Neuropilin-2 (NRP2) is a single transmembrane receptor and was first found in the nervous system to play a role in axon guidance. Interestingly, NRP2 was also found on many tumor cells and various studies showed that NRP2 is associated with a poor prognosis in different cancers and is involved in migration and therapy resistance. We investigated the prognostic potential of NRP2 in the pancreatic ductal adenocarcinoma (PDAC) and found out that in contrast to other kinds of cancer a high expression of NRP2 is associated with a longer cancer specific survival. We hypothesized that this effect could be either triggered through an expression of different interaction partners of NRP2. Both semaphorine 3F and VEGFs can bind to NRP2 but have different effects on cancer cells. Semaphorine 3F was found to have a great potential as a cancer inhibitor in pancreatic cancer whereas VEGFs are often associated with a worse prognosis. Both compete for the binding to NRP2.
Furthermore, we found high expression of NRP2 in tumor-associated macrophages (TAMs) in PDACs. Until now, NRP2 expression and function is poorly analyzed in the immune system. Therefore, we next focused on the investigation of NRP2 in the immune system during cancer progression. We used LysM:cre-NRP2LoxP/LoxP (conditional knock-out of NRP2 in macrophages) and Vav:cre-NRP2LoxP/LoxP (conditional knock-out in all immune cells) for our experiments. We showed that NRP2 is upregulated during the differentiation/maturation of macrophages. Next, we injected LLC cells subcutaneously to analyze the effect of NRP2 knock-out in macrophages (LysM:cre) or in the all immune cells (Vav:cre). No difference was detected in tumor size, but the vascularization was impaired in both mouse models. Different tumor models with extended tumor growth times and metastasis should be performed next to proof the importance of NRP2 in immune cells during tumor progression.
Due to the broad expression of NRP2 in the immune system we used the Vav:cre-NRP2LoxP/LoxP mouse to investigate the role of NRP2 during an immune response. We used a mild allergic inflammation model of the lung and analyzed the different immune cell populations. Interestingly, T cells and eosinophils were reduced during the inflammation indicating, that the conditional knock-out of NRP2 is inhibiting the immune response. We further analyzed the role of NRP2 in T cells and found out, that the expression of NRP2 is very different in the various T cell populations. CD8+ T cells express ca. 10 times as much mRNA for NRP2 compared to CD4+ T cells. Also, the CD4 subpopulation showed a diverse expression of NRP2. Th2 and Th17 express a lot of NRP2 and Treg and Th1 very low levels. These results suggest an important role of NRP2 in certain cells. The knock-out of NRP2 in Th2 cells leads to an upregulation of IL-13, IL-5 and IL10.
We first showed the importance of NRP2 during an immune response and found interesting regulations in immune cell populations and important cytokines. More work needs to be done to understand the functions of NRP2 during an immune response.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa.de:bsz:14-qucosa-235135 |
| Date | 20 April 2018 |
| Creators | Schellenburg, Samuel |
| Contributors | Technische Universität Dresden, Fakultät Mathematik und Naturwissenschaften, Prof. Dr. G. Vollmer, Prof. Dr. Michael Muders, Prof. Dr. G. Vollmer, Prof. Dr. Michael Muders |
| Publisher | Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | doc-type:doctoralThesis |
| Format | application/pdf |
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