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An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
Cancer gene therapy using mesenchymal stem cells expressing interferon-beta in a mouse prostate cancer lung
1Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA.
Abstract:
Cell-based therapy for cancer is a promising new field. Among cell types that can be used for this purpose, mesenchymal stem cells (MSCs) appear to hold great advantage for reasons including easier propagation in culture, possible genetic modification to express therapeutic proteins and preferential homing to sites of cancer growth upon in vivo transfer. The present study evaluated the potential of genetically modified MSC, constitutively expressing interferon (IFN)-beta, in an immunocompetent mouse model of prostate cancer lung metastasis. A recombinant adeno-associated virus (rAAV) encoding mouse IFN-beta was constructed and initially tested in vitro for high-level expression and bioactivity of the transgenic protein. MSCs were transduced by the rAAV-IFN-beta or green fluorescent protein ex vivo and used as cellular vehicles to target lung metastasis of TRAMP-C2 prostate cancer cells in a therapy model. Cohorts of mice were killed on days 30 and 75 to determine the effect of therapy by measurement of tumor volume, histology, immunohistochemistry, enzyme-linked immunosorbent assay and flow cytometry. Results indicated a significant reduction in tumor volume in lungs following IFN-beta-expressing MSC therapy. Immunohistochemistry of the lung demonstrated increased tumor cell apoptosis and decreased tumor cell proliferation and blood vessel counts. A significant increase in the natural kill cell activity was observed following IFN-beta therapy correlating the antitumor effect. Systemic level of IFN-beta was not significantly elevated from this targeted cell therapy. These data demonstrate the potential of MSC-based IFN-beta therapy for prostate cancer lung metastasis.
Insights
Mesenchymal stem cells (MSCs) engineered to express interferon-beta show promise in treating prostate cancer lung metastasis. This targeted cell therapy significantly reduced tumor volume and increased cancer cell death in a mouse model.
Area of Science:
- Oncology
- Cell-based therapy
- Cancer immunotherapy
Background:
- Cell-based cancer therapy is an emerging field with mesenchymal stem cells (MSCs) offering advantages like ease of culture, genetic modification, and tumor-homing capabilities.
- Interferon-beta (IFN-beta) has demonstrated anti-tumor properties, making it a candidate for therapeutic protein expression in cell-based strategies.
Purpose of the Study:
- To evaluate the efficacy of genetically modified MSCs expressing interferon-beta (IFN-beta) as a targeted therapy for prostate cancer lung metastasis.
- To assess the impact of this therapy on tumor volume, cell proliferation, apoptosis, angiogenesis, and immune cell activity in a preclinical mouse model.
Main Methods:
- Construction of a recombinant adeno-associated virus (rAAV) encoding mouse IFN-beta, with in vitro validation of expression and bioactivity.
- Transduction of MSCs with rAAV-IFN-beta or a control vector (green fluorescent protein) for ex vivo cell therapy.
- Administration of engineered MSCs to mice with TRAMP-C2 prostate cancer lung metastasis, followed by analysis of tumor burden and relevant biomarkers.
Main Results:
- IFN-beta-expressing MSC therapy led to a significant reduction in lung tumor volume.
- Immunohistochemistry revealed increased tumor cell apoptosis, decreased proliferation, and reduced vascularization in treated lungs.
- Therapy correlated with enhanced natural killer (NK) cell activity, while systemic IFN-beta levels remained largely unchanged.
Conclusions:
- Genetically modified MSCs expressing IFN-beta demonstrate significant anti-tumor effects against prostate cancer lung metastasis in a preclinical model.
- This targeted cell therapy approach holds potential for improving outcomes in metastatic prostate cancer by modulating the tumor microenvironment and enhancing immune surveillance.
