Angiopoietin-2 Promotes Disease Progression of Neuroendocrine Tumors

Abstract

Purpose: 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 tumorangiogenesis. We therefore addressed the expression and biological significance of Ang-2 in human neuroendocrine tumors. Experimental Design: 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 ≥75th percentile predicted shorter survival (P = 0.0003). Conclusion: Induction of Ang-2 in neuroendocrine tumors represents a clinically relevant pathomechanism of disease progression and constitutes an adverse prognostic marker. Clin Cancer Res; 16(2); 420–9.

The Complex Role of Angiopoietin-2 in the Angiopoietin-Tie Signaling Pathway

“…In this study, both progression-free survival and overall survival were reduced in melanoma patients with high levels of circulating Ang2 (using a threshold of 1.8 ng/mL). Finally, a study of neuroendocrine tumors found that the average level of circulating Ang2 increased from 2.6 ng/mL in control samples to 4.0 ng/ mL in patients with neuroendocrine tumors, with values in the cancer group up to 25 ng/ mL (Detjen et al 2010). Again, in this tumor type, higher levels of Ang2 were associated with worse overall survival.…”

“…However, several in situ hybridization studies have revealed increased levels of Ang2 expression in cancers of different origin, including neuroendocrine tumors (Detjen et al 2010), hepatocellular cancer (Chen et al 2001;Scholz et al 2007), gastric cancer (Moon et al 2006), angiosarcoma (Brown et al 2000), carcinosarcoma (Emoto et al 2004), and astrocytoma (Zagzag et al 1999). Interestingly, some studies report increased expression of Ang2 in both endothelial cells and tumor cells (e.g., Helfrich et al 2009;Detjen et al 2010), whereas other studies have shown Ang2 expression limited to the vasculature and not in tumor cells (Stratmann et al 1998;Zagzag et al 1999;Moon et al 2006;Goede et al 2010). In addition to in situ hybridization methods, analyses of RNA from whole and microdissected tissue have shown increased Ang2 in tumors versus corresponding normal tissue (e.g., Durkin et al 2004;Helfrich et al 2009;Goede et al 2010).…”

Molecular challenges of neuroendocrine tumors (Review)

“…Poor short term survival was reported with neurokinin A concentrations (>50 pg/ml) (158). Uniform expression of Angiopoietin-2 (Ang-2) messenger RNA (mRNA) described in endothelial cells of both nontransformed pancreatic tissue and pan NET tissue (159).…”

Placental growth factor supports neuroendocrine tumor growth and predicts disease prognosis in patients

“…administration of Ketanest (100 mg/kg) and Rompun (10 mg/kg). For tumor induction, the pancreas was exposed and 1!10 6 BON cells were injected into the head of the pancreas as previously described (Detjen et al 2010). Treatment of engrafted tumors was initiated at week 3 following tumor cell implantation.…”

“…Both drugs act at least in part via inhibition of tumor angiogenesis, promoting interest in the vascular features of NETs (Alexandraki & Kaltsas 2012). Well-established angiogenic growth factors, such as VEGF-A (Terris et al 1998) or angiopoietins (Srirajaskanthan et al 2009, Detjen et al 2010, are present in NETs. In addition, characteristic neuroendocrine secretion products, including chromogranin A fragments (Corti 2010) and serotonin (Asada et al 2009), affect angiogenesis and vascular permeability, altogether creating a unique stromal microenvironment.…”