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Antiangiogenic therapy of transgenic mice impairs de novo tumor growth
S Parangi1, M O'Reilly, G Christofori
1Department of Biochemistry and Biophysics, Hormone Research Institute, University of California, San Francisco, CA 94143-0534, USA.
Abstract:
Angiogenesis is activated during multistage tumorigenesis prior to the emergence of solid tumors. Using a transgenic mouse model, we have tested the proposition that treatment with angiogenesis inhibitors can inhibit the progression of tumorigenesis after the switch to the angiogenic phenotype. In this model, islet cell carcinomas develop from multifocal, hyperproliferative nodules that show the histological hallmarks of human carcinoma in situ. Mice were treated with a combination of the angiogenesis inhibitor AGM-1470 (TNP-470), the antibiotic minocycline, and interferon alpha/beta. The treatment regimen markedly attenuated tumor growth but did not prevent tumor formation; tumor volume was reduced to 11% and capillary density to 40% of controls. The proliferation index of tumor cells in treated and control mice was similar, whereas the apoptotic index was doubled in treated tumors. This study shows that de novo tumor progression can be restricted solely by antiangiogenic therapy. The results suggest that angiogenesis inhibitors represent a valid component of anticancer strategies aimed at progression from discrete stages of tumorigenesis and demonstrate that transgenic mouse models can be used to evaluate efficacy of candidate antiangiogenic agents.
Insights
Antiangiogenic therapy, including TNP-470, minocycline, and interferon alpha/beta, significantly reduced tumor volume and capillary density in a mouse model. This demonstrates that inhibiting angiogenesis can restrict tumor progression after the angiogenic switch.
Area of Science:
- Oncology
- Cancer Biology
- Angiogenesis Research
Background:
- Tumorigenesis involves multistage processes, with angiogenesis activation preceding solid tumor formation.
- The angiogenic switch is a critical step in tumor progression, enabling sustained growth.
- Transgenic mouse models offer valuable platforms for studying tumorigenesis and evaluating therapeutic interventions.
Purpose of the Study:
- To investigate the efficacy of antiangiogenic therapy in inhibiting tumor progression post-angiogenic switch.
- To assess the impact of a combination therapy (TNP-470, minocycline, interferon alpha/beta) on established angiogenic tumors.
- To evaluate the utility of a transgenic mouse model for assessing antiangiogenic agent efficacy.
Main Methods:
- Utilized a transgenic mouse model developing islet cell carcinomas from hyperproliferative nodules.
- Administered a combination treatment of the angiogenesis inhibitor AGM-1470 (TNP-470), minocycline, and interferon alpha/beta.
- Quantified tumor volume, capillary density, tumor cell proliferation index, and apoptotic index.
Main Results:
- The combination therapy significantly attenuated tumor growth, reducing tumor volume to 11% of controls.
- Capillary density was reduced to 40% of control levels in treated mice.
- While tumor cell proliferation remained similar, the apoptotic index was doubled in treated tumors, indicating increased cell death.
Conclusions:
- De novo tumor progression can be effectively restricted by antiangiogenic therapy alone.
- Angiogenesis inhibitors are a valid component of anticancer strategies targeting tumorigenesis progression.
- Transgenic mouse models are suitable for evaluating the efficacy of antiangiogenic agents in preclinical settings.