VEGF receptor‐2/neuropilin 1 <i>trans</i>‐complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival

Morin, Eric; Sjöberg, Elin; Tjomsland, Vegard; Testini, Chiara; Lindskog, Cecilia; Franklin, Oskar; Sund, Malin; Öhlund, Daniel; Kiflemariam, Sara; Sjöblom, Tobias; Claesson‐Welsh, Lena

doi:10.1002/path.5141

Cited by 34 publications

(45 citation statements)

References 52 publications

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“…However, the compartment-specific expression of NRP1, and the ability to form VEGFR2/NRP1 complexes in trans were not explored in these studies. Findings from our previous work, supported by the present study, suggest that the NRP1 expression pattern, not only the overall expression levels, is of critical importance for tumor progression and patient prognosis [22]. Thus, tumor cell expression of NRP1 (see supplementary material, Figure S4A,B) and more importantly, perivascular tumor cell expression ( Figure 3A,B), correlated with improved outcome in two independent RCC cohorts.…”

Section: Discussionsupporting

confidence: 83%

“…The pattern of VEGFR2 and NRP1 expression in RCC, that is, VEGFR2 in the endothelial cells and NRP1 in both endothelial and tumor cells, indicated that VEGFR2/NRP1 complexes could form both in trans and cis configurations. To identify such complexes in human RCC tissue, in situ PLA was performed on consecutive sections with antibodies against VEGFR2 and NRP1, as described previously (Figure C) . Patient biopsies were scored positive or negative for VEGFR2/NRP1 complexes in trans and cis configurations (see material and methods for details).…”

Section: Resultsmentioning

confidence: 99%

“…Slides were incubated with primary antibodies overnight at 4 °C and with secondary antibodies for 1 hour at room temperature, thereafter with Hoechst 33342 before mounting with Fluoromount mounting medium (Merck, Kenilworth, NJ, USA). The specificity and sensitivity of antibodies against NRP1, VEGFR2, and CD34 were validated by staining of porcine aortic endothelial (PAE) cells stably overexpressing human VEGFR2 and NRP1 (as described in detail previously ) and RCC tumor tissue, with target specific antibodies or the corresponding isotype control.…”

Section: Methodsmentioning

confidence: 99%

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Perivascular Neuropilin‐1 expression is an independent marker of improved survival in renal cell carcinoma

Morin

Lindskog

Johansson

et al. 2020

The Journal of Pathology

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Renal cell carcinoma (RCC) treatment has improved 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 cell compartment. Moreover, complex formation between NRP1 and the main VEGF receptor, VEGFR2, was determined. Two RCC tissue microarrays were used; a discovery cohort consisting of 64 patients and a validation cohort of 314 patients. VEGFR2/NRP1 complex formation in cis (on the same cell) and trans (between cells) configurations was determined by in situ proximity ligation assay (PLA), and NRP1 protein expression in three compartments (endothelial cells, perivascular tumor cells, and general tumor cell expression) was determined by immunofluorescent staining. Expression of NRP1 in perivascular tumor cells was explored as a marker for RCC survival in the two RCC cohorts. Results were further validated using a publicly available gene expression dataset of clear cell RCC (ccRCC). We found that VEGFR2/NRP1 trans complexes were detected in 75% of the patient samples. The presence of trans VEGFR2/NRP1 complexes or perivascular NRP1 expression was associated with a reduced tumor vessel density and size. When exploring NRP1 as a biomarker for RCC prognosis, perivascular NRP1 and general tumor cell NRP1 protein expression correlated with improved survival in the two independent cohorts, and significant results were obtained also at the mRNA level using the publicly available ccRCC gene expression dataset. Only perivascular NRP1 expression remained significant in multivariable analysis. Our work shows that perivascular NRP1 expression is an independent marker of improved survival in RCC patients, and reduces tumor vascularization by forming complexes in trans with VEGFR2 in the tumor endothelium. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Discussionsupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Perivascular Neuropilin‐1 expression is an independent marker of improved survival in renal cell carcinoma

Morin

Lindskog

Johansson

et al. 2020

The Journal of Pathology

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“…human cancers have been confirmed with animal studies showing that exacerbated angiogenesis and a poor prognosis is correlated with NRP1 expression (Ellis, 2006). Only in pancreatic cancers, a high expression of NRP1 correlates with reduced vascularized areas, decreased tumor growth, and improved survival (Morin et al, 2018).…”

Section: Functions Of Neuropilins In Cancermentioning

confidence: 85%

Neuropilins, as Relevant Oncology Target: Their Role in the Tumoral Microenvironment

Dumond

Pagès

2020

Front. Cell Dev. Biol.

