title: High VEGF serum values are associated with locoregional spread of gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
abstract: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly vascularized neoplasms, capable of synthethisizing VEGF-A, a key mediator of angiogenesis. In pancreatic neuroendocrine tumors (pNETs) VEGF expression is higher in benign and low-grade tumors and associated with good prognosis (neuroendocrine paradox) while the VEGF role in gastrointestinal NETs (GI-NETs) is still unclear. In this study, we examined the VEGF-1154A/G polymorphism in 145 GEP-NET patients and 150 controls. Next, we measured VEGF serum levels and VEGF tumor protein expression, comparing it with Ki67 and tumor grade. Patients' VEGF serum levels were compared with VEGF -1145A/G genotypes and metastatic status as well as with chromogranin A (CgA) and 5-hydroxyindolacetic acid (5-HIAA) in case of GI-NET patients. In this study GEP-NET patients had elevated VEGF serum values when compared to healthy controls (p = 0.0013). VEGF-1145G allele correlated with higher VEGF serum levels (p = 0.002). Patients with metastatic tumors had higher VEGF serum values when compared to patients without metastases (p = 0.033), and highest levels were observed in case of lymph node metastases (p = 0.008). VEGF-1145G allele was more frequent in non-functional GI-NET patients than in healthy controls (p = 0.041). CgA was superior to VEGF in tumor detection, while VEGF was superior to 5-HIAA. A correlation was observed between VEGF immunohistochemical staining and Ki-67 (p = 0.028). Tumours with weaker VEGF protein expression were more aggressive than tumours with stronger VEGF expression, confirming a "neuroendocrine paradox" in GI-NETs. Our results suggest the role of VEGF in GI-NETs locoregional spread.
authors.affiliation: Department for Endocrinology, Diabetes and Metabolism, University Clinical Hospital Centre "Sestre milosrdnice", Zagreb, Croatia. Electronic address: Croatia.mberkovi@xnet.hr.
authors.forename: Maja
authors.initials: M
authors.lastname: Cigrovski Berković
authors.affiliation: Laboratory for Personalized Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
authors.forename: Tamara
authors.initials: T
authors.lastname: Čačev
authors.affiliation: Laboratory for Personalized Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
authors.forename: Tina
authors.initials: T
authors.lastname: Catela Ivković
authors.affiliation: Department for Endocrinology, Diabetes and Metabolism, University Clinical Hospital Centre "Sestre milosrdnice", Zagreb, Croatia.
authors.forename: Jasminka
authors.initials: J
authors.lastname: Marout
authors.affiliation: Department for Clinical Pathology, University Clinical Hospital Centre "Sestre milosrdnice", Zagreb, Croatia.
authors.forename: Monika
authors.initials: M
authors.lastname: Ulamec
authors.affiliation: Department for Endocrinology, Diabetes and Metabolism, University Clinical Hospital Centre "Sestre milosrdnice", Zagreb, Croatia.
authors.forename: Vanja
authors.initials: V
authors.lastname: Zjačić-Rotkvić
authors.affiliation: Laboratory for Personalized Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
authors.forename: Sanja
authors.initials: S
authors.lastname: Kapitanović
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000097:blood* / Q000235:genetics* / Q000378:metabolism
chemical_list: D019394:Ki-67 Antigen; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Gastroenteropancreatic neuroendocrine tumors; Gastrointestinal neuroendocrine tumors; Metastasis; Pancreatic neuroendocrine tumors; Polymorphism; VEGF