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Neuropilin-1 regulation of tumor vascularization and growth
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University.
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. , p. 69
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1512
Keywords [en]
Angiogenesis, Neuropilin-1, VEGFR2, tumor biology, pancreatic ductal adenocarcinoma, renal cell carcinoma
National Category
Cell and Molecular Biology Cancer and Oncology
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-364415ISBN: 978-91-513-0495-3 (print)OAI: oai:DiVA.org:uu-364415DiVA, id: diva2:1258981
Public defence
2018-12-14, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-11-22 Created: 2018-10-26 Last updated: 2018-11-30
List of papers
1. NRP1 Presented in trans to the Endothelium Arrests VEGFR2 Endocytosis, Preventing Angiogenic Signaling and Tumor Initiation
Open this publication in new window or tab >>NRP1 Presented in trans to the Endothelium Arrests VEGFR2 Endocytosis, Preventing Angiogenic Signaling and Tumor Initiation
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2014 (English)In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 28, no 6, p. 633-646Article in journal (Refereed) Published
Abstract [en]

Neuropilin 1 (NRP1) modulates angiogenesis by binding vascular endothelial growth factor (VEGF) and its receptor, VEGFR2. We examined the consequences when VEGFR2 and NRP1 were expressed on the same cell (cis) or on different cells (trans). In cis, VEGF induced rapid VEGFR2/NRP1 complex formation and internalization. In trans, complex formation was delayed and phosphorylation of phospholipase C gamma (PLC gamma) and extracellular regulated kinase 2 (ERK2) was prolonged, whereas ERK1 phosphorylation was reduced. Trans complex formation suppressed initiation and vascularization of NRP1-expressing mouse fibrosarcoma and melanoma. Suppression in trans required high-affinity, steady-state binding of VEGF to NRP1, which was dependent on the NRP1 C-terminal domain. Compatible with a trans effect of NRP1, quiescent vasculature in the developing retina showed continuous high NRP1 expression, whereas angiogenic sprouting occurred where NRP1 levels fluctuated between adjacent endothelial cells. Therefore, through communication in trans, NRP1 can modulate VEGFR2 signaling and suppress angiogenesis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-224353 (URN)10.1016/j.devcel.2014.02.010 (DOI)000333765900005 ()
Available from: 2014-05-13 Created: 2014-05-09 Last updated: 2018-10-26
2. VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival
Open this publication in new window or tab >>VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival
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2018 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 246, no 3, p. 311-322Article in journal (Refereed) Published
Abstract [en]

Unstable and dysfunctional tumor vasculature promotes cancer progression and spread. Signal transduction by the pro-angiogenic vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) is modulated by VEGFA-dependent complex formation with neuropilin 1 (NRP1). NRP1 expressed on tumor cells can form VEGFR2/NRP1 trans-complexes between tumor cells and endothelial cells which arrests VEGFR2 on the endothelial surface, thus interfering with productive VEGFR2 signaling. In mouse fibrosarcoma, VEGFR2/NRP1 trans-complexes correlated with reduced tumor vessel branching and reduced tumor cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) strongly expressed NRP1 on both tumor cells and endothelial cells, in contrast to other common cancer forms. Using proximity ligation assay, VEGFR2/NRP1 trans-complexes were identified in human PDAC tumor tissue, and its presence was associated with reduced tumor vessel branching, reduced tumor cell proliferation, and improved patient survival after adjusting for other known survival predictors. We conclude that VEGFR2/NRP1 trans-complex formation is an independent predictor of PDAC patient survival. 

Keywords
VEGF, neuropilin 1, pancreatic adenocarcinoma, trans-complex, branching
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-363966 (URN)10.1002/path.5141 (DOI)000447161600007 ()30027561 (PubMedID)
Funder
Swedish Research Council, 2015-02375Swedish Cancer Society, CAN2016/578Knut and Alice Wallenberg Foundation, KAW 2015.0030Knut and Alice Wallenberg Foundation, KAW 2015.0275
Available from: 2018-10-22 Created: 2018-10-22 Last updated: 2019-06-26Bibliographically approved
3. Perivascular Neuropilin-1 expression is an independent marker of improved survival in renal cell carcinoma
Open this publication in new window or tab >>Perivascular Neuropilin-1 expression is an independent marker of improved survival in renal cell carcinoma
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(English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827Article in journal (Other academic) Submitted
Abstract [en]

Background: Considerable progress in renal cell carcinoma (RCC) treatment has been made in the last decade with the introduction of drugs targeting tumor angiogenesis. However, the 5-year survival of metastatic disease is still only 10-15%. Here, we explored the prognostic significance of compartment-specific expression of Neuropilin 1 (NRP1), a co-receptor for vascular endothelial growth factor (VEGF). NRP1 expression was analyzed in RCC tumor vessels, in perivascular tumor cells and generally in the tumor cells. Moreover, complex formation between NRP1 and the main VEGF receptor, VEGFR2, was determined.

Methods: VEGFR2/NRP1 complex formation in cis (on the same cell) and trans (between cells) configurations was determined by in situ proximity ligation assay, and NRP1 protein expression in three compartments (endothelial cells, perivascular tumor cells and general tumor cell expression) was determined by immunofluorescent staining, in a cohort of 64 advanced renal cell carcinoma patients.

Results: VEGFR2/NRP1 trans complexes were detected in 75% of the patient samples. The presence of trans VEGFR2/NRP1 complexes or perivascular NRP1 was associated with a reduced tumor vessel density. The presence of VEGFR2/NRP1 trans complexes, perivascular NRP1 and general tumor cell NRP1 expression correlated with improved survival, however, only VEGFR2/NRP1 trans complexes and perivascular NRP1 expression remained significant in multivariable analysis.

Conclusion: Our work shows that VEGFR2/NRP1 complexes in trans, as well as perivascular NRP1 expression, are independent markers of improved survival in advanced renal cell carcinoma.

Keywords
renal cell carcinoma, NRP1, VEGFR2, angiogenesis, trans complex formation
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-363970 (URN)
Available from: 2018-10-22 Created: 2018-10-22 Last updated: 2018-10-26

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