Cancer Research Infection and Cancer: Biology, Therapeutics, and Prevention Cancer Health Disparities Conference 2009
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhang, L.
Right arrow Articles by Coukos, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhang, L.
Right arrow Articles by Coukos, G.
[Cancer Research 63, 3403-3412, June 15, 2003]
© 2003 American Association for Cancer Research

Tumor Biology

Tumor-derived Vascular Endothelial Growth Factor Up-Regulates Angiopoietin-2 in Host Endothelium and Destabilizes Host Vasculature, Supporting Angiogenesis in Ovarian Cancer1

Lin Zhang, Nuo Yang, Jin-Wan Park, Dionyssios Katsaros, Stefano Fracchioli, Gaoyuan Cao, Ann O’Brien-Jenkins, Thomas C. Randall, Stephen C. Rubin and George Coukos2

Abramson Family Cancer Research Institute [L. Z., G. Co.], Center for Research on Reproduction and Women’s Health [L. Z., J-W. P., A. O-J., G. Co.], Division of Gynecologic Oncology, Department of Obstetrics and Gynecology [T. C. R., S. C. R., G. Co.], Cell and Molecular Biology Program and Department of Genetics [N. Y.], Division of Pulmonary, Allergy and Critical Care, Department of Medicine [G. Ca.], University of Pennsylvania, Philadelphia, Pennsylvania 19104, and Department of Obstetrics and Gynecology, University of Turin, Turin, Italy [D. K., S. F.]

Vascular remodeling in host tissues surrounding growing tumors is implicated in the successful development of tumor neovasculature. Cooperation between vascular endothelial growth factor (VEGF) and angiopoietins (Angs) is considered to be critical in this context. However, the mechanisms regulating the coordinated expression of these molecules remain, to date, elusive. In this study, we used a murine ovarian cancer angiogenesis model induced by overexpression of VEGF, as well as 52 human ovarian cancer specimens and 36 established cancer cell lines to characterize the expression and regulation of Ang-2 in the context of tumor angiogenesis. Using a combination of immunohistochemistry, laser capture microdissection and real-time quantitative reverse transcription-PCR, we showed that tumor-derived VEGF significantly up-regulated the expression of Ang-2 in host stroma endothelial cells, resulting in markedly increased Ang-2/Tie-2 mRNA copy number ratio in vivo. In vitro experiments showed that VEGF directly up-regulated Ang-2, which is mediated via VEGF receptor-2/flk-1/KDR pathway, in cultured endothelial cells through transcriptional activation rather than the enhanced mRNA stability. In human ovarian cancer, Ang-2 was primarily expressed in stroma endothelial cells and detectable in tumor cells of only 12% tumor specimens; however, it was not detected in the majority of established ovarian cancer cell lines. In addition, a significant correlation was observed between VEGF and Ang-2 mRNA expression (P < 0.01) but not between VEGF and Ang-1 or Tie-2 in human ovarian cancer specimens. In the mouse ovarian cancer model, up-regulation of Ang-2 in host stroma endothelial cells was significantly associated with pericyte loss and instability of the host vasculature surrounding the tumor. Our study suggests a novel mechanism by which tumor-derived VEGF interacts with Angs/Tie-2 system in host stroma endothelial cells and induces in a paracrine manner the remodeling of host vasculature to support angiogenesis during tumor growth.




This article has been cited by other articles:


Home page
 Mol. Pharmacol.Home page
H. Cho, H.-Y. Lee, D.-R. Ahn, S. Y. Kim, S. Kim, K. B. Lee, Y. M. Lee, H. Park, and E. G. Yang
Baicalein Induces Functional Hypoxia-Inducible Factor-1{alpha} and Angiogenesis
Mol. Pharmacol., July 1, 2008; 74(1): 70 - 81.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
A. Braun, H. Xu, F. Hu, P. Kocherlakota, D. Siegel, P. Chander, Z. Ungvari, A. Csiszar, M. Nedergaard, and P. Ballabh
Paucity of Pericytes in Germinal Matrix Vasculature of Premature Infants
J. Neurosci., October 31, 2007; 27(44): 12012 - 12024.
[Abstract] [Full Text] [PDF]

