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.
Highlights
Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of death in men worldwide[1] and its treatment differs depending on patient’s age, stage and grade of the tumor.[2]
We show that the recruitment of smooth muscle actin-positive cells to tumor microvessels is defective in Cav1-deficient mice with potential relevance for increased tumor growth
We show for the first time that the recruitment, association and integration of smooth muscle cells into the wall of newly formed blood vessels is defective in prostate MPR31-4 tumors grown in Cav1-deficient mice giving rise to vessels of a less stabilized, proangiogenic phenotype that facilitate tumor growth
Summary
Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of death in men worldwide[1] and its treatment differs depending on patient’s age, stage and grade of the tumor.[2] The grade of differentiation of acinar adenocarcinomas of the prostate is expressed by the Gleason score, which is a sum of the primary and secondary Gleason patterns in resection specimens.[3,4] Radical prostatectomy, hormone ablation therapy, percutaneous radiotherapy and interstitial radiation methods are available for the treatment of localized stages yielding 450% of local control.[5,6,7,8] Radiotherapy is an integral part of the treatment protocols for inoperable locally advanced prostate cancer. Despite the use of classical chemotherapy (mainly taxanes), hormone ablation therapy, radiopharmaceuticals and refined radiation methods such as intensitymodulated radiation therapy allowing the delivery of increased radiation doses, no curative treatment for advanced stages is available to date. Novel therapy approaches are needed for patients with hormone-refractory disease.[9,10,11,12]
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