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Efficient human interferon-alpha gene transfer to neuroendocrine tumor cells with long-term and stable expression
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi. (Kjell Öberg)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi. (Kjell Öberg)
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2005 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 82, no 5-6, 264-73 p.Article in journal (Refereed) Published
Abstract [en]

Interferon (IFN)-alpha has been used in the treatment of neuroendocrine (NE) tumors; however, the feasibility of IFN-alpha gene therapy has not been evaluated in NE tumor cells. In this study, human IFN-alpha2 (hIFN-alpha2) gene has been transferred into a NE tumor cell line BON. hIFN-alpha2-expressing BON cells were subcutaneously inoculated in nude mice. The results demonstrated that hIFN-alpha2 exerted significant antiproliferative effects on NE tumor cell lines (BON and LCC18) and other tumor cell lines (CA46 and SW480) as well as porcine aorta cell line. Furthermore, hIFN-alpha2 demonstrated its antineovascular activity in mice tumor and a direct antiangiogenic effect in chicken chorioallantoic membrane assay. hIFN-alpha2-expressing BON cells had a stable and long-term expression. Mice implanted with hIFN-alpha2-expressing BON cells showed a lower incidence, a delayed development and a significantly longer doubling time of the tumor compared to both wild-type (WT) and vector group. In addition, IFN-alpha significantly inhibited cell adhesion of WT BON cells. hIFN-alpha2-expressing BON tumors had a high level of hIFN-alpha2 protein. Finally, mice implanted with a mixture of WT and hIFN-alpha2-expressing BON cells (1:1) presented a delayed tumor development and had an even lower incidence of tumors than those implanted with hIFN-alpha2-expressing BON cells only. The doubling time of tumor was also longest in the mixture group. Our data suggest that hIFN-alpha2 gene therapy might be possible to be used as a new treatment for NE tumor patients. Further studies on the regulation of hIFN-alpha expression are needed, especially in combination with other cytokines, which could lead to a better understanding and improvements of hIFN-alpha gene therapy.

Place, publisher, year, edition, pages
2005. Vol. 82, no 5-6, 264-73 p.
Keyword [en]
Actins/analysis, Animals, Cell Adhesion/drug effects/physiology, Cell Differentiation, Cell Line; Tumor, Cell Movement/drug effects/physiology, Cytoskeleton/chemistry/pathology, Gene Expression Regulation; Neoplastic/*genetics/physiology, Gene Therapy, Gene Transfer Techniques, Humans, Immunohistochemistry, Interferon-alpha/analysis/*genetics/physiology/therapeutic use, Mice, Mice; Nude, Neoplasm Invasiveness/physiopathology, Neovascularization; Pathologic/drug therapy, Neuroendocrine Tumors/*genetics/pathology/therapy, Recombinant Proteins/analysis/genetics, Swine, Time Factors, eIF-2 Kinase/analysis/genetics/physiology
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-22760DOI: 10.1159/000092862PubMedID: 16721032OAI: oai:DiVA.org:uu-22760DiVA: diva2:50533
Available from: 2007-01-22 Created: 2007-01-22 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Gene Therapy with Interferon Alpha and the Angiogenic Inhibitor, Vasostatin, in Neuroendocrine Tumors of the Digestive System
Open this publication in new window or tab >>Gene Therapy with Interferon Alpha and the Angiogenic Inhibitor, Vasostatin, in Neuroendocrine Tumors of the Digestive System
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

IFN-α has been applied in medical treatment of various neuroendocrine (NE) tumors, either alone or combination with somatostatin analogues. They can improve clinical symptoms in 50-70% of patients but a significant tumor reduction is only observed in 5-15% patients. Vasostatin (vaso) is believed to be an angiogenic inhibitor. The aim of this study is to evaluate the feasibility to use IFN-α and vasostatin gene therapy in NE tumors.

We constructed plasmid vectors carrying human IFN-α2 (hIFN-α2) gene and human vasostatin gene, which were transfected into BON I cell to obtain stable gene-expressing cell lines. We found that in animal tumor model and cell experiments gene transfer of vasostatin caused a faster cell growth and tumor development via down-regulation of the tumor suppressor gene and p27. Cell adhesion, spreading, migration and invasion ability were increased in vaso-expressing BON I cells. Transfecting chicken vinculin could reverse the malignant behavior and restored expression of tumor suppressor genes. Moreover, vinculin knockdown could result in a faster cell growth and an increased colony formation.

Condition medium taken from hIFN-α2-expressing BON I cells showed significant antiproliferative effects both on the NE tumor cells, BON I and LCC18, and the endothelial cells, PAE. It also suppressed cell adhesion and cell invasion and inhibited angiogenesis on CAM assay. Mice implanted with a mixture of WT BON cells and hIFN-α2-expressing BON cells (1:1) demonstrated significantly lower tumor incidence and longer tumor doubling time. Furthermore, long-acting IFN-α2b (PEGIntron®) demonstrated a better anti-tumor effect in contrast with IFN-α2b (IntronA®). Intratumoral injection of hIFN-α2 plasmids significantly inhibited NE tumor growth and caused tumor regression.

We concluded that gene transfer of vasostatin into BON I cells might cause an enhanced malignant tumor behavior. Therefore, vasostatin therapy can not be recommended for patients with NE tumors. Vinculin might play an important role in NE tumor development and growth regulation. Gene therapy by using plasmid DNA carrying hIFN-α2 gene is feasible and promising in NE tumors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 70 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 219
Keyword
Internal medicine, neuroendocrine tumor, interferon-α, vasostatin, vinculin, tumor suppressor gene, nude mice, gene therapy, Invärtesmedicin
Identifiers
urn:nbn:se:uu:diva-7453 (URN)978-91-554-6784-5 (ISBN)
Public defence
2007-02-21, Rosénsalen, Entrance 95/96, Uppsala University Hospital, uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2007-01-31 Created: 2007-01-31 Last updated: 2009-05-13Bibliographically approved

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Liu, MinghuiGerwins, PärÖberg, KjellZhou, Yinghua

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