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Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor:
R K Jain1, N Safabakhsh, A Sckell
1Edwin L. Steele Laboratory, Department of Radiation Oncology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA. jain@steele.mgh.harvard.edu
Abstract:
The sequence of events that leads to tumor vessel regression and the functional characteristics of these vessels during hormone-ablation therapy are not known. This is because of the lack of an appropriate animal model and monitoring technology. By using in vivo microscopy and in situ molecular analysis of the androgen-dependent Shionogi carcinoma grown in severe combined immunodeficient mice, we show that castration of these mice leads to tumor regression and a concomitant decrease in vascular endothelial growth factor (VEGF) expression. Androgen withdrawal is known to induce apoptosis in Shionogi tumor cells. Surprisingly, tumor endothelial cells begin to undergo apoptosis before neoplastic cells, and rarefaction of tumor vessels precedes the decrease in tumor size. The regressing vessels begin to exhibit normal phenotype, i.e., lower diameter, tortuosity, vascular permeability, and leukocyte adhesion. Two weeks after castration, a second wave of angiogenesis and tumor growth begins with a concomitant increase in VEGF expression. Because human tumors often relapse following hormone-ablation therapy, our data suggest that these patients may benefit from combined anti-VEGF therapy.
Insights
Hormone-ablation therapy causes tumor vessel regression before tumor cell death, with vessels regaining normal function. Tumor regrowth occurs with increased vascular endothelial growth factor (VEGF) after initial regression.
Area of Science:
- Oncology
- Vascular Biology
- Cancer Research
Background:
- The mechanisms of tumor vessel regression during hormone-ablation therapy are poorly understood due to limitations in animal models and monitoring technologies.
- Understanding these processes is crucial for improving cancer treatment strategies.
Purpose of the Study:
- To investigate the sequence of events and functional changes in tumor vasculature during hormone-ablation therapy.
- To identify potential therapeutic targets to prevent tumor relapse.
Main Methods:
- Utilized in vivo microscopy and in situ molecular analysis in an androgen-dependent Shionogi carcinoma mouse model.
- Monitored tumor regression, vascular endothelial growth factor (VEGF) expression, apoptosis, and vessel characteristics following castration.
Main Results:
- Castration induced tumor regression and decreased VEGF expression.
- Tumor endothelial cells underwent apoptosis before neoplastic cells, with vessel rarefaction preceding tumor shrinkage.
- Regressing vessels exhibited normalization of phenotype (reduced diameter, tortuosity, permeability, leukocyte adhesion).
- A second wave of angiogenesis and tumor growth initiated two weeks post-castration, correlating with increased VEGF.
Conclusions:
- Tumor vessel regression precedes tumor cell death and involves endothelial cell apoptosis and vessel normalization during hormone-ablation therapy.
- The observed relapse suggests a potential benefit from combining hormone-ablation therapy with anti-VEGF agents in patients.
- This study provides insights into tumor vascular dynamics during therapy and relapse, informing future treatment strategies.