The online version of this article (doi:10.1186/1476-4598-11-86) contains supplementary material, which is available to authorized users.
Zhen-Lin Nie, Yu-Qin Pan contributed equally to this work.
The authors declare that they have no competing interests.
SW, YP, and ZN designed the study and wrote the protocols. ZN performed most of the experiments. BH, LG, and LC contributed to administrative, technical or material support. RL, YX, and TG managed the literature searches and analyses. GS undertook the statistical analysis. ZN drafted the manuscript. AH and JH provided critiques of the manuscript. All authors read and approved the final manuscript.
Colorectal cancer is one of the most common malignant tumors worldwide. Loss of imprinting (LOI) of the insulin-like growth factor 2 (IGF2) gene is an epigenetic abnormality observed in human colorectal neoplasms. Our aim was to investigate the feasibility of using the IGF2 imprinting system for targeted gene therapy of colorectal cancer.
We constructed a novel oncolytic adenovirus, Ad315-E1A, and a replication-deficient recombinant adenovirus, Ad315-EGFP, driven by the IGF2 imprinting system by inserting the H19 promoter, CCCTC binding factor, enhancer, human adenovirus early region 1A (E1A) and enhanced green fluorescent protein (EGFP) reporter gene into a pDC-315 shuttle plasmid. Cell lines with IGF2 LOI (HCT-8 and HT-29), which were infected with Ad315-EGFP, produced EGFP. However, no EGFP was produced in cell lines with maintenance of imprinting (HCT116 and GES-1). We found that Ad315-E1A significantly decreased cell viability and induced apoptosis only in LOI cell lines in vitro. In addition, mice bearing HCT-8-xenografted tumors, which received intratumoral administration of the oncolytic adenovirus, showed significantly reduced tumor growth and enhanced survival.
Our recombinant oncolytic virus targeting the IGF2 LOI system inhibits LOI cell growth in vitro and in vivo, and provides a novel approach for targeted gene therapy.
Authors’ original file for figure 112943_2012_1070_MOESM1_ESM.pdf
Authors’ original file for figure 212943_2012_1070_MOESM2_ESM.tiff
Authors’ original file for figure 312943_2012_1070_MOESM3_ESM.pdf
Authors’ original file for figure 412943_2012_1070_MOESM4_ESM.pdf
Authors’ original file for figure 512943_2012_1070_MOESM5_ESM.pdf
Authors’ original file for figure 612943_2012_1070_MOESM6_ESM.tiff
World Health Organization: The global burden of disease: 2004 update. 2008, http://www.who.int/healthinfo/global_burden_disease/2004_report_update/en/index.html.
Zhang H, Niu B, Hu JF, Ge S, Wang H, Li T, Ling J, Steelman BN, Qian G, Hoffman AR: Interruption of intrachromosomal looping by CCCTC binding factor decoy proteins abrogates genomic imprinting of human insulin-like growth factor II. J Cell Biol. 2011, 193: 475-487. 10.1083/jcb.201101021 PubMedCentralCrossRefPubMed
Shirakawa T: The current status of adenovirus-based cancer gene therapy. Mol Cells. 2008, 25: 462-466. PubMed
Wang H, Song X, Zhang H, Zhang J, Shen X, Zhou Y, Fan X, Dai L, Qian G, Hoffman AR, Hu JF, Ge S: Potentiation of tumor radiotherapy by a radiation-inducible oncolytic and oncoapoptotic adenovirus in cervical cancer xenografts. Int J Cancer. 2012, 130: 443-453. 10.1002/ijc.26013 PubMedCentralCrossRefPubMed
Liikanen I, Monsurrò V, Ahtiainen L, Raki M, Hakkarainen T, Diaconu I, Escutenaire S, Hemminki O, Dias JD, Cerullo V, Kanerva A, Pesonen S, Marzioni D, Colombatti M, Hemminki A: Induction of interferon pathways mediates in vivo resistance to oncolytic adenovirus. Mol Ther. 2011, 19: 1858-66.6. 10.1038/mt.2011.144 PubMedCentralCrossRefPubMed
Nishihara S, Hayashida T, Mitsuya K, Schulz TC, Ikeguchi M, Kaibara N, Oshimura M: Multipoint imprinting analysis in sporadic colorectal cancers with and without microsatellite instability. Int J Oncol. 2000, 17: 317-322. PubMed
Yu DC, Working P, Ando D: Selectively replicating oncolytic adenoviruses as cancer therapeutics. Curr Opin Mol Ther. 2002, 4: 435-443. PubMed
Khuri FR, Nemunaitis J, Ganly I, Arseneau J, Tannock IF, Romel L, Gore M, Ironside J, MacDougall RH, Heise C: A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med. 2000, 6: 879-885. 10.1038/78638 CrossRefPubMed
Lamfers ML, Grill J, Dirven CM, Van Beusechem VW, Geoerger B: Potential of the conditionally replicative adenovirus Ad5-Delta24RGD in the treatment of malignant gliomas and its enhanced effect with radiotherapy. Cancer Res. 2002, 62: 5736-5742. PubMed
- Gene therapy for colorectal cancer by an oncolytic adenovirus that targets loss of the insulin-like growth factor 2 imprinting system
Andrew R Hoffman
- BioMed Central
Neu im Fachgebiet Onkologie
Mail Icon II