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Neuropilin-1 Regulation of Tumor Vascularization and Growth

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Neuropilin-1 Regulation of Tumor Vascularization and Growth Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1512 Neuropilin-1 regulation of tumor vascularization and growth ERIC MORIN ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-513-0495-3 UPPSALA urn:nbn:se:uu:diva-364415 2018 Dissertation presented at Uppsala University to be publicly examined in Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, Friday, 14 December 2018 at 09:15 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Faculty examiner: Professor Hellmut Augustin (German Cancer Research Center, Heidelberg, Germany). Abstract Morin, E. 2018. Neuropilin-1 regulation of tumor vascularization and growth. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1512. 69 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-0495-3. Angiogenesis, the formation of new blood vessels from existing ones, is dysregulated during tumor progression as a result of chronic hypoxia and inflammation. Such alterations lead to a lack of vessel hierarchy, and the formation of poorly perfused, leaky and blunt-ended vessels, contributing to disease progression. This thesis explores the impact of neuropilin-1 (NRP1) presentation of vascular endothelial growth factor-A (VEGF-A) to its cognate receptor, VEGFR2. NRP1 presentation of VEGF-A occurs in cis (when NRP1 and VEGFR2 are present on the same cell) or in trans (when molecules are present on adjacent cells). As shown in this thesis, the different modes of NRP1 presentation influence endothelial cell signaling and tumor angiogenesis. The overall aim with the studies has been to identify new biomarkers for cancer survival and potential therapeutic targets. In paper I, we explored if signaling downstream of VEGFR2 was affected by NRP1 presentation in cis compared to trans. Complex formation in trans was readily identified, however, the kinetics were delayed and prolonged, inhibiting VEGFR2 internalization and downstream signaling. Additionally, in vivo tumor studies in mice demonstrated that trans presentation of NRP1 led to early inhibition of angiogenesis and suppressed tumor initiation. In paper II, the presence and clinical impact of trans VEGFR2/NRP1 complexes in human cancer was investigated. We first identified gastric and pancreatic adenocarcinomas (PDAC) as candidates for further investigation. VEGFR2/NRP1 complexes were identified in both tumor types but were more prevalent in PDAC. Trans presentation of NRP1 in PDAC correlated with a reduction in several vessel parameters and tumor cell proliferation. Importantly, this study identified the presence of trans complexes as an independent marker of longer overall survival for PDAC patients. In paper III, we explored the impact of NRP1 presentation modes on renal cell carcinoma (RCC) patient survival. We performed in situ proximity ligation assay (PLA) and immunofluorescence staining on a RCC cohort. Tumor cell NRP1, either trans-complexed with endothelial cell-expressed VEGFR2 as detected by in situ PLA, or alternatively, detected by immunofluorescent staining, was identified as an independent predictor of increased overall survival. These data reinforce the importance of the cell type-specific expression of cancer biomarkers. Keywords: Angiogenesis, Neuropilin-1, VEGFR2, tumor biology, pancreatic ductal adenocarcinoma, renal cell carcinoma Eric Morin, Department of Immunology, Genetics and Pathology, Vascular Biology, Rudbecklaboratoriet, Uppsala University, SE-751 85 Uppsala, Sweden. © Eric Morin 2018 ISSN 1651-6206 ISBN 978-91-513-0495-3 urn:nbn:se:uu:diva-364415 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-364415) Little by little, one travels far - J.R.R. Tolkien List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Koch S.*, van Meeteren L.*, Morin E.*, Testini C., Weström S., Björkelund H., Le Jan S., Adler J., Berger P., Claesson- Welsh L. (2014) NRP1 presented in trans to the endothelium arrests VEGFR2 endocytosis, preventing angiogenic signaling and tumor initiation. Developmental Cell, 28(6):633-46. doi: 10.1016/ j.devcel.2014.02.010 *Equal contribution by the authors II Morin E., Sjöberg E., Tjomsland V., Testini C., Lindskog C., Franklin O., Sund M., Öhlund D., Kiflemariam S., Sjöblom T., Claesson-Welsh L. (2018) VEGF receptor-2/neuropilin1 trans- complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival. Journal of Pathology, 246(3):311-322. doi: 10.1002/path.5141 III Morin E., Lindskog C., Egevad L., Sandström P., Harmen- berg U., Claesson-Welsh L., Sjöberg E. (2018) Perivascular Neuropilin-1 expression is an independent marker of improved survival in renal cell carcinoma. Submitted manuscript Reprints were made with permission from the respective publishers. Contents Introduction ................................................................................................... 