Utility of adeno-associated viruses to target members of the TGF-β superfamily in prostate cancer therapy


Components of the TGF-β superfamily have been well established in their intricate and multifaceted roles in cancer progression and survival. The TGF-βs have been targeted therapeutically in an attempt to modify complex tumour networks to favour cancer cell destruction. Goals of these therapies are often to attack the “hallmarks” of cancer: characteristics acquired by cancer cells via re-wiring or manipulating existing biological pathways to their survival advantage. Of the multitude of targeted therapies currently available, viral therapies have shown much promise in their efficacy of treatment. This review highlights current viral therapies targeting members of the TGF-β superfamily, with a focus on the strengths and limitations associated with this form of targeted cancer therapy.

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Ramarao, P. and Gold, E. (2013) Utility of adeno-associated viruses to target members of the TGF-β superfamily in prostate cancer therapy. Advances in Bioscience and Biotechnology, 4, 8-14. doi: 10.4236/abb.2013.410A4002.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] McEntee, M.F., Ziegler, C., Reel, D., et al. (2008) Dietary n-3 polyunsaturated fatty acids enhance hormone ablation therapy in androgen-independent prostate cancer. American Journal of Pathology, 173, 256-268.
[2] Chu, G.C., Dunn, N.R., Anderson, D.C., et al. (2004) Differential requirements for Smad4 in TGFB-dependent patterning of the early mouse embryo. Development, 131, 3501-3512. http://dx.doi.org/10.1242/dev.01248
[3] Fields, S.Z., et al. (2013) Activin receptor antagonists for cancer-related anaemia and bone disease. Expert Opinion on Investigational Drugs, 22, 87-101.
[4] Levy, L. and Hill, C.S. (2005) Smad4 dependency defines two classes of transforming growth factor B (TGF-B) target genes and distinguishes TGF-B induced epithelialmesenchymal transition from its antiproliferative and migratory responses. Molecular and Cellular Biology, 25, 8108-8125.
[5] Attisano, L. and Wrana, J.L. (2002) Signal Transduction by the TGF-B superfamily. Science, 296, 1646-1647.
[6] Heldin, C.H., Miyazono, K. and Dijke, P.T. (1997) TGFB signalling from cell membrane to nucleus through SMAD proteins. Nature, 390, 465-471.
[7] Derynck, R. and Zheng, Y.E. (2003) Smad-dependent and Smad-independent pathways in TGFB family signalling. Nature, 425, 577-584.
[8] Ramel, M.C. and Hill, C.S. (2012) Spatial regulation of BMP activity. FEBS Letters, 586, 1929-1941.
[9] Mesnard, D., Guzman-Ayala, M. and Constam, D.B. (2006) Nodal specifies embryonic visceral endoderm and sustains pluripotent cells in the epiblast before overt axial patterning. Development, 133, 2497-2505.
[10] Ogawa, K., et al. (2007) Activin-Nodal signalling is involved in propagation of mouse embryonic stem cells. Journal of Cell Science, 120, 55-65.
[11] Wu, Z., et al. (2008) Combinatorial signals of activin/nodal and bone morphogenic protein regulate the early lineage segregation of human embryonic stem cells. The Journal of Biological Chemistry, 283, 24991-25002.
[12] Topczewska, J.M., et al. (2006) Embryonic and tumorigenic pathways converge via nodal signalling: Role in melanoma aggressiveness. Nature Medicine, 12, 925-932.
[13] Bujis, J.T., et al. (2007) BMP7, a putative regulator of epithelial homeostasis in the human prostate, is a potent inhibitor of prostate cancer bone metastasis in Vivo. American Journal of Pathology, 171, 1047-1057.
[14] Kingsley, D.M. (1994) The TGF-beta superfamily: New members, new receptors, and new genetic tests of function in different organisms. Genes & Development, 8, 133-146. http://dx.doi.org/10.1101/gad.8.2.133
[15] Massague, J. and Gomis, R.R. (2006) The logic of TGFB signalling. FEBS Letters, 12, 2811-2820.
[16] Katusno, Y., et al. (2008) Bone morphogenetic protein signalling enhances invasion and bone metastasis of breast cancer cells through Smad pathway. Oncogene, 27, 6322-6333. http://dx.doi.org/10.1038/onc.2008.232
[17] Kang, H.Y., et al. (2001) From transforming growth factor-B signalling to androgen action: Identification of Smad3 as an androgen receptor coregulator in prostate cancer cells. PNAS, 90, 3018-3023.
[18] Iyer, S., et al. (2005) Targeting TGF-B Signaling for Cancer Therapy. Cancer Biology & Therapy, 4, 261-266.
[19] Schlingensiepen, K.H., et al. (2004) The TGFbeta1 antisense oligonucleotide AP 11014 for treatment of nonsmall cell lung colorectal and prostate cancers: Preclinical studies. Journal of Clinical Oncology, 22, 31-32.
[20] Seth, P., et al. (2006) Development of oncolytic adenovirus armed with a fusion of soluble transforming growth factor B receptor II and human immunoglobulin Fc for breast cancer therapy. Human Gene Therapy, 17, 1152-1160.
[21] Thalmann, G.N., et al. (2000) LNCaP progression model of human prostate cancer: Androgen-independence and osseous metastasis. Prostate, 44, 91-103.
[22] Lasaro, M.O. and Ertl, H.C. (2009) New insights on adenovirus as vaccine vectors. Molecular Therapy, 17, 1333-1339. http://dx.doi.org/10.1038/mt.2009.130
[23] Khare, R., et al. (2011) Advances and future challenges in adenoviral vector pharmacology and targeting. Current Gene Therapy, 11, 241-258.
[24] Hu, Z., et al. (2012) Systemic delivery of oncolytic adenoviruses targeting transforming growth factor-b inhibits established bone metastasis in a prostate cancer mouse model. Human Gene Therapy, 23, 1-12.
[25] Oh, S., et al. (2013) Transforming growth factor-B gene silencing using adenovirus expressing using adenovirus expressing TGF-B1 or TGF-B2 shRNA. Cancer Gene Therapy, 20, 94-100.
[26] Freytag, S.O., et al. (2003) Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate-to high-risk prostate cancer. Cancer Research, 63, 7497-7506.
[27] Lubaroff, D.M., et al. (2006) Clinical protocol: Phase I study of an adenovirus/prostate-specific antigen vaccine in men with metastatic prostate cancer. Human Gene Therapy, 17, 220-229.
[28] Shobana, R., et al. (2013) Prostate-specific antigen-retargeted recombinant newcastle disease virus for prostate cancer virotherapy. Journal of Virology, 87, 3792-3800.
[29] Sun, A., et al. (2009) Adeno-associated virus-delivered short hairpin-structured RNA for androgen receptor gene silencing induces tumour eradication of prostate cancer xenografts in nude mice: A preclinical study. Cancer Therapy, 126, 764-774.
[30] Pan, J.G., et al. (2012) The adeno-associated virus-mediated HSV-TK/GCV suicide system: A potential strategy for the treatment of bladder carcinoma. Medical Oncology, 29, 1938-1947.
[31] Eertwegh, A.J.M., et al. (2012) Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: A phase 1 dose-escalation trial. Lancet Oncology, 13, 509-517.
[32] Manno, C.S., et al. (2003) AAV-mediated factor IX gene transfer in skeletal muscle in patients with severe haemophilia B. Blood, 101, 2963-2972.
[33] Manno, C.S., et al. (2006) Successful transduction of liver in haemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nature Medicine, 12, 342-347. http://dx.doi.org/10.1038/nm1358

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