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Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
Increased basic fibroblast growth factor release and proliferation in xenotransplanted squamous cell
Kai Fruth1, Stefan Weber, Yunus Okcu
1Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Abstract:
Novel strategies of cancer therapy combine irradiation and anti-angiogenic active compounds. However, little is known concerning the undesired cellular and molecular effects caused by this novel treatment concept. We used a mouse squamous cell carcinoma (SCC) xenotransplantation model to evaluate the potential undesired effects which compromise the success of this therapeutic combination. SCCs were subcutanously implanted in nude mice. Animals were treated with a fractionated irradiation scheme (5x4 Gy) alone or in combination with daily injections of anti-vascular endothelial growth factor (VEGF) antibodies. Controls remained untreated. Before and after treatment, resonance imaging (MRI), ultrasound and near-infrared spectrometry were used to evaluate tumor vessel integrity. Finally, tumors were explanted and VEGF, basic fibroblast growth factor (bFGF), vessel density, proliferation and apoptotic activity were analyzed by immunohistochemistry. Irradiation caused VEGF release and we found evidence for VEGF-mediated vessel protection. In the tumors derived from the combined treatment, blood volume was decreased, and apoptotic indices were increased. Remarkably, bFGF levels and proliferative indices were also increased. Combined irradiation/anti-VEGF treatment resulted in the desired VEGF depletion and increased tumor cell apoptosis. Nonetheless, bFGF and proliferation also increased, possibly suggesting a compensatory response. The application of additional targeted drugs may help develop more effective SCC treatments.
Insights
Combining cancer irradiation with anti-angiogenic therapy targeting vascular endothelial growth factor (VEGF) shows promise. However, this approach may trigger compensatory increases in basic fibroblast growth factor (bFGF) and proliferation, necessitating further research.
Area of Science:
- Oncology
- Cancer Research
- Experimental Therapeutics
Background:
- Novel cancer therapies integrate irradiation with anti-angiogenic agents.
- Potential undesired cellular and molecular effects of this combination therapy remain poorly understood.
Purpose of the Study:
- To evaluate the undesired effects of combining irradiation and anti-vascular endothelial growth factor (VEGF) antibody treatment in a mouse model.
- To assess the impact on tumor biology, including vascular integrity, proliferation, and apoptosis.
Main Methods:
- A mouse squamous cell carcinoma (SCC) xenotransplantation model was utilized.
- Tumors were treated with fractionated irradiation alone or combined with anti-VEGF antibodies.
- Tumor vessel integrity was assessed using MRI, ultrasound, and near-infrared spectrometry; molecular analyses included immunohistochemistry for VEGF, bFGF, proliferation, and apoptosis.
Main Results:
- Irradiation alone induced VEGF release and evidence of VEGF-mediated vessel protection.
- Combined treatment decreased tumor blood volume and increased apoptotic indices.
- Remarkably, basic fibroblast growth factor (bFGF) levels and proliferative indices also increased in the combined treatment group.
Conclusions:
- Combined irradiation and anti-VEGF therapy achieved desired VEGF depletion and increased tumor cell apoptosis.
- The observed increase in bFGF and proliferation suggests a potential compensatory response.
- Further research into combination therapies, possibly including additional targeted drugs, is warranted for more effective SCC treatments.
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