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Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas
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| Zeitschriftentitel: | Clinical Cancer Research |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , |
| In: | Clinical Cancer Research, 16, 2010, 14, S. 3618-3627 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Association for Cancer Research (AACR)
|
| Schlagwörter: |
| author_facet |
Chae, Sung-Suk Kamoun, Walid S. Farrar, Christian T. Kirkpatrick, Nathaniel D. Niemeyer, Elisabeth de Graaf, Annemarie M.A. Sorensen, A. Gregory Munn, Lance L. Jain, Rakesh K. Fukumura, Dai Chae, Sung-Suk Kamoun, Walid S. Farrar, Christian T. Kirkpatrick, Nathaniel D. Niemeyer, Elisabeth de Graaf, Annemarie M.A. Sorensen, A. Gregory Munn, Lance L. Jain, Rakesh K. Fukumura, Dai |
|---|---|
| author |
Chae, Sung-Suk Kamoun, Walid S. Farrar, Christian T. Kirkpatrick, Nathaniel D. Niemeyer, Elisabeth de Graaf, Annemarie M.A. Sorensen, A. Gregory Munn, Lance L. Jain, Rakesh K. Fukumura, Dai |
| spellingShingle |
Chae, Sung-Suk Kamoun, Walid S. Farrar, Christian T. Kirkpatrick, Nathaniel D. Niemeyer, Elisabeth de Graaf, Annemarie M.A. Sorensen, A. Gregory Munn, Lance L. Jain, Rakesh K. Fukumura, Dai Clinical Cancer Research Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas Cancer Research Oncology |
| author_sort |
chae, sung-suk |
| spelling |
Chae, Sung-Suk Kamoun, Walid S. Farrar, Christian T. Kirkpatrick, Nathaniel D. Niemeyer, Elisabeth de Graaf, Annemarie M.A. Sorensen, A. Gregory Munn, Lance L. Jain, Rakesh K. Fukumura, Dai 1078-0432 1557-3265 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1078-0432.ccr-09-3073 <jats:title>Abstract</jats:title> <jats:p>Purpose: In brain tumors, cerebral edema is a significant source of morbidity and mortality. Recent studies have shown that inhibition of vascular endothelial growth factor (VEGF) signaling induces transient vascular normalization and reduces cerebral edema, resulting in a modest survival benefit in glioblastoma patients. During anti-VEGF treatment, circulating levels of angiopoietin (Ang)-2 remained high after an initial minor reduction. It is not known, however, whether Ang-2 can modulate anti-VEGF treatment of glioblastoma. Here, we used an orthotopic glioma model to test the hypothesis that Ang-2 is an additional target for improving the efficacy of current anti-VEGF therapies in glioma patients.</jats:p> <jats:p>Experimental Design: To recapitulate high levels of Ang-2 in glioblastoma patients during anti-VEGF treatment, Ang-2 was ectopically expressed in U87 glioma cells. Animal survival and tumor growth were assessed to determine the effects of Ang-2 and anti–VEGF receptor 2 (VEGFR2) treatment. We also monitored morphologic and functional vascular changes using multiphoton laser scanning microscopy and immunohistochemistry.</jats:p> <jats:p>Results: Ectopic expression of Ang-2 had no effect on vascular permeability, tumor growth, or survival, although it resulted in higher vascular density, with dilated vessels and reduced mural cell coverage. On the other hand, when combined with anti-VEGFR2 treatment, Ang-2 destabilized vessels without affecting vessel regression and compromised the survival benefit of VEGFR2 inhibition by increasing vascular permeability. VEGFR2 inhibition normalized tumor vasculature whereas ectopic expression of Ang-2 diminished the beneficial effects of VEGFR2 blockade by inhibiting vessel normalization.</jats:p> <jats:p>Conclusion: Cancer treatment regimens combining anti-VEGF and anti-Ang-2 agents may be an effective strategy to improve the efficacy of current anti-VEGF therapies. Clin Cancer Res; 16(14); 3618–27. ©2010 AACR.</jats:p> Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas Clinical Cancer Research |
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American Association for Cancer Research (AACR), 2010 |
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American Association for Cancer Research (AACR), 2010 |
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1557-3265 1078-0432 |
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| title |
Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas |
| title_unstemmed |
Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas |
| title_full |
Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas |
| title_fullStr |
Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas |
| title_full_unstemmed |
Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas |
| title_short |
Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas |
| title_sort |
angiopoietin-2 interferes with anti-vegfr2–induced vessel normalization and survival benefit in mice bearing gliomas |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1158/1078-0432.ccr-09-3073 |
| publishDate |
2010 |
| physical |
3618-3627 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>Purpose: In brain tumors, cerebral edema is a significant source of morbidity and mortality. Recent studies have shown that inhibition of vascular endothelial growth factor (VEGF) signaling induces transient vascular normalization and reduces cerebral edema, resulting in a modest survival benefit in glioblastoma patients. During anti-VEGF treatment, circulating levels of angiopoietin (Ang)-2 remained high after an initial minor reduction. It is not known, however, whether Ang-2 can modulate anti-VEGF treatment of glioblastoma. Here, we used an orthotopic glioma model to test the hypothesis that Ang-2 is an additional target for improving the efficacy of current anti-VEGF therapies in glioma patients.</jats:p>
<jats:p>Experimental Design: To recapitulate high levels of Ang-2 in glioblastoma patients during anti-VEGF treatment, Ang-2 was ectopically expressed in U87 glioma cells. Animal survival and tumor growth were assessed to determine the effects of Ang-2 and anti–VEGF receptor 2 (VEGFR2) treatment. We also monitored morphologic and functional vascular changes using multiphoton laser scanning microscopy and immunohistochemistry.</jats:p>
<jats:p>Results: Ectopic expression of Ang-2 had no effect on vascular permeability, tumor growth, or survival, although it resulted in higher vascular density, with dilated vessels and reduced mural cell coverage. On the other hand, when combined with anti-VEGFR2 treatment, Ang-2 destabilized vessels without affecting vessel regression and compromised the survival benefit of VEGFR2 inhibition by increasing vascular permeability. VEGFR2 inhibition normalized tumor vasculature whereas ectopic expression of Ang-2 diminished the beneficial effects of VEGFR2 blockade by inhibiting vessel normalization.</jats:p>
<jats:p>Conclusion: Cancer treatment regimens combining anti-VEGF and anti-Ang-2 agents may be an effective strategy to improve the efficacy of current anti-VEGF therapies. Clin Cancer Res; 16(14); 3618–27. ©2010 AACR.</jats:p> |
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| author | Chae, Sung-Suk, Kamoun, Walid S., Farrar, Christian T., Kirkpatrick, Nathaniel D., Niemeyer, Elisabeth, de Graaf, Annemarie M.A., Sorensen, A. Gregory, Munn, Lance L., Jain, Rakesh K., Fukumura, Dai |
| author_facet | Chae, Sung-Suk, Kamoun, Walid S., Farrar, Christian T., Kirkpatrick, Nathaniel D., Niemeyer, Elisabeth, de Graaf, Annemarie M.A., Sorensen, A. Gregory, Munn, Lance L., Jain, Rakesh K., Fukumura, Dai, Chae, Sung-Suk, Kamoun, Walid S., Farrar, Christian T., Kirkpatrick, Nathaniel D., Niemeyer, Elisabeth, de Graaf, Annemarie M.A., Sorensen, A. Gregory, Munn, Lance L., Jain, Rakesh K., Fukumura, Dai |
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| description | <jats:title>Abstract</jats:title> <jats:p>Purpose: In brain tumors, cerebral edema is a significant source of morbidity and mortality. Recent studies have shown that inhibition of vascular endothelial growth factor (VEGF) signaling induces transient vascular normalization and reduces cerebral edema, resulting in a modest survival benefit in glioblastoma patients. During anti-VEGF treatment, circulating levels of angiopoietin (Ang)-2 remained high after an initial minor reduction. It is not known, however, whether Ang-2 can modulate anti-VEGF treatment of glioblastoma. Here, we used an orthotopic glioma model to test the hypothesis that Ang-2 is an additional target for improving the efficacy of current anti-VEGF therapies in glioma patients.</jats:p> <jats:p>Experimental Design: To recapitulate high levels of Ang-2 in glioblastoma patients during anti-VEGF treatment, Ang-2 was ectopically expressed in U87 glioma cells. Animal survival and tumor growth were assessed to determine the effects of Ang-2 and anti–VEGF receptor 2 (VEGFR2) treatment. We also monitored morphologic and functional vascular changes using multiphoton laser scanning microscopy and immunohistochemistry.