Endothelial Caveolin-1 regulates the radiation response of epithelial prostate tumors
D Klein1, T Schmitz1, V Verhelst1
1Department of Molecular Cell Biology, Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, University Hospital Essen, Essen, Germany.
Abstract:
The membrane protein caveolin-1 (Cav1) recently emerged as a novel oncogene involved in prostate cancer progression with opposed regulation in epithelial tumor cells and the tumor stroma. Here we examined the role of stromal Cav1 for growth and radiation response of MPR31-4 prostate cancer xenograft tumors using Cav1-deficient C57Bl/6 mice. Syngeneic MPR31-4 tumors grew faster when implanted into Cav1-deficient mice. Increased tumor growth on Cav1-deficient mice was linked to decreased integration of smooth muscle cells into the wall of newly formed blood vessels and thus with a less stabilized vessel phenotype compared with tumors from Cav1 wild-type animals. However, tumor growth delay of MPR31-4 tumors grown on Cav1 knockout mice to a single high-dose irradiation with 20 Gray was more pronounced compared with tumors grown on wild-type mice. Increased radiation-induced tumor growth delay in Cav1-deficient mice was associated with an increased endothelial cell apoptosis. In vitro studies using cultured endothelial cells (ECs) confirmed that the loss of Cav1 expression increases sensitivity of ECs to radiation-induced apoptosis and reduces their clonogenic survival after irradiation. Immunohistochemical analysis of human tissue specimen further revealed that although Cav1 expression is mostly reduced in the tumor stroma of advanced and metastatic prostate cancer, the vascular compartment still expresses high levels of Cav1. In conclusion, the radiation response of MPR31-4 prostate tumors is critically regulated by Cav1 expression in the tumor vasculature. Thus, Cav1 might be a promising therapeutic target for combinatorial therapies to counteract radiation resistance of prostate cancer at the level of the tumor vasculature.
Insights
Stromal caveolin-1 (Cav1) influences prostate cancer growth and radiation response. Loss of Cav1 in tumor vasculature enhances radiation sensitivity by increasing endothelial cell apoptosis, suggesting Cav1 as a therapeutic target.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Medicine
Background:
- Caveolin-1 (Cav1) is a membrane protein implicated in prostate cancer progression.
- Cav1 exhibits opposing regulatory roles in prostate tumor epithelial cells and the surrounding stroma.
- Stromal Cav1's specific impact on tumor growth and radiation response requires further investigation.
Purpose of the Study:
- To investigate the role of stromal caveolin-1 (Cav1) in the growth and radiation response of prostate cancer xenografts.
- To determine the effect of Cav1 deficiency in the tumor microenvironment on tumor vascularization and radiosensitivity.
- To explore Cav1 as a potential therapeutic target for overcoming prostate cancer radiation resistance.
Main Methods:
- Utilized Cav1-deficient and wild-type C57Bl/6 mice for xenograft implantation of MPR31-4 prostate cancer cells.
- Assessed tumor growth, vascularization (smooth muscle cell integration), and endothelial cell apoptosis post-irradiation.
- Conducted in vitro studies on cultured endothelial cells (ECs) to evaluate radiation sensitivity and clonogenic survival.
- Performed immunohistochemical analysis on human prostate cancer tissue specimens.
Main Results:
- MPR31-4 tumors exhibited faster growth in Cav1-deficient mice, linked to less stabilized tumor vasculature.
- Tumor growth delay following high-dose irradiation was more pronounced in Cav1-deficient mice.
- Loss of Cav1 increased endothelial cell apoptosis and reduced clonogenic survival after irradiation, both in vivo and in vitro.
- Human prostate cancer stroma shows reduced Cav1, but the vascular compartment retains high Cav1 expression.
Conclusions:
- Stromal caveolin-1 (Cav1) critically regulates the radiation response of prostate tumors, particularly within the tumor vasculature.
- Cav1 deficiency in the tumor vasculature enhances radiosensitivity by promoting endothelial cell apoptosis.
- Targeting Cav1 in the tumor vasculature presents a promising strategy for combinatorial therapies to improve prostate cancer radiation treatment outcomes.
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