Related Experiment Video
Updated: May 22, 2026
Pre-clinical Orthotopic Murine Model of Human Prostate Cancer
Published on: August 29, 2016
Systemic delivery of oncolytic adenoviruses targeting transforming growth factor-β inhibits established bone
Zebin Hu1, Janhavi Gupta, Zhenwei Zhang
1Gene Therapy Program, Department of Medicine, NorthShore Research Institute, Evanston, IL 60201, USA.
Abstract:
We have examined whether Ad.sTβRFc and TAd.sTβRFc, two oncolytic viruses expressing soluble transforming growth factor-β receptor II fused with human Fc (sTGFβRIIFc), can be developed to treat bone metastasis of prostate cancer. Incubation of PC-3 and DU-145 prostate tumor cells with Ad.sTβRFc and TAd.sTβRFc produced sTGFβRIIFc and viral replication; sTGFβRIIFc caused inhibition of TGF-β-mediated SMAD2 and SMAD3 phosphorylation. Ad(E1-).sTβRFc, an E1(-) adenovirus, produced sTGFβRIIFc but failed to replicate in tumor cells. To examine the antitumor response of adenoviral vectors, PC-3-luc cells were injected into the left heart ventricle of nude mice. On day 9, mice were subjected to whole-body bioluminescence imaging (BLI). Mice bearing hind-limb tumors were administered viral vectors via the tail vein on days 10, 13, and 17 (2.5×10(10) viral particles per injection per mouse, each injection in a 0.1-ml volume), and subjected to BLI and X-ray radiography weekly until day 53. Ad.sTβRFc, TAd.sTβRFc, and Ad(E1-).sTβRFc caused significant inhibition of tumor growth; however, Ad.sTβRFc was the most effective among all the vectors. Only Ad.sTβRFc and TAd.sTβRFc inhibited tumor-induced hypercalcemia. Histomorphometric and synchrotron micro-computed tomographic analysis of isolated bones indicated that Ad.sTβRFc induced significant reduction in tumor burden, osteoclast number, and trabecular and cortical bone destruction. These studies suggest that Ad.sTβRFc and TAd.sTβRFc can be developed as potential new therapies for prostate cancer bone metastasis.
Insights
Two oncolytic viruses, Ad.sTβRFc and TAd.sTβRFc, show promise in treating prostate cancer bone metastasis by inhibiting tumor growth and reducing bone destruction. Ad.sTβRFc demonstrated the highest efficacy in preclinical models.
Area of Science:
- Oncolytic virotherapy
- Cancer biology
- Bone metastasis
Background:
- Prostate cancer frequently metastasizes to bone, causing significant morbidity.
- Transforming growth factor-beta (TGF-β) signaling plays a critical role in prostate cancer progression and bone metastasis.
- Developing effective therapies to target bone metastasis is a major clinical challenge.
Purpose of the Study:
- To evaluate the therapeutic potential of Ad.sTβRFc and TAd.sTβRFc, oncolytic adenoviruses expressing soluble TGF-β receptor II fused with human Fc (sTGFβRIIFc), against prostate cancer bone metastasis.
- To assess the efficacy of these viral vectors in preclinical models of bone metastasis.
Main Methods:
- In vitro incubation of prostate cancer cells (PC-3, DU-145) with Ad.sTβRFc and TAd.sTβRFc to assess sTGFβRIIFc production, viral replication, and inhibition of TGF-β signaling.
- In vivo studies using nude mice with PC-3-luc cell-induced bone metastasis, treated with viral vectors administered intravenously.
- Tumor growth monitoring via bioluminescence imaging (BLI) and X-ray radiography, alongside assessment of hypercalcemia and bone histomorphometry.
Main Results:
- Ad.sTβRFc and TAd.sTβRFc successfully produced sTGFβRIIFc and replicated in tumor cells, inhibiting TGF-β signaling.
- All tested adenoviral vectors (Ad.sTβRFc, TAd.sTβRFc, Ad(E1-).sTβRFc) significantly inhibited tumor growth, with Ad.sTβRFc being the most effective.
- Ad.sTβRFc and TAd.sTβRFc effectively inhibited tumor-induced hypercalcemia.
- Ad.sTβRFc treatment led to significant reductions in bone tumor burden, osteoclast numbers, and both trabecular and cortical bone destruction.
Conclusions:
- Ad.sTβRFc and TAd.sTβRFc represent promising oncolytic viral candidates for the treatment of prostate cancer bone metastasis.
- Ad.sTβRFc exhibits superior efficacy in reducing tumor burden and mitigating bone destruction in preclinical models.
- These findings support the further development of Ad.sTβRFc and TAd.sTβRFc as novel therapeutic strategies for advanced prostate cancer.
