title: The association of the angiopoietin/Tie-2 system with the development of metastasis and leukocyte migration in neuroendocrine tumors.
abstract: The aim of this study was to explore the possible involvement of the angiopoietin (Ang)-1, -2/Tie-2 system in the development, growth, and metastases evolution of gastroenteropancreatic-neuroendocrine tumors (GEP-NETs). We prospectively examined the serum levels of Tie-2, Ang-1, and Ang-2 by ELISA in 42 patients with proven GEP-NETs and 27 controls. We also determined the expression of the Ang/Tie-2 system in freshly isolated peripheral blood monocytes and in tumor cells from malignant primary tumors and/or liver metastases samples from GEP-NET patients by flow cytometry and/or RT-PCR. Furthermore, the function of the Ang/Tie-2 system in monocytes from controls and patients was assessed by a chemotaxis assay. GEP-NET patients showed enhanced serum levels of soluble form of Tie-2 (sTie-2), Ang-1, and Ang-2 (P<0.05 in all cases), compared to controls. sTie-2 and Ang-2 levels were significantly higher in GEP-NETs with metastases compared to those with no metastases. In addition, a significant correlation was detected between Ang-2 levels and chromogranin A or sTie-2 concentrations or 5-hydroxy-indole acetic acid excretion (r=0.71, r=0.60, and r=0.81 respectively, P<0.01 in all cases). Furthermore, we observed an enhanced expression of Ang-1, Ang-2, and Tie-2 in freshly isolated tumor cells from GEP-NET both by immunohistochemistry and by RT-PCR. Interestingly, an enhanced expression and function of Tie-2 was detected in monocytes from GEP-NET patients. Our data suggest that the Ang/Tie-2 system is involved in the growth and development of metastases of GEP-NETs, and that favors the recruitment of Tie-2(+) monocytes to the tumor site, where they can promote inflammation and angiogenesis.
authors.affiliation: Service of Endocrinology, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Nicté
authors.initials: N
authors.lastname: Figueroa-Vega
authors.forename: Angel
authors.initials: A
authors.lastname: Díaz
authors.forename: Magdalena
authors.initials: M
authors.lastname: Adrados
authors.forename: Cristina
authors.initials: C
authors.lastname: Alvarez-Escolá
authors.forename: Amalia
authors.initials: A
authors.lastname: Paniagua
authors.forename: Julián
authors.initials: J
authors.lastname: Aragonés
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-Pérez
authors.forename: Susanna
authors.initials: S
authors.lastname: Leskela
authors.forename: Ricardo
authors.initials: R
authors.lastname: Moreno-Otero
authors.forename: Roberto
authors.initials: R
authors.lastname: González-Amaro
authors.forename: Mónica
authors.initials: M
authors.lastname: Marazuela
mesh_terms: D042683:Angiopoietin-1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis / Q000502:physiology; D053379:Chromogranin A / Q000097:blood; D004067:Digestive System Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000652:urine; D007150:Immunohistochemistry; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000556:secondary; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D011446:Prospective Studies; D012334:RNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D042787:Receptor, TIE-2 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D053379:Chromogranin A; D012334:RNA, Neoplasm; D006897:Hydroxyindoleacetic Acid; D042787:Receptor, TIE-2