Angiopoietin-2 promotes disease progression of neuroendocrine tumors.
OBJECTIVE
Inhibition of angiogenesis represents a promising therapeutic strategy in neuroendocrine tumors. Angiopoietin-2 (Ang-2), a ligand of the endothelial tyrosine kinase Tie-2, is emerging as a key regulator of vascular remodeling during tumor angiogenesis. We therefore addressed the expression and biological significance of Ang-2 in human neuroendocrine tumors.


METHODS
Surgical specimens and serum from neuroendocrine tumor patients were used to determine Ang-2 expression by in situ hybridization or ELISA (circulating Ang-2). Ang-2 biological effects were evaluated following stable transfection into BON human pancreatic neuroendocrine tumor cells. BON clones were grown as orthotopic xenografts in nude mice to determine tumor growth and abdominal metastatic spread. Further analyses included microvessel density, lymphatic vessel density, and nodal invasion.


RESULTS
Specimens from pancreatic neuroendocrine tumors and nontransformed pancreatic tissue revealed uniform expression of Ang-2 mRNA in endothelial cells. In contrast, epithelial expression of Ang-2 mRNA occurred exclusively in neuroendocrine tumors. Overexpression of Ang-2 in BON orthotopic xenografts did not affect primary tumor growth, although successful Ang-2 induction was confirmed from elevated serum levels. However, increased microvessel density and enhanced lymphatic metastasis were evident in Ang-2-expressing tumors, indicating a functional role of Ang-2 in experimental neuroendocrine tumors. Consistent with this notion, circulating Ang-2 was significantly elevated in neuroendocrine tumor patients compared with healthy controls. Circulating Ang-2 furthermore correlated with metastatic versus localized disease. The highest Ang-2 concentrations occurred in patients with liver metastasis, and concentrations >or=75th percentile predicted shorter survival (P = 0.0003).


CONCLUSIONS
Induction of Ang-2 in neuroendocrine tumors represents a clinically relevant pathomechanism of disease progression and constitutes an adverse prognostic marker.
Detjen
Katharina M
KM
Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum, Charité-Universitätsmedizin, Berlin, Germany. katharina.detjen@charite.de
Rieke
Svenja
S
Deters
Antje
A
Schulz
Petra
P
Rexin
Annett
A
Vollmer
Sonja
S
Hauff
Peter
P
Wiedenmann
Bertram
B
Pavel
Marianne
M
Scholz
Arne
A
D000328:Adult; D000368:Aged; D042702:Angiopoietin-2 / Q000097:blood / Q000235:genetics / Q000502:physiology*; D000818:Animals; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000097:blood / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics; D018358:Neuroendocrine Tumors / Q000097:blood / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000097:blood / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D055815:Young Adult
D042702:Angiopoietin-2