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Angiogenesis is one of the key mechanisms involved in tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) and its receptors (VEGFR) represent one of the major signaling pathways which mediates angiogenesis. The VEGF/VEGFR axis was intensively targeted by monoclonal antibodies or by tyrosine kinase inhibitors to destroy the tumor vascular network. By inhibiting oxygen and nutrient supply, this strategy was supposed to cure cancers. However, despite a lengthening of the progression free survival in several types of tumors including colon, lung, breast, kidney, and ovarian cancers, modest improvements in overall survival were reported. Anti-angiogenic therapies targeting VEGF/VEGFR are still used in colon and ovarian cancer and remain reference treatments for renal cell carcinoma. Although the concept of inhibiting angiogenesis remains relevant, new targets need to be discovered to improve the therapeutic index of anti-VEGF/VEGFR. Neuropilin 1 and 2 (NRP1/2), initially described as neuronal receptors, stimulate angiogenesis, lymphangiogenesis and immune tolerance. Moreover, overexpression of NRPs in several tumors is synonymous of patients' shorter survival. This article aims to overview the different roles of NRPs in cells constituting the tumor microenvironment to highlight the therapeutic relevance of their targeting.

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“…A previously described tissue microarray was used for the tissue studies . The tissue microarray has core areas of 1 mm in diameter selected by an experienced pathologist (WW).…”

Section: Methodsmentioning

confidence: 99%

Novel prognostic markers within the CD44‐stromal ligand network in pancreatic cancer

Franklin

Billing

Öhlund

et al. 2018

The Journal of Pathology CR

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The dense stroma in pancreatic cancer tumours is rich in secreted extracellular matrix proteins and proteoglycans. Secreted hyaluronan, osteopontin and type IV collagen sustain oncogenic signalling by interactions with CD44s and its variant isoform CD44v6 on cancer cell membranes. Although well established in animal and in vitro models, this oncogenic CD44‐stromal ligand network is less explored in human cancer. Here, we use a pancreatic cancer tissue microarray from 69 primary tumours and 37 metastatic lymph nodes and demonstrate that high tumour cell expression of CD44s and, surprisingly, low stromal deposition of osteopontin correlate with poor survival independent of established prognostic factors for pancreatic cancer. High stromal expression of hyaluronan was a universal trait of both primary tumours and metastatic lymph nodes. However, hyaluronan species of different molecular mass are known to function differently in pancreatic cancer biology and immunohistochemistry cannot distinguish between them. Using gas‐phase electrophoretic molecular mobility analysis, we uncover a shift towards high molecular mass hyaluronan in pancreatic cancer tissue compared to normal pancreas and at a transcriptional level, we find that hyaluronan synthesising HAS2 correlates positively with CD44. The resulting prediction that high molecular mass hyaluronan would then correlate with poor survival in pancreatic cancer was confirmed in serum samples, where we demonstrate that hyaluronan >27 kDa measured before surgery is an independent predictor of postoperative survival. Our findings confirm the prognostic value of CD44 tissue expression and highlight osteopontin tissue expression and serum high molecular mass hyaluronan as novel prognostic markers in pancreatic cancer.

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VEGF receptor‐2/neuropilin 1 trans‐complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival

Cited by 34 publications

References 52 publications

Perivascular Neuropilin‐1 expression is an independent marker of improved survival in renal cell carcinoma

Perivascular Neuropilin‐1 expression is an independent marker of improved survival in renal cell carcinoma

Neuropilins, as Relevant Oncology Target: Their Role in the Tumoral Microenvironment

Novel prognostic markers within the CD44‐stromal ligand network in pancreatic cancer

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