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Axon guidance factor Slit2 inhibits neural invasion and metastasis in pancreatic cancer

Item Type:Article
Title:Axon guidance factor Slit2 inhibits neural invasion and metastasis in pancreatic cancer
Creators Name:Goehrig, A., Detjen, K.M., Hilfenhaus, G., Koerner, J., Welzel, M., Arsenic, R., Schmuck, R., Bahra, M., Wu, J.Y., Wiedenmann, B. and Fischer, C.
Abstract:Pancreatic ductal adenocarcinoma (PDAC) metastasizes by neural, vascular and local invasion routes, which limit patient survival. In nerves and vessels, Slit2 and its Robo receptors constitute repellent guidance cues that also direct epithelial branching. Thus, the Slit2-Robo system may represent a key pinch point to regulate PDAC spread. In this study, we examined the hypothesis that escaping from repellent Slit2-Robo signaling is essential to enable PDAC cells to appropriate their local stromal infrastructure for dissemination. Through immunohistochemical analysis, we detected Slit2 receptors Robo1 and Robo4 on epithelia, nerves and vessels in healthy pancreas and PDAC specimens, respectively. Slit2 mRNA expression was reduced in PDAC compared to non-transformed pancreatic tissues and cell lines, suggesting a reduction in Slit2-Robo pathway activity in PDAC. In support of this interpretation, restoring the Slit2 expression in Slit2-deficient PDAC cells inhibited their bidirectional chemoattraction with neural cells, and more specifically impaired unidirectional PDAC cell navigation along outgrowing neurites in models of neural invasion. Restoring autocrine/paracrine Slit2 signaling was also sufficient to inhibit the directed motility of PDAC cells, but not their random movement. Conversely, RNAi-mediated silencing of Robo1 stimulated the motility of Slit2-competent PDAC cells. Furthermore, culture supernatants from Slit2-competent PDAC cells impaired migration of endothelial cells (HUVEC) whereas an N-terminal Slit2 cleavage fragment stimulated such migration. In vivo investigations of orthotopic pancreatic tumors with restored Slit2 expression demonstrated reduced invasion, metastasis and vascularization, with opposing effects produced by Robo1 silencing in tumor cells or sequestration of endogenous Slit2. Analysis of clinical specimens of PDAC showed that those with low Slit2-mRNA expression exhibited a higher incidence and a higher fraction of tumor-infiltrated lymph nodes. Taken together, our findings argue that disrupting Slit2-Robo signaling in PDAC may enhance metastasis and predispose PDAC cells to neural invasion.
Keywords:Slit2, Axon Guidance, Pancreatic Cancer, Neural Invasion, Metastasis
Source:Cancer Research
Publisher:American Association for Cancer Research
Page Range:1529-1540
Date:1 March 2014
Official Publication:https://doi.org/10.1158/0008-5472.CAN-13-1012
PubMed:View item in PubMed

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