Home page
 Mol Cancer ResHome page
N. Said, M. J. Socha, J. J. Olearczyk, A. A. Elmarakby, J. D. Imig, and K. Motamed
Normalization of the Ovarian Cancer Microenvironment by SPARC
Mol. Cancer Res., October 1, 2007; 5(10): 1015 - 1030.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
L. Zhang, J. Huang, N. Yang, J. Greshock, S. Liang, K. Hasegawa, A. Giannakakis, N. Poulos, A. O'Brien-Jenkins, D. Katsaros, et al.
Integrative Genomic Analysis of Phosphatidylinositol 3'-Kinase Family Identifies PIK3R3 as a Potential Therapeutic Target in Epithelial Ovarian Cancer
Clin. Cancer Res., September 15, 2007; 13(18): 5314 - 5321.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Y. Zou, Y. Chen, Y. Jiang, J. Gao, and J. Gu
Targeting Matrix Metalloproteinases and Endothelial Cells with a Fusion Peptide against Tumor
Cancer Res., August 1, 2007; 67(15): 7295 - 7300.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Ophthalmol.Home page
A. M Abu El-Asrar, L. Missotten, and K. Geboes
Expression of hypoxia-inducible factor-1{alpha} and the protein products of its target genes in diabetic fibrovascular epiretinal membranes
Br. J. Ophthalmol., June 1, 2007; 91(6): 822 - 826.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Y. Cao, P. Sonveaux, S. Liu, Y. Zhao, J. Mi, B. M. Clary, C.-Y. Li, C. D. Kontos, and M. W. Dewhirst
Systemic Overexpression of Angiopoietin-2 Promotes Tumor Microvessel Regression and Inhibits Angiogenesis and Tumor Growth
Cancer Res., April 15, 2007; 67(8): 3835 - 3844.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
N. Kociok, S. Radetzky, T. U. Krohne, C. Gavranic, and A. M. Joussen
Pathological but Not Physiological Retinal Neovascularization Is Altered in TNF-Rp55-Receptor-Deficient Mice
Invest. Ophthalmol. Vis. Sci., November 1, 2006; 47(11): 5057 - 5065.
[Abstract] [Full Text] [PDF]

Home page
 JNMHome page
P. Kunz, J. Hoffend, A. Altmann, A. Dimitrakopoulou-Strauss, D. Koczan, M. Eisenhut, G. A. Bonaterra, T. J. Dengler, W. Mier, U. Haberkorn, et al.
Angiopoietin-2 Overexpression in Morris Hepatoma Results in Increased Tumor Perfusion and Induction of Critical Angiogenesis-Promoting Genes
J. Nucl. Med., September 1, 2006; 47(9): 1515 - 1524.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. Zhang, J. A.F. Hannay, J. Liu, P. Das, M. Zhan, T. Nguyen, D. J. Hicklin, D. Yu, R. E. Pollock, and D. Lev
Vascular Endothelial Growth Factor Overexpression by Soft Tissue Sarcoma Cells: Implications for Tumor Growth, Metastasis, and Chemoresistance.
Cancer Res., September 1, 2006; 66(17): 8770 - 8778.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
X.-B. Liang, L.-J. Ma, T. Naito, Y. Wang, M. Madaio, R. Zent, A. Pozzi, and A. B. Fogo
Angiotensin Type 1 Receptor Blocker Restores Podocyte Potential to Promote Glomerular Endothelial Cell Growth
J. Am. Soc. Nephrol., July 1, 2006; 17(7): 1886 - 1895.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. Zhang, J. Huang, N. Yang, S. Liang, A. Barchetti, A. Giannakakis, M. G. Cadungog, A. O'Brien-Jenkins, M. Massobrio, K. F. Roby, et al.
Integrative Genomic Analysis of Protein Kinase C (PKC) Family Identifies PKC{iota} as a Biomarker and Potential Oncogene in Ovarian Carcinoma.
Cancer Res., May 1, 2006; 66(9): 4627 - 4635.
[Abstract] [Full Text] [PDF]

Home page
 aacredbookHome page
O. Martinez-Maza
Overview of the Immune System and Use of Immunologic Biomarkers to Interrogate Cancer Etiology
Am. Assoc. Cancer Res. Educ. Book, April 1, 2006; 2006(1): 31 - 34.
[Full Text] [PDF]

