© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 6, 437-448,
March 19, 2003
© 2003 Oxford University Press
ARTICLE |
Effects of Interferon Alpha on Vascular Endothelial Growth Factor Gene Transcription and Tumor Angiogenesis
Affiliations of authors: Z. von Marschall, A. Scholz, T. Cramer, G. Schäfer, B. Wiedenmann, M. Höcker, S. Rosewicz, Department of Hepatology, Gastroenterology, Endocrinology and Metabolism, Charité, Campus Virchow-Klinikum, Humboldt-University, Berlin, Germany; M. Schirner, Corporate Research, Schering AG, Berlin; K. Öberg, Department of Internal Medicine, University Hospital, Uppsala, Sweden.
Correspondence to: Stefan Rosewicz, M.D., Department of Hepatology, Gastroenterology, Endocrinology and Metabolism, Charité, Campus Virchow-Klinikum, Humboldt-University, Augustenburger Platz 1, 13353 Berlin, Germany (e-mail: stefan.rosewicz{at}charite.de).
Background: Interferon alpha (IFN-
) has antiangiogenic activity, although the underlying mechanism of action is unclear. Because human neuroendocrine (NE) tumors are highly vascularized and sensitive to IFN-, we investigated whether the therapeutic effects of IFN- result from an inhibition of angiogenesis mediated by a decrease in vascular endothelial growth factor (VEGF) gene expression. Methods: VEGF gene and protein expression was analyzed in NE tumors by immunohistochemistry and in NE tumor cell lines by quantitative competitive reverse transcription–polymerase chain reaction (RT–PCR) and enzyme-linked immunosorbent assay (ELISA). VEGF promoter–reporter gene constructs containing various deletions or mutations and gel shift assays were used to identify minimal promoter requirements and potential transcription factors. A xenograft nude mouse model (five mice per group) was used to determine the effect of IFN- on tumor growth (NE Bon cells and pancreatic Capan-1 cells) and microvessel density. Liver metastases from eight patients with NE tumors were analyzed for microvessel density, VEGF mRNA content, and VEGF plasma levels before and after initiation of IFN- therapy. Results: NE tumors and cell lines expressed VEGF mRNA and secreted VEGF protein. In vitro, IFN- decreased transcription of VEGF gene expression through an Sp1- and/or Sp3-dependent inhibition of VEGF promoter activity. Compared with vehicle treatment in mice, IFN- inhibited tumor growth by 36% and reduced microvessel density from 56 (95% confidence interval [CI] = 49 to 69) to 37 per x400 Field (95% CI = 32 to 41, P = .015). Patients with NE tumors had lower VEGF plasma levels and reduced VEGF mRNA levels and microvessel density in liver metastasis biopsy material after IFN- treatment. Conclusion: IFN- confers its antitumor activity, at least in part, by its antiangiogenic activity, which results from Sp1- and/or Sp3-mediated inhibition of VEGF gene transcription.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. A. Nemec and A. Barchowsky Signal Transducer and Activator of Transcription 1 (STAT1) is Essential for Chromium Silencing of Gene Induction in Human Airway Epithelial Cells Toxicol. Sci., July 1, 2009; 110(1): 212 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Calabro, P. Gasperini, I. M. Di Gangi, S. Indraccolo, M. Barbierato, A. Amadori, and L. Chieco-Bianchi Antineoplastic activity of lentiviral vectors expressing interferon-{alpha} in a preclinical model of primary effusion lymphoma Blood, May 7, 2009; 113(19): 4525 - 4533. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Persano, L. Moserle, G. Esposito, V. Bronte, V. Barbieri, M. Iafrate, M. P. Gardiman, P. Larghero, U. Pfeffer, E. Naschberger, et al. Interferon-{alpha} counteracts the angiogenic switch and reduces tumor cell proliferation in a spontaneous model of prostatic cancer Carcinogenesis, May 1, 2009; 30(5): 851 - 860. