregulates the hypoxia-inducible factor-1α (HIF1α) protein and VEGF mRNA levels by blocking the Akt-mTOR signaling pathway (Potiron et al, 2007). These findings indicate that SEMA3F suppresses the angiogenic property of tumor cells by inhibiting the production and secretion of VEGF and interrupting VEGF-NRP binding. The MEK inhibitor U0126, reduced CatB expression in medulloblastoma These inhibition results suggest that netrin-1 secreted by medulloblastoma cells, stimulates medulloblastoma cell invasiveness by activating the CatB via the MAPK pathway (Akino et al, 2014). These results suggest that the netrin-1-neogenin (or UNC5B) pathway is a promising therapeutic target to inhibit medulloblastoma invasiveness, and that the measurement of netrin-1 might be useful to detect invasive and disseminated phenotypes of medulloblastoma to predict the disease status (Akino et al, 2014)
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