Impact of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) single nucleotide polymorphisms on outcome in gastroenteropancreatic neuroendocrine neoplasms

Berardi, Rossana; Torniai, Mariangela; Partelli, Stefano; Rubini, Corrado; Pagliaretta, Silvia; Savini, Agnese; Polenta, Vanessa; Santoni, Matteo; Giampieri, Riccardo; Onorati, S.; Barucca, Federica; Murrone, Alberto; Bianchi, Francesca; Falconi, Massimo

doi:10.1371/journal.pone.0197035

Cited by 19 publications

(18 citation statements)

References 47 publications

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“…There was no significant association of the expression levels of VEGFR 1-3 and overall survival. Nonetheless, these results are in line with previous studies on other gastrointestinal malignancies [ 35 , 36 ]. This might in part be explained by the fact that well- to moderately differentiated GEP-NENs have a favorable overall survival even in the presence of distant metastases and that there was no significant correlation between tumor grading and the expression of VEGFRs.…”

Section: Discussionsupporting

confidence: 93%

Distinct Expression Patterns of VEGFR 1-3 in Gastroenteropancreatic Neuroendocrine Neoplasms: Supporting Clinical Relevance, but not a Prognostic Factor

Bösch

Altendorf-Hofmann

Jacob

et al. 2020

JCM

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Introduction: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are an increasing tumor entity. Since many patients are diagnosed at an advanced stage, treatment is still challenging and dependent on many tumor and patient specific factors. Therefore, the aim of the present study was to elucidate the expression rates and the prognostic value of vascular endothelial growth factor receptor (VEGFR) 1-3 in GEP-NENs. A potential association to immune checkpoint markers was further investigated. Material and Methods: The expression levels of VEGFR 1-3 were analyzed by immunohistochemistry and correlated with the expression of the checkpoint markers PD-1 and PD-L1. Furthermore, the tumor samples of 249 GEP-NEN patients were studied and correlated with overall survival rates and clinicopathological features. Kaplan–Meier analyses and the log rank test were used for survival analyses. Categorical variables were compared by the χ2 test. Results: The most common primary tumor site was the small intestine (50.6%), followed by the pancreas (25.7%). VEGFR 1 was highly expressed in 59%, VEGFR 2 in 6.4%, and VEGFR 3 in 61.8% of the analyzed samples. The expression of VEGFR 1-3 was not significantly associated with survival rates. Pancreatic NENs had the highest expression of VEGFR 1 and 3 in 80% of the cases. VEGFR 1-3 positivity correlated with the expression levels of immune checkpoint markers. Discussion: VEGFR 1-3 show a distinct expression pattern in different subgroups of neuroendocrine neoplasias indicating a conceivable target. Moreover, there was a substantial association between VEGFRs and immune checkpoint markers. Taken together, anti-VEGFR therapy represents a promising therapeutic approach in GEP-NEN patients and should be addressed in future studies.

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Section: Discussionsupporting

confidence: 93%

Distinct Expression Patterns of VEGFR 1-3 in Gastroenteropancreatic Neuroendocrine Neoplasms: Supporting Clinical Relevance, but not a Prognostic Factor

Bösch

Altendorf-Hofmann

Jacob

et al. 2020

JCM

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“…In total, 66 tagSNPs (27 from KDR gene, 32 from NRP-1 gene and 7 from PDGFβ) were selected, however due to financial constraints, 10 SNPs (rs7692791, rs6838752, rs2034965, rs1531290, rs13109660 from KDR, rs2070296, rs2804495, rs2065364 from NRP-1, and rs4821877, and rs9622978 from PDGFβ) were randomly selected from the tagSNPs. In addition, five disease-associated SNPs (rs1870377 and rs2305948 from KDR, rs6554162 and rs1800812 from PDGFRα, and rs2302273 from PDGFRβ) were selected according to their use in previous literature (19–24). Finally, the 15 SNPs (Table SI) of KDR rs7692791, rs2305948, rs6838752, rs2034965, rs1531290, rs13109660 and rs1870377, of NRP-1 rs2070296, rs2804495 and rs2065364, of PDGFβ rs4821877 and rs9622978, of PDGFRα rs6554162 and rs1800812, and of PDGFRβ rs2302273, were obtained from the SNP database of the NCBI ().…”

Section: Methodsmentioning

confidence: 99%

NRP‑1 and KDR polymorphisms are associated with survival time in patients with advanced gastric cancer

