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.

We have examined the effect of adenoviruses expressing soluble transforming growth factor receptorII-Fc (sTGFßRIIFc) 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-).sTßRFc, or with two oncolytic adenoviruses, Ad.sTßRFc and TAd.sTßRFc, expressing sTGFßRIIFc (the human TERT promoter drives viral replication in TAd.sTßRFc) produced sTGFßRIIFc protein. Oncolytic adenoviruses produced viral replication and induced cytotoxicity in 4T1 cells. 4T1 cells were resistant to the cytotoxic effects of TGFß-1 (up to 10 ng ml(-1)). However, TGFß-1 induced the phosphorylation of SMAD2 and SMAD3, which were inhibited by co-incubation with sTGFßRIIFc protein. TGFß-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.sTßRFc (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.sTßRFc (P<0.01) and TAd.sTßRFc (P<0.05). Replication-deficient virus Ad(E1-).sTßRFc expressing sTGFßRIIFc showed some inhibition of bone metastasis, whereas Ad(E1-).Null was not effective in inhibiting bone metastases. Thus, systemic administration of Ad.sTßRFc and TAd.sTßRFc can inhibit bone metastasis in the 4T1 mouse mammary tumor model, and can be developed as potential anti-tumor agents for breast cancer.