Angiopoietin-2 Promotes Disease Progression of Neuroendocrine Tumors
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 a...
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| Veröffentlicht in: | Clinical cancer research 2010-01, Vol.16 (2), p.420-429 |
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| creator | Detjen, Katharina M Rieke, Svenja Deters, Antje Schulz, Petra Rexin, Annett Vollmer, Sonja Hauff, Peter Wiedenmann, Bertram Pavel, Marianne Scholz, Arne |
| description | 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. |
| doi_str_mv | 10.1158/1078-0432.CCR-09-1924 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_733869083</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>733869083</sourcerecordid><originalsourceid>FETCH-LOGICAL-c439t-a468b56984e27e1d53d2b8cd2df3151bf0edb06f975cdfcacfd88f217d8a7d383</originalsourceid><addsrcrecordid>eNpFkMtOwzAQRS0EoqXwCaDsWKX4ESfOskp5SRUgVNaWY49boyYudiPE35OoLaxmNDp3ZnQQuiZ4SggXdwQXIsUZo9Oqek9xmZKSZidoTDgvUkZzftr3R2aELmL8xJhkBGfnaEQxzgUuyjGaz9qV81vvYOfalCZvwTd-BzGZuwgqwjBYBYjR-TbxNnmBLnhojdfBtZAsu8aHeInOrNpEuDrUCfp4uF9WT-ni9fG5mi1SnbFyl6osFzXPS5EBLYAYzgythTbUWEY4qS0GU-PclgXXxmqlrRHCUlIYoQrDBJug2_3ebfBfHcSdbFzUsNmoFnwXZcGYyEssWE_yPamDjzGAldvgGhV-JMFy8CcHN3JwI3t_Epdy8Nfnbg4XuroB85c6Cvt_Ye1W628XQGrVagi9IlBBryXJJZUZxewXbgx6Ww</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>733869083</pqid></control><display><type>article</type><title>Angiopoietin-2 Promotes Disease Progression of Neuroendocrine Tumors</title><source>MEDLINE</source><source>American Association for Cancer Research</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Detjen, Katharina M ; Rieke, Svenja ; Deters, Antje ; Schulz, Petra ; Rexin, Annett ; Vollmer, Sonja ; Hauff, Peter ; Wiedenmann, Bertram ; Pavel, Marianne ; Scholz, Arne</creator><creatorcontrib>Detjen, Katharina M ; Rieke, Svenja ; Deters, Antje ; Schulz, Petra ; Rexin, Annett ; Vollmer, Sonja ; Hauff, Peter ; Wiedenmann, Bertram ; Pavel, Marianne ; Scholz, Arne</creatorcontrib><description>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.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-09-1924</identifier><identifier>PMID: 20068079</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Adult ; Aged ; angiopoietin ; Angiopoietin-2 - blood ; Angiopoietin-2 - genetics ; Angiopoietin-2 - physiology ; Animals ; Case-Control Studies ; Disease Progression ; Female ; Gastrointestinal Neoplasms - blood ; Gastrointestinal Neoplasms - diagnosis ; Gastrointestinal Neoplasms - genetics ; Gastrointestinal Neoplasms - pathology ; Gene Expression Regulation, Neoplastic ; Humans ; Lymphatic Metastasis ; Male ; Mice ; Middle Aged ; Neoplasm Transplantation ; Neovascularization, Pathologic - genetics ; neuroendocrine tumors ; Neuroendocrine Tumors - blood ; Neuroendocrine Tumors - diagnosis ; Neuroendocrine Tumors - genetics ; Neuroendocrine Tumors - pathology ; Pancreatic Neoplasms - blood ; Pancreatic Neoplasms - diagnosis ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - pathology ; Prognosis ; prognostic marker ; Transplantation, Heterologous ; Tumor Cells, Cultured ; Young Adult</subject><ispartof>Clinical cancer research, 2010-01, Vol.16 (2), p.420-429</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c439t-a468b56984e27e1d53d2b8cd2df3151bf0edb06f975cdfcacfd88f217d8a7d383</citedby><cites>FETCH-LOGICAL-c439t-a468b56984e27e1d53d2b8cd2df3151bf0edb06f975cdfcacfd88f217d8a7d383</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20068079$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Detjen, Katharina