Adeno-associated virus 2-mediated intratumoral prostate cancer gene therapy: long-term maspin expression efficiently suppresses tumor growth
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Published on: March 22, 2011
Masami Watanabe1, Yasutomo Nasu, Yuji Kashiwakura
1Department of Urology, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan. masami5@cf6.so-net.ne.jp
Abstract:
Maspin is a member of the serine protease inhibitors and the maspin gene, a tumor suppressor gene, is down-regulated in a large fraction of prostate cancers. We evaluated the use of adeno-associated virus (AAV, serotype 2) vector encoding maspin as a means for in vivo gene therapy for human prostate cancer. TUNEL assay of subcutaneously formed LNCaP or DU145 tumors in nude mice showed that intratumoral AAV-mediated maspin expression significantly upregulated the number of apoptotic cells compared with AAV-LacZ treatment. Immunofluorescence double staining for maspin protein and apoptosis in LNCaP tumors showed that the percentage of apoptotic cells in AAV-maspin-mediated maspin-expressing cells was significantly high compared with that in AAV-GFP-mediated GFP-expressing cells. Moreover, significantly fewer CD31-positive microvessels were observed in AAV-maspin-treated tumors compared with the control tumors. These therapeutic responses were highly correlated to persistent maspin expression in tumors, confirmed by Western blot analysis until at least day 56 after treatment. Finally, intratumoral delivery of AAV-maspin significantly suppressed growth of LNCaP and DU145 tumors and improved survival of mice. We conclude that AAV-mediated prolonged maspin expression efficiently suppresses human prostate tumor growth in vivo by apoptosis induction and inhibition of angiogenesis.
Insights
Adeno-associated virus (AAV) delivering the maspin gene effectively suppressed prostate tumors in mice. This gene therapy induced cancer cell death and reduced blood vessel formation, improving survival.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Maspin, a serine protease inhibitor, acts as a tumor suppressor gene.
- Maspin gene expression is frequently reduced in prostate cancers.
- Gene therapy offers a potential strategy for prostate cancer treatment.
Purpose of the Study:
- To evaluate adeno-associated virus (AAV) serotype 2 vector encoding maspin for in vivo gene therapy of human prostate cancer.
- To assess the efficacy of AAV-mediated maspin expression in suppressing tumor growth and improving survival.
Main Methods:
- Intratumoral delivery of AAV vectors encoding maspin into human prostate cancer xenografts (LNCaP, DU145) in nude mice.
- Assessment of apoptosis using TUNEL assay and immunofluorescence.
- Evaluation of angiogenesis by counting CD31-positive microvessels.
- Confirmation of persistent maspin expression via Western blot analysis.
Main Results:
- AAV-maspin significantly increased apoptosis in LNCaP and DU145 tumors compared to controls (AAV-LacZ, AAV-GFP).
- Reduced microvessel density (CD31-positive) was observed in tumors treated with AAV-maspin.
- Therapeutic effects correlated with sustained maspin expression up to 56 days post-treatment.
- Intratumoral AAV-maspin delivery suppressed tumor growth and improved mouse survival.
Conclusions:
- AAV-mediated maspin gene therapy is a promising approach for prostate cancer treatment.
- Prolonged maspin expression suppresses tumor growth through apoptosis induction and anti-angiogenesis.
- This strategy holds potential for in vivo gene therapy of human prostate cancer.
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