</jats:p> <jats:p>Results: Ectopic expression of Ang-2 had no effect on vascular permeability, tumor growth, or survival, although it resulted in higher vascular density, with dilated vessels and reduced mural cell coverage. On the other hand, when combined with anti-VEGFR2 treatment, Ang-2 destabilized vessels without affecting vessel regression and compromised the survival benefit of VEGFR2 inhibition by increasing vascular permeability. VEGFR2 inhibition normalized tumor vasculature whereas ectopic expression of Ang-2 diminished the beneficial effects of VEGFR2 blockade by inhibiting vessel normalization.</jats:p> <jats:p>Conclusion: Cancer treatment regimens combining anti-VEGF and anti-Ang-2 agents may be an effective strategy to improve the efficacy of current anti-VEGF therapies. Clin Cancer Res; 16(14); 3618–27. ©2010 AACR.</jats:p> |
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| imprint | American Association for Cancer Research (AACR), 2010 |
| imprint_str_mv | American Association for Cancer Research (AACR), 2010 |
| institution | DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1, DE-105, DE-14, DE-Ch1, DE-L229 |
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| spelling | Chae, Sung-Suk Kamoun, Walid S. Farrar, Christian T. Kirkpatrick, Nathaniel D. Niemeyer, Elisabeth de Graaf, Annemarie M.A. Sorensen, A. Gregory Munn, Lance L. Jain, Rakesh K. Fukumura, Dai 1078-0432 1557-3265 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1078-0432.ccr-09-3073 <jats:title>Abstract</jats:title> <jats:p>Purpose: In brain tumors, cerebral edema is a significant source of morbidity and mortality. Recent studies have shown that inhibition of vascular endothelial growth factor (VEGF) signaling induces transient vascular normalization and reduces cerebral edema, resulting in a modest survival benefit in glioblastoma patients. During anti-VEGF treatment, circulating levels of angiopoietin (Ang)-2 remained high after an initial minor reduction. It is not known, however, whether Ang-2 can modulate anti-VEGF treatment of glioblastoma. Here, we used an orthotopic glioma model to test the hypothesis that Ang-2 is an additional target for improving the efficacy of current anti-VEGF therapies in glioma patients.</jats:p> <jats:p>Experimental Design: To recapitulate high levels of Ang-2 in glioblastoma patients during anti-VEGF treatment, Ang-2 was ectopically expressed in U87 glioma cells. Animal survival and tumor growth were assessed to determine the effects of Ang-2 and anti–VEGF receptor 2 (VEGFR2) treatment. We also monitored morphologic and functional vascular changes using multiphoton laser scanning microscopy and immunohistochemistry.</jats:p> <jats:p>Results: Ectopic expression of Ang-2 had no effect on vascular permeability, tumor growth, or survival, although it resulted in higher vascular density, with dilated vessels and reduced mural cell coverage. On the other hand, when combined with anti-VEGFR2 treatment, Ang-2 destabilized vessels without affecting vessel regression and compromised the survival benefit of VEGFR2 inhibition by increasing vascular permeability. VEGFR2 inhibition normalized tumor vasculature whereas ectopic expression of Ang-2 diminished the beneficial effects of VEGFR2 blockade by inhibiting vessel normalization.</jats:p> <jats:p>Conclusion: Cancer treatment regimens combining anti-VEGF and anti-Ang-2 agents may be an effective strategy to improve the efficacy of current anti-VEGF therapies. Clin Cancer Res; 16(14); 3618–27. ©2010 AACR.</jats:p> Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas Clinical Cancer Research |
| spellingShingle | Chae, Sung-Suk, Kamoun, Walid S., Farrar, Christian T., Kirkpatrick, Nathaniel D., Niemeyer, Elisabeth, de Graaf, Annemarie M.A., Sorensen, A. Gregory, Munn, Lance L., Jain, Rakesh K., Fukumura, Dai, Clinical Cancer Research, Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas, Cancer Research, Oncology |
| title | Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas |
| title_full | Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas |
| title_fullStr | Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas |
| title_full_unstemmed | Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas |
| title_short | Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas |
| title_sort | angiopoietin-2 interferes with anti-vegfr2–induced vessel normalization and survival benefit in mice bearing gliomas |
| title_unstemmed | Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1158/1078-0432.ccr-09-3073 |