Angiopoietin-2 Serum Levels Are Elevated in Patients With Liver Cirrhosis and Hepatocellular Carcinoma

Scholz, Arne; Rehm, Vanessa Annina; Rieke, S.; Derkow, Katja; Schulz, Petra; Neumann, Konrad; Koch, Inga; Pascu, Maria; Wiedenmann, Bertram; Berg, Thomas; Schott, Eckart

doi:10.1111/j.1572-0241.2007.01377.x

Cited by 59 publications

(57 citation statements)

References 42 publications

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“…Given the limited value of CgA in this subgroup of patients, Ang-2 might prove useful for tumor follow-up under these conditions. Similar observations of potential prognostic use of Ang-2 have been reported in selected tumor entities such as hepatocellular carcinoma (19), melanoma (15), or lung cancer (20), although elevated serum levels are not necessarily prognostic indicators (12). Taken together, our clinical and experimental data strongly link Ang-2 to disease progression of neuroendocrine tumors.…”

Section: Discussionsupporting

confidence: 68%

“…digoxigenin-UTP-labeled sense and antisense RNA-probes were generated by in vitro transcription (DIG-RNA Labeling Kit, Roche) of a 1,519-bp human Ang-2 cDNA fragment subcloned into the pBluescript II SK vector. The in situ hybridization procedure was done as previously described (19). A grading system for semiquantitative evaluation of Ang-2 mRNA expression was applied (grade 0, ≤5% of epithelial cells; grade 1, 5-25%; grade 2, 25-75%; grade 3, ≥75%).…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, overexpression of Ang-2 is associated with advanced disease and poor prognosis in several tumor entities such as breast cancer, gastric cancer, melanoma, lung cancer, colorectal cancer, and hepatocellular cancer (15,(17)(18)(19)(20)(21).…”

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confidence: 99%

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Angiopoietin-2 Promotes Disease Progression of Neuroendocrine Tumors

Detjen

Rieke²,

Deters³

et al. 2010

Clinical Cancer Research

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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.

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Section: Discussionsupporting

confidence: 68%

Section: Methodsmentioning

confidence: 99%

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Angiopoietin-2 Promotes Disease Progression of Neuroendocrine Tumors

Detjen

Rieke²,

Deters³

et al. 2010

Clinical Cancer Research

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“…In the presence of VEGF A, ANGPT2 potentiates the maturational activity of ANGPT1 on neovessels, whereas in its absence, ANGPT2 competes with ANGPT1, thus promoting vascular regression (26,27). Additionally, the interaction between ANGPT2 and VEGF plays a role in both liver fibrosis (28) and hepatocellular carcinoma (29). Our findings on the additive effect of ANGPT1 and ANGPT2 on MT in patients with BA may be explained by the fact that VEGF A is strongly expressed in portal structures, including the medial layer of hepatic artery branches in these patients (9).…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin 1 and angiopoietin 2 are associated with medial thickening of hepatic arterial branches in biliary atresia

et al. 2013

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Background: Biliary atresia (BA) is an infantile disorder characterized by progressive sclerosing cholangiopathy leading to biliary obstruction. First-line treatment of BA is hepatoportoenterostomy, the prognosis of which is related to age at surgery and to histological variables such as extent of fibrosis and ductular reaction. Hepatic arterial medial thickening (MT) suggests an arteriopathy in BA pathogenesis. We evaluated the expression of angiopoietin (ANGPT)/tyrosine kinase with immunoglobulin-like and epidermal growth factorlike domains 2 (TIE2) system in liver samples obtained from patients with BA, correlating it with MT, variables associated with disease severity, and postoperative prognosis. Methods: ANGPT1, ANGPT2, and TIE2 expression levels were assessed by quantitative PCR in liver samples obtained from BA patients (n = 23) at portoenterostomy and age-matched infants with intrahepatic cholestasis (IHC; n = 7). Histological variables were morphometrically assessed. results: ANGPT1 and ANGPT2 were overexpressed in BA in comparison with IHC (P = 0.024 and P = 0.029, respectively). In BA, ANGPTs expression was positively correlated with MT (ANGPT1: r s = 0.59, P = 0.013; ANGPT2: r s = 0.52, P = 0.032), not with the variables associated with disease severity. TIE2 and ANGPTs expression levels were negatively correlated (ANGPT1: r s = −0.73, P < 0.001; ANGPT2: r s = −0.54, P = 0.007). conclusion: In BA, there is overexpression of both ANGPT1 and ANGPT2, which is correlated with MT but not with age at portoenterostomy or with the histological variables associated with disease severity at the time of procedure. Biliary atresia (BA) is an infantile hepatobiliary disorder characterized by the obstruction of bile ducts associated with a progressive sclerosing cholangiopathy. The primary treatment for BA is a hepatoportoenterostomy, which should be performed as soon as possible, because its chances of longterm success decrease when the age at surgery increases (1). In addition to age at portoenterostomy, histological findings observed in biopsies collected at the time of the procedure, such as the extents of fibrosis and ductular reaction, represent variables associated with disease severity and can help foresee the postoperative outcomes (2).Regardless of portoenterostomy, BA induces cirrhosis by the continuous sclerosing cholangiopathy process, thus making this entity the leading cause of liver transplantation in children.The etiology of such a cholangiopathy remains elusive, and BA seems to represent more a phenotype than a unique disease. Our group is interested in the putative role of an arteriopathy in the development of BA because there are arteriographic (3), ultrasonographic (4-6), computed tomographic (7), histological (8), and immunohistochemical (9) evidences of medial thickening (MT) in hepatic artery branches owing to a vascular remodeling associated with hypoxia-ischemia in the portal tracts and porta hepatis. Knowledge on the behavior of angiogenic molecules in the liver of the affected patients...

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“…Because of a paucity of antibodies to Ang2 that allow robust immunohistochemistry, very few studies have documented the levels or location of Ang2 protein in diseased human tissue. 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).…”

Section: Expression Of Ang2 Is Increased In Several Disease Settingsmentioning

confidence: 99%