Zhuo

Shi

2019

Oncol Lett

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Neuropilin-1 (NRP-1), a member of the NRP-family, has been reported to be vital for tumor angiogenesis, growth and metastasis. As a co-receptor of vascular endothelial growth factor (VEGF), NRP-1 can bind to VEGF and meditate vascular development through the VEGF-VEGF receptor 2 (VEGFR2) signaling pathway. Furthermore, NRP-1 is capable of binding with platelet-derived growth factor (PDGF) to regulate the PDGF-PDGF receptor (PDGR) signaling pathway in tumor angiogenesis. In the present study, The DNA was obtained from the paraffin-embedded tissues of patients with advanced gastric cancer (AGC), amplified using PCR and subsequently sequenced to determine the polymorphisms within NRP-1, VEGFR2 [kinase insert domain receptor (KDR)] and PDGF. The effect of the functional polymorphism of the aforementioned genes on the overall survival (OS) and progression-free survival (PFS) of 81 patients with advanced gastric cancer was examined. Three single nucleotide polymorphisms (SNPs) of KDR were significantly associated with clinical outcomes. The rs1870377 TT genotype was positively associated with longer OS and PFS times compared with the AA+AT genotype (PFS, P=0.012; OS, P=0.038), the rs7692791 wild-type TT genotype was positively associated with longer PFS time and the rs2034965 AA+GA genotype was associated with shorter OS time (P=0.034). With regards to the SNPs of NRP-1, the rs2065364 AA genotype was significantly associated with improved OS and PFS times (PFS, P=0.023; OS, P=0.045). Following multivariate analysis using Cox proportional hazards regression models, patients with the KDR rs7692791 TT genotype experienced a longer PFS time compared with those with the CT genotype (P=0.016), and patients with the NRP-1 rs2065364 variant-type AA genotype still experienced a longer PFS time compared with those patients with the AG+GG genotypes (P=0.006). Regarding OS, the results demonstrated that the KDR rs2034965 AG+GG genotypes presented with a significant reduction in OS time (P=0.029), and that the KDR rs1870377 AT+AA genotypes had worse OS times compared with the wild-type TT genotype (P=0.021). In addition, increased mortality risk and AGC progression were significantly associated with the number of adverse alleles for combinations of NRP-1 rs2065364 and KDR rs1870377. In conclusion, the data from the present study demonstrated that the selected KDR and NRP-1 gene polymorphisms may be potential prognostic biomarkers in AGC.

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“…It was also observed that the expressions of VEGFR-2 (p = 0.032) and VEGFR-3 (p = 0.034) receptors in the lymph nodes of CRC patients were significantly related to cancer recurrence. Although scarce, some literature data endorse these findings, since they assign to the presence of angiogenic cytokine receptors an increased risk of relapse of several types of cancer [24][25][26]. In view of this finding, it may be important to implement a tighter follow-up plan for patients with positive expression of VEGFR-2 and VEGFR-3 receptors in the resected lymph nodes in order to make an earlier detection of cancer recurrence.…”

Section: Discussionmentioning

confidence: 99%

VEGF Expression in Colorectal Cancer Metastatic Lymph Nodes: Clinicopathological Correlation and Prognostic Significance

Mazeda

Martins

García

et al. 2020

Gastrointestinal Disorders

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Background: Angiogenesis plays an important role in colorectal cancer (CRC) tumorigenesis and metastatic progression. Methods: The present series consisted of CRC lymph node metastasis (LNM) tissue samples from 210 patients. Archival paraffin embedded LNM tissue were used to build up tissue microarray blocks and VEGF expression was immunohistochemically assessed. Results: VEGF-A and VEGF-C are overexpressed in LNM. VEGF-A was associated with patient age (p < 0.001), and VEGFR-2 and VEGFR-3 with CRC relapse (p = 0.032; p = 0.030, respectively). VEGF-C positivity was associated with VEGFR-3 positivity (p = 0.031), and VEGF-D with VEGFR-2 and VEGFR-3 (p ≤ 0.001). Matching the expression in LNM with CRC, in CRC VEGF-A positivity associates with VEGF-A, VEGF-C, VEGF-D, VEGF-R2, VEGF-R3 positivity in LNM; CRC VEGF-C with VEGF-D, VEGFR-2, VEGFR-3; CRC VEGFR-2 with VEGF-A, VEGF-C, VEGF-D, VEGFR-2, VEGFR-3; CRC VEGFR-3 with VEGF-A, VEGF-C, VEGF-D, VEGFR-2, VEGFR-3 in LNM. Conclusion: This study provides new information, revealing that VEGF family expression is increased in LNM. The association between the expression of VEGFR-2 and VEGFR-3 in LNM with CRC relapse reveals its impact on patient prognosis. Interesting data were found when the relationship between these proteins in primary tumor and their metastasis, were analyzed; VEGFA positivity in primary tumor is positively related to VEGF-A, VEGF-C, VEGF-D, VEGFR-2 and VEGFR-3 in their respective LNM suggesting mutual influence.

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Impact of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) single nucleotide polymorphisms on outcome in gastroenteropancreatic neuroendocrine neoplasms

Cited by 19 publications

References 47 publications

Distinct Expression Patterns of VEGFR 1-3 in Gastroenteropancreatic Neuroendocrine Neoplasms: Supporting Clinical Relevance, but not a Prognostic Factor

Distinct Expression Patterns of VEGFR 1-3 in Gastroenteropancreatic Neuroendocrine Neoplasms: Supporting Clinical Relevance, but not a Prognostic Factor

NRP‑1 and KDR polymorphisms are associated with survival time in patients with advanced gastric cancer

VEGF Expression in Colorectal Cancer Metastatic Lymph Nodes: Clinicopathological Correlation and Prognostic Significance

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