11 The blood vascular system ....................................................................... 11 Angiogenesis ............................................................................................ 13 Vascular endothelial growth factor signaling ...................................... 16 Neuropilin-1 ............................................................................................. 20 Tumor angiogenesis ................................................................................. 22 Anti-angiogenic therapy ...................................................................... 25 NRP1 in cancer ......................................................................................... 28 In situ proximity ligation assay ................................................................ 30 Renal cell carcinoma ................................................................................ 32 Pancreatic ductal adenocarcinoma ........................................................... 33 Gastric adenocarcinoma ........................................................................... 34 Present investigations .................................................................................... 37 Aims ......................................................................................................... 37 Summary of the papers ............................................................................. 38 Paper I .................................................................................................. 38 Paper II ................................................................................................ 41 Paper III ............................................................................................... 43 Graphical summary of the papers ............................................................. 44 Future perspectives ....................................................................................... 45 Acknowledgements ....................................................................................... 49 References ..................................................................................................... 52 Abbreviations ANG Angiopoietin BMP Bone morphogenetic protein BRET Bioluminescent resonance energy transfer CAF Cancer-associated fibroblasts CCM Cerebral cavernous malformation CDKN2A Cyclin-dependent kinase inhibitor 2A CFP Cyan fluorescent protein CREB cAMP response element binding protein Dll4 Delta-like 4 E Embryonic day EGFR Epidermal growth factor receptor eNOS Endothelial nitric oxide synthase ERK Extracellular signal-regulated kinase FAK Focal adhesion kinase FGF Fibroblast growth factor FOXO1 Forkhead box protein O1 FRET Fluorescence resonance energy transfer GAC Gastric adenocarcinoma Gal1 Galectin-1 GLUT1 Glucose transporter 1 HER2 Human epidermal growth factor receptor 2 HGF Hepatocyte growth factor HIF Hypoxia inducible factor IL Interleukin JAM Junctional adherens molecule KLF Krüppel-like factor MMP Matrix metalloproteinase mTOR Mammalian target of rapamycin NEM Neuropilin-1-expressing monocytes NFκB Nuclear factor κ-light-chain-enhancer of acti- vated B cells NRP Neuropilin PDAC Pancreatic ductal adenocarcinoma PDGF Platelet-derived growth factor PDGFR PDGF receptor PI3K Phosphatidylinositol 3-kinase PKC Protein kinase C PLA Proximity ligation assay PLCγ Phospholipase C γ PlGF Placental growth factor PTP Protein tyrosine phosphatase RAB Ras-associated binding protein RCC Renal cell carcinoma Sema Semaphorin SH Src homology domain SHB SH2 domain containing adaptor protein B TAM Tumor-associated macrophages TCGA The cancer genome atlas TGFβ Transforming growth factor β TMA Tissue microarray TNFα Tumor necrosis factor α TP53 Tumor protein 53 TSAd T-cell-specific adapter protein VE-cadherin Vascular endothelial cadherin VEGF Vascular endothelial growth factor VEGFR VEGF receptor VE-PTP Vascular endothelial PTP YFP Yellow fluorescent protein ZO-1 Zonula occludens-1 Introduction The blood vascular system Blood vessels are essential for organ homeostasis by distributing oxygen, nutrients, metabolites, cytokines and hormones, immune and inflammatory cells, and regulating coagulation, inflammation and fluid exchange. Vessels are organized into a tree-like hierarchy. Arteries transport oxygenated blood, branching into smaller arterioles, which slows down blood flow. Arterioles split further before connecting to the capillary bed where blood flow is fur- ther reduced to optimize time for gas and nutrient
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