Sustained production of a soluble IGF-I receptor by gutless adenovirus-transduced host cells protects from tumor growth in the liver

• Published in: Cancer gene therapy Vol. 20; no. 4; pp. 229 - 236
• Main Authors: Wang, N, Lu, Y, Pinard, M, Pilotte, A, Gilbert, R, Massie, B, Brodt, P
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-04-2013; Nature Publishing Group
• Subjects: 631/154/51/201; 631/326/596/2561; 631/61/2300; 692/699/67/322; Adenoviridae - genetics; Adenovirus; Adenoviruses; Animals; Biomedical and Life Sciences; Biomedicine; Bone marrow; Cancer; Carcinoma, Lewis Lung - pathology; Carcinoma, Lewis Lung - therapy; Cell death; Cell Line, Tumor; Cell migration; Cell Movement; Cell Proliferation; Cell survival; Clinical trials; Development and progression; Female; Gene Expression; Gene Therapy; Gene transfer; Genetic aspects; Growth; Growth factors; Health aspects; HEK293 Cells; Humans; Immune response; Injection; Insulin-like growth factor I; Liver; Liver - pathology; Liver - virology; Liver cancer; Liver Neoplasms, Experimental - secondary; Liver Neoplasms, Experimental - therapy; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Organ Specificity; original-article; Physiological aspects; Plasma levels; Receptor, IGF Type 1 - biosynthesis; Receptor, IGF Type 1 - genetics; Stromal cells; Transduction, Genetic; Tumor Burden; Tumors; Canada; gutless adenoviral vector; cancer; soluble IGF-IR; liver metastases
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/cgt.2013.10

The IGF-I receptor (IGF-IR) has an important role in malignant disease and is the target of several drugs presently in clinical trials. Gene therapy has been explored as cancer treatment, mainly for delivery of genes that induce cell death or enhance the immunological response to cancer. Previously, we have shown that the implantation of autologous bone-marrow stromal cells producing a soluble form of IGF-IR (sIGFIR) inhibited experimental liver metastasis of several tumor types in mice. Here, we evaluated the utility of adenovirus-based gene delivery for generating therapeutically effective plasma levels of this decoy. We constructed a third generation gutless adenovirus expressing sIGFIR and found that HEK-293 cells transduced by this, but not control adenoviruses, secreted soluble receptor protein that blocked IGF-I-induced tumor cell migration, proliferation and survival
in vitro
. Following virus injection
in vivo
, viral DNA was detectable by PCR in several host organs, particularly the liver, and this resulted in the production of measurable sIGFIR plasma levels for up to 21 days post injection. In mice producing virus-encoded sIGFIR, experimental liver metastasis was inhibited, indicating that sIGFIR levels were therapeutically effective. The results show that adenovirus-based delivery of inhibitory soluble proteins can provide an effective anticancer strategy.