M</creatorcontrib><creatorcontrib>Rieke, Svenja</creatorcontrib><creatorcontrib>Deters, Antje</creatorcontrib><creatorcontrib>Schulz, Petra</creatorcontrib><creatorcontrib>Rexin, Annett</creatorcontrib><creatorcontrib>Vollmer, Sonja</creatorcontrib><creatorcontrib>Hauff, Peter</creatorcontrib><creatorcontrib>Wiedenmann, Bertram</creatorcontrib><creatorcontrib>Pavel, Marianne</creatorcontrib><creatorcontrib>Scholz, Arne</creatorcontrib><title>Angiopoietin-2 Promotes Disease Progression of Neuroendocrine Tumors</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>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.</description><subject>Adult</subject><subject>Aged</subject><subject>angiopoietin</subject><subject>Angiopoietin-2 - blood</subject><subject>Angiopoietin-2 - genetics</subject><subject>Angiopoietin-2 - physiology</subject><subject>Animals</subject><subject>Case-Control Studies</subject><subject>Disease Progression</subject><subject>Female</subject><subject>Gastrointestinal Neoplasms - blood</subject><subject>Gastrointestinal Neoplasms - diagnosis</subject><subject>Gastrointestinal Neoplasms - genetics</subject><subject>Gastrointestinal Neoplasms - pathology</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Lymphatic Metastasis</subject><subject>Male</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Neoplasm Transplantation</subject><subject>Neovascularization, Pathologic - genetics</subject><subject>neuroendocrine tumors</subject><subject>Neuroendocrine Tumors - blood</subject><subject>Neuroendocrine Tumors - diagnosis</subject><subject>Neuroendocrine Tumors - genetics</subject><subject>Neuroendocrine Tumors - pathology</subject><subject>Pancreatic Neoplasms - blood</subject><subject>Pancreatic Neoplasms - diagnosis</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Prognosis</subject><subject>prognostic marker</subject><subject>Transplantation, Heterologous</subject><subject>Tumor Cells, Cultured</subject><subject>Young Adult</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkMtOwzAQRS0EoqXwCaDsWKX4ESfOskp5SRUgVNaWY49boyYudiPE35OoLaxmNDp3ZnQQuiZ4SggXdwQXIsUZo9Oqek9xmZKSZidoTDgvUkZzftr3R2aELmL8xJhkBGfnaEQxzgUuyjGaz9qV81vvYOfalCZvwTd-BzGZuwgqwjBYBYjR-TbxNnmBLnhojdfBtZAsu8aHeInOrNpEuDrUCfp4uF9WT-ni9fG5mi1SnbFyl6osFzXPS5EBLYAYzgythTbUWEY4qS0GU-PclgXXxmqlrRHCUlIYoQrDBJug2_3ebfBfHcSdbFzUsNmoFnwXZcGYyEssWE_yPamDjzGAldvgGhV-JMFy8CcHN3JwI3t_Epdy8Nfnbg4XuroB85c6Cvt_Ye1W628XQGrVagi9IlBBryXJJZUZxewXbgx6Ww</recordid><startdate>20100115</startdate><enddate>20100115</enddate><creator>Detjen, Katharina M</creator><creator>Rieke, Svenja</creator><creator>Deters, Antje</creator><creator>Schulz, Petra</creator><creator>Rexin, Annett</creator><creator>Vollmer, Sonja</creator><creator>Hauff, Peter</creator><creator>Wiedenmann, Bertram</creator><creator>Pavel, Marianne</creator><creator>Scholz, Arne</creator><general>American Association for Cancer Research</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20100115</creationdate><title>Angiopoietin-2 Promotes Disease Progression of Neuroendocrine Tumors</title><author>Detjen, Katharina M ; Rieke, Svenja ; Deters, Antje ; Schulz, Petra ; Rexin, Annett ; Vollmer, Sonja ; Hauff, Peter ; Wiedenmann, Bertram ; Pavel, Marianne ; Scholz, Arne</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c439t-a468b56984e27e1d53d2b8cd2df3151bf0edb06f975cdfcacfd88f217d8a7d383</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adult</topic><topic>Aged</topic><topic>angiopoietin</topic><topic>Angiopoietin-2 - blood</topic><topic>Angiopoietin-2 - genetics</topic><topic>Angiopoietin-2 - physiology</topic><topic>Animals</topic><topic>Case-Control Studies</topic><topic>Disease Progression</topic><topic>Female</topic><topic>Gastrointestinal Neoplasms - blood</topic><topic>Gastrointestinal Neoplasms - diagnosis</topic><topic>Gastrointestinal Neoplasms - genetics</topic><topic>Gastrointestinal Neoplasms - pathology</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Lymphatic Metastasis</topic><topic>Male</topic><topic>Mice</topic><topic>Middle Aged</topic><topic>Neoplasm Transplantation</topic><topic>Neovascularization, Pathologic - genetics</topic><topic>neuroendocrine tumors</topic><topic>Neuroendocrine Tumors - blood</topic><topic>Neuroendocrine Tumors - diagnosis</topic><topic>Neuroendocrine Tumors - genetics</topic><topic>Neuroendocrine Tumors - pathology</topic><topic>Pancreatic Neoplasms - blood</topic><topic>Pancreatic Neoplasms - diagnosis</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Prognosis</topic><topic>prognostic marker</topic><topic>Transplantation, Heterologous</topic><topic>Tumor Cells, Cultured</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Detjen, Katharina M</creatorcontrib><creatorcontrib>Rieke, Svenja</creatorcontrib><creatorcontrib>Deters, Antje</creatorcontrib><creatorcontrib>Schulz, Petra</creatorcontrib><creatorcontrib>Rexin, Annett</creatorcontrib><creatorcontrib>Vollmer, Sonja</creatorcontrib><creatorcontrib>Hauff, Peter</creatorcontrib><creatorcontrib>Wiedenmann, Bertram</creatorcontrib><creatorcontrib>Pavel, Marianne</creatorcontrib><creatorcontrib>Scholz, Arne</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Detjen, Katharina M</au><au>Rieke, Svenja</au><au>Deters, Antje</au><au>Schulz, Petra</au><au>Rexin, Annett</au><au>Vollmer, Sonja</au><au>Hauff, Peter</au><au>Wiedenmann, Bertram</au><au>Pavel, Marianne</au><au>Scholz, Arne</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Angiopoietin-2 Promotes Disease Progression of Neuroendocrine Tumors</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2010-01-15</date><risdate>2010</risdate><volume>16</volume><issue>2</issue><spage>420</spage><epage>429</epage><pages>420-429</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><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.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>20068079</pmid><doi>10.1158/1078-0432.CCR-09-1924</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Clinical cancer research, 2010-01, Vol.16 (2), p.420-429 |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adult Aged angiopoietin Angiopoietin-2 - blood Angiopoietin-2 - genetics Angiopoietin-2 - physiology Animals Case-Control Studies Disease Progression Female Gastrointestinal Neoplasms - blood Gastrointestinal Neoplasms - diagnosis Gastrointestinal Neoplasms - genetics Gastrointestinal Neoplasms - pathology Gene Expression Regulation, Neoplastic Humans Lymphatic Metastasis Male Mice Middle Aged Neoplasm Transplantation Neovascularization, Pathologic - genetics neuroendocrine tumors Neuroendocrine Tumors - blood Neuroendocrine Tumors - diagnosis Neuroendocrine Tumors - genetics Neuroendocrine Tumors - pathology Pancreatic Neoplasms - blood Pancreatic Neoplasms - diagnosis Pancreatic Neoplasms - genetics Pancreatic Neoplasms - pathology Prognosis prognostic marker Transplantation, Heterologous Tumor Cells, Cultured Young Adult |
| title | Angiopoietin-2 Promotes Disease Progression of Neuroendocrine Tumors |
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