Home page
 Stem CellsHome page
A. S. Arbab, V. Frenkel, S. D. Pandit, S. A. Anderson, G. T. Yocum, M. Bur, H. M. Khuu, E. J. Read, and J. A. Frank
Magnetic Resonance Imaging and Confocal Microscopy Studies of Magnetically Labeled Endothelial Progenitor Cells Trafficking to Sites of Tumor Angiogenesis
Stem Cells, March 1, 2006; 24(3): 671 - 678.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
N. Said and K. Motamed
Absence of Host-Secreted Protein Acidic and Rich in Cysteine (SPARC) Augments Peritoneal Ovarian Carcinomatosis
Am. J. Pathol., December 1, 2005; 167(6): 1739 - 1752.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
H Yoshiji, S Kuriyama, R Noguchi, J Yoshii, Y Ikenaka, K Yanase, T Namisaki, M Kitade, M Uemura, T Masaki, et al.
Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice
Gut, December 1, 2005; 54(12): 1768 - 1775.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
A. Armulik, A. Abramsson, and C. Betsholtz
Endothelial/Pericyte Interactions
Circ. Res., September 16, 2005; 97(6): 512 - 523.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
J. S. Hardwick, Y. Yang, C. Zhang, B. Shi, R. McFall, E. J. Koury, S. L. Hill, H. Dai, R. Wasserman, R. L. Phillips, et al.
Identification of biomarkers for tumor endothelial cell proliferation through gene expression profiling
Mol. Cancer Ther., March 1, 2005; 4(3): 413 - 425.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
M. Scharpfenecker, U. Fiedler, Y. Reiss, and H. G. Augustin
The Tie-2 ligand Angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism
J. Cell Sci., February 15, 2005; 118(4): 771 - 780.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. Zhang, N. Yang, J. Huang, R. J. Buckanovich, S. Liang, A. Barchetti, C. Vezzani, A. O'Brien-Jenkins, J. Wang, M. R. Ward, et al.
Transcriptional Coactivator Drosophila Eyes Absent Homologue 2 Is Up-Regulated in Epithelial Ovarian Cancer and Promotes Tumor Growth
Cancer Res., February 1, 2005; 65(3): 925 - 932.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Ophthalmol.Home page
P L Lip, S Chatterjee, G J Caine, M Hope-Ross, J Gibson, A D Blann, and G Y H Lip
Plasma vascular endothelial growth factor, angiopoietin-2, and soluble angiopoietin receptor tie-2 in diabetic retinopathy: effects of laser photocoagulation and angiotensin receptor blockade
Br. J. Ophthalmol., December 1, 2004; 88(12): 1543 - 1546.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
A. Hegen, S. Koidl, K. Weindel, D. Marme, H. G. Augustin, and U. Fiedler
Expression of Angiopoietin-2 in Endothelial Cells Is Controlled by Positive and Negative Regulatory Promoter Elements
Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1803 - 1809.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
O. Stoeltzing, M. F. McCarty, J. S. Wey, F. Fan, W. Liu, A. Belcheva, C. D. Bucana, G. L. Semenza, and L. M. Ellis
Role of Hypoxia-Inducible Factor 1{alpha} in Gastric Cancer Cell Growth, Angiogenesis, and Vessel Maturation
J Natl Cancer Inst, June 16, 2004; 96(12): 946 - 956.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
U. Fiedler, M. Scharpfenecker, S. Koidl, A. Hegen, V. Grunow, J. M. Schmidt, W. Kriz, G. Thurston, and H. G. Augustin
The Tie-2 ligand Angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies
Blood, June 1, 2004; 103(11): 4150 - 4156.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
C. Daly, V. Wong, E. Burova, Y. Wei, S. Zabski, J. Griffiths, K.-M. Lai, H. C. Lin, E. Ioffe, G. D. Yancopoulos, et al.
Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1)
Genes & Dev., May 1, 2004; 18(9): 1060 - 1071.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
K. Asosingh, H. De Raeve, E. Menu, I. Van Riet, E. Van Marck, B. Van Camp, and K. Vanderkerken
Angiogenic switch during 5T2MM murine myeloma tumorigenesis: role of CD45 heterogeneity
Blood, April 15, 2004; 103(8): 3131 - 3137.
[Abstract] [Full Text] [PDF]

Home page
 Recent Prog Horm ResHome page
M. L. Wahl, T. L. Moser, and S. V. Pizzo
Angiostatin and Anti-angiogenic Therapy in Human Disease
Recent Prog. Horm. Res., January 1, 2004; 59(1): 73 - 104.
[Abstract] [Full Text]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2003 by the American Association for Cancer Research.