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Intravenous administration of adenoviruses targeting transforming growth factor beta signaling inhibits established bone metastases in 4T1 mouse mammary tumor model in an immunocompetent syngeneic host

Cancer Gene Therapy volume 19, pages 630–636 (2012)Cite this article

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Abstract

We have examined the effect of adenoviruses expressing soluble transforming growth factor receptorII-Fc (sTGFβRIIFc) in a 4T1 mouse mammary tumor bone metastasis model using syngeneic BALB/c mice. Infection of 4T1 cells with a non-replicating adenovirus, Ad(E1−).sTβRFc, or with two oncolytic adenoviruses, Ad.sTβRFc and TAd.sTβRFc, expressing sTGFβRIIFc (the human TERT promoter drives viral replication in TAd.sTβRFc) produced sTGFβRIIFc protein. Oncolytic adenoviruses produced viral replication and induced cytotoxicity in 4T1 cells. 4T1 cells were resistant to the cytotoxic effects of TGFβ-1 (up to 10 ng ml−1). However, TGFβ-1 induced the phosphorylation of SMAD2 and SMAD3, which were inhibited by co-incubation with sTGFβRIIFc protein. TGFβ-1 also induced interleukin-11, a well-known osteolytic factor. Intracardiac injection of 4T1-luc2 cells produced bone metastases by day 4. Intravenous injection of Ad.sTβRFc (on days 5 and 7) followed by bioluminescence imaging (BLI) of mice on days 7, 11 and 14 in tumor-bearing mice indicated inhibition of bone metastasis progression (P<0.05). X-ray radiography of mice on day 14 showed a significant reduction of the lesion size by Ad.sTβRFc (P<0.01) and TAd.sTβRFc (P<0.05). Replication-deficient virus Ad(E1−).sTβRFc expressing sTGFβRIIFc showed some inhibition of bone metastasis, whereas Ad(E1−).Null was not effective in inhibiting bone metastases. Thus, systemic administration of Ad.sTβRFc and TAd.sTβRFc can inhibit bone metastasis in the 4T1 mouse mammary tumor model, and can be developed as potential anti-tumor agents for breast cancer.

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Acknowledgements

The research described here was funded by a grant from the National Cancer Institutes Grant #R01CA127380 (PS). We are thankful to Janardan Khandekar, Theodore Mazzone, Bruce Brockstein and an anonymous source for their generous support.

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Author notes

  1. Z Hu

    Present address: 5Present address: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, China.,

  2. Z Zhang and Z Hu: The first two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Gene Therapy Program, NorthShore Research Institute, Evanston, IL, USA

    Z Zhang, Z Hu, J Gupta, J D Krimmel, H M Gerseny, A F Berg, J S Robbins & P Seth

  2. Center for Clinical and Research Informatics, NorthShore Research Institute, Evanston, IL, USA (an Affiliate of the University of Chicago, Chicago, IL, USA),

    H Du

  3. Department of Microbiology and Immunology, the University of Illinois at Chicago, Chicago, IL, USA

    B Prabhakar

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Correspondence to P Seth.

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Zhang, Z., Hu, Z., Gupta, J. et al. Intravenous administration of adenoviruses targeting transforming growth factor beta signaling inhibits established bone metastases in 4T1 mouse mammary tumor model in an immunocompetent syngeneic host. Cancer Gene Ther 19, 630–636 (2012). https://doi.org/10.1038/cgt.2012.41

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  • DOI: https://doi.org/10.1038/cgt.2012.41

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