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Scholz, K Wagner, M Welzel, F Remlinger, B Wiedenmann, G Siemeister, S Rosewicz, and K M Detjen The oral multitarget tumour growth inhibitor, ZK 304709, inhibits growth of pancreatic neuroendocrine tumours in an orthotopic mouse model Gut, February 1, 2009; 58(2): 261 - 270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Melichar, P. Koralewski, A. Ravaud, A. Pluzanska, S. Bracarda, C. Szczylik, C. Chevreau, M. Filipek, R. Delva, E. Sevin, et al. First-line bevacizumab combined with reduced dose interferon-{alpha}2a is active in patients with metastatic renal cell carcinoma Ann. Onc., August 1, 2008; 19(8): 1470 - 1476. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Yao, A. Phan, P. M. Hoff, H. X. Chen, C. Charnsangavej, S.-C. J. Yeung, K. Hess, C. Ng, J. L. Abbruzzese, and J. A. Ajani Targeting Vascular Endothelial Growth Factor in Advanced Carcinoid Tumor: A Random Assignment Phase II Study of Depot Octreotide With Bevacizumab and Pegylated Interferon Alfa-2b J. Clin. Oncol., March 10, 2008; 26(8): 1316 - 1323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Gollob, W. K. Rathmell, T. M. Richmond, C. B. Marino, E. K. Miller, G. Grigson, C. Watkins, L. Gu, B. L. Peterson, and J. J. Wright Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First- or Second-Line Therapy in Patients With Metastatic Renal Cell Cancer J. Clin. Oncol., August 1, 2007; 25(22): 3288 - 3295. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. V. Dickson, J. B. Hamner, C. J. Streck, C. Y.C. Ng, M. B. McCarville, C. Calabrese, R. J. Gilbertson, C. F. Stewart, C. M. Wilson, M. W. Gaber, et al. Continuous Delivery of IFN-{beta} Promotes Sustained Maturation of Intratumoral Vasculature Mol. Cancer Res., June 1, 2007; 5(6): 531 - 542. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Kalie, D. A. Jaitin, R. Abramovich, and G. Schreiber An Interferon {alpha}2 Mutant Optimized by Phage Display for IFNAR1 Binding Confers Specifically Enhanced Antitumor Activities J. Biol. Chem., April 13, 2007; 282(15): 11602 - 11611. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Indraccolo, U. Pfeffer, S. Minuzzo, G. Esposito, V. Roni, S. Mandruzzato, N. Ferrari, L. Anfosso, R. Dell'Eva, D. M. Noonan, et al. Identification of Genes Selectively Regulated by IFNs in Endothelial Cells J. Immunol., January 15, 2007; 178(2): 1122 - 1135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Fischer, H. Sanchez-Ruderisch, M. Welzel, B. Wiedenmann, T. Sakai, S. Andre, H.-J. Gabius, L. Khachigian, K. M. Detjen, and S. Rosewicz Galectin-1 Interacts with the {alpha}5{beta}1 Fibronectin Receptor to Restrict Carcinoma Cell Growth via Induction of p21 and p27 J. Biol. Chem., November 4, 2005; 280(44): 37266 - 37277. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. L. Lain and P. R. Carrington Imiquimod Treatment of Exuberant Granulation Tissue in a Nonhealing Diabetic Ulcer Arch Dermatol, November 1, 2005; 141(11): 1368 - 1370. [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Streck, P. V. Dickson, C. Y.C. Ng, J. Zhou, J. T. Gray, A. C. Nathwani, and A. M. Davidoff Adeno-Associated Virus Vector-Mediated Systemic Delivery of IFN-{beta} Combined with Low-Dose Cyclophosphamide Affects Tumor Regression in Murine Neuroblastoma Models Clin. Cancer Res., August 15, 2005; 11(16): 6020 - 6029. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Prell, B. Li, J. M. Lin, M. VanRoey, and K. Jooss Administration of IFN-{alpha} Enhances the Efficacy of a Granulocyte Macrophage Colony Stimulating Factor-Secreting Tumor Cell Vaccine Cancer Res., March 15, 2005; 65(6): 2449 - 2456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Pages and J. Pouyssegur Transcriptional regulation of the Vascular Endothelial Growth Factor gene-a concert of activating factors Cardiovasc Res, February 15, 2005; 65(3): 564 - 573. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zheng, C. Wasylyk, A. Ayadi, J. Abecassis, J. A Schalken, H. Rogatsch, N. Wernert, S.-M. Maira, M.-C. Multon, and B. Wasylyk The transcription factor Net regulates the angiogenic switch Genes & Dev., September 15, 2003; 17(18): 2283 - 2297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Tosato Interferon-{alpha} Is Implicated in the Transcriptional Regulation of Vascular Endothelial Growth Factor J Natl Cancer Inst, March 19, 2003; 95(6): 420 - 421. [Full Text] [PDF]
|
|