Effects of interferon alpha on vascular endothelial growth factor gene transcription and tumor angiogenesis.

Publisher: Oxford University Press Country of Publication: United States NLM ID: 7503089 Publication Model: Print Cited Medium: Print ISSN: 0027-8874 (Print) Linking ISSN: 00278874 NLM ISO Abbreviation: J Natl Cancer Inst Subsets: MEDLINE

Publication: <2003-> : Cary, NC : Oxford University Press
Original Publication: Bethesda, Md., U. S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health; Washington, for sale by the Supt. of Docs., U. S. Govt. Print. Off.

Biomarkers, Tumor*; Angiogenesis Inhibitors/*pharmacology ; Antineoplastic Agents/*pharmacology ; Endothelial Growth Factors/*metabolism ; Intercellular Signaling Peptides and Proteins/*metabolism ; Interferon-alpha/*pharmacology ; Lymphokines/*metabolism ; Neovascularization, Pathologic/*drug therapy ; Neuroendocrine Tumors/*drug therapy ; Neuroendocrine Tumors/*metabolism ; Receptors, Vascular Endothelial Growth Factor/*metabolism ; Transcription, Genetic/*drug effects; Animals ; Electrophoretic Mobility Shift Assay ; Endothelial Growth Factors/genetics ; Enzyme-Linked Immunosorbent Assay ; Gene Expression Regulation, Neoplastic/drug effects ; Genes, Reporter/drug effects ; Immunohistochemistry ; Intercellular Signaling Peptides and Proteins/genetics ; Luciferases/metabolism ; Lymphokines/drug effects ; Lymphokines/genetics ; Mice ; Mice, Nude ; Neovascularization, Pathologic/metabolism ; Neuroendocrine Tumors/blood supply ; Pregnancy Proteins/metabolism ; Promoter Regions, Genetic/drug effects ; RNA, Messenger/metabolism ; Receptors, Immunologic/metabolism ; Receptors, Vascular Endothelial Growth Factor/drug effects ; Receptors, Vascular Endothelial Growth Factor/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Time Factors ; Transplantation, Heterologous ; Tumor Cells, Cultured ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors

Background: Interferon alpha (IFN-alpha) has antiangiogenic activity, although the underlying mechanism of action is unclear. Because human neuroendocrine (NE) tumors are highly vascularized and sensitive to IFN-alpha, we investigated whether the therapeutic effects of IFN-alpha 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-alpha 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-alpha therapy.
Results: NE tumors and cell lines expressed VEGF mRNA and secreted VEGF protein. In vitro, IFN-alpha 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-alpha 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-alpha treatment.
Conclusion: IFN-alpha 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.

Comment in: J Natl Cancer Inst. 2003 Mar 19;95(6):420-1. (PMID: 12644529)

0 (Angiogenesis Inhibitors)
0 (Antineoplastic Agents)
0 (Biomarkers, Tumor)
0 (Endothelial Growth Factors)
0 (Intercellular Signaling Peptides and Proteins)
0 (Interferon-alpha)
0 (Lymphokines)
0 (Pregnancy Proteins)
0 (RNA, Messenger)
0 (Receptors, Immunologic)
0 (Vascular Endothelial Growth Factor A)
0 (Vascular Endothelial Growth Factors)
0 (trophoblastic beta 1-glycoprotein receptor, human)
EC 1.13.12.- (Luciferases)
EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)

Date Created: 20030320 Date Completed: 20030411 Latest Revision: 20220310

20221213

10.1093/jnci/95.6.437

12644537