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. 2012 Sep;19(9):630-6. doi: 10.1038/cgt.2012.41. Epub 2012 Jun 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Adenoviridae / metabolism*
  • Adenoviridae / physiology
  • Administration, Intravenous
  • Animals
  • Bone Neoplasms / secondary
  • Bone Neoplasms / therapy*
  • Cell Line, Tumor
  • Female
  • Humans
  • Immunocompetence
  • Luminescent Measurements / methods
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Neoplasms, Experimental / therapy*
  • Mice
  • Mice, Inbred BALB C
  • Oncolytic Virotherapy / methods
  • Oncolytic Viruses / genetics
  • Oncolytic Viruses / metabolism
  • Oncolytic Viruses / physiology
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction
  • Smad2 Protein / genetics
  • Smad2 Protein / metabolism
  • Telomerase / genetics
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism
  • Transplantation, Isogeneic / methods
  • Tumor Stem Cell Assay / methods
  • Virus Replication

Substances

  • Receptors, Transforming Growth Factor beta
  • Smad2 Protein
  • Smad2 protein, mouse
  • Transforming Growth Factor beta1
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • TERT protein, human
  • Telomerase