Klein D, Schmitz T, Verhelst V, Panic A, Schenck M, Reis H, Drab M, Sak A, Herskind C, Maier P, Jendrossek V
Department of Molecular Cell Biology, Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, University Hospital Essen, Essen, Germany.
1] Department of Molecular Cell Biology, Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, University Hospital Essen, Essen, Germany [2] Department of Urology and Urooncology, University of Duisburg-Essen, University Hospital Essen, Essen, Germany.
Oncogenesis. 2015 May 18;4(5):e148. doi: 10.1038/oncsis.2015.9.
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.
膜蛋白小窝蛋白-1（Cav1）最近作为一种新型癌基因出现，参与前列腺癌进展，在上皮肿瘤细胞和肿瘤基质中具有相反的调节作用。在这里，我们使用Cav1缺陷型C57Bl/6小鼠研究了基质Cav1对MPR31-4前列腺癌异种移植肿瘤生长和辐射反应的作用。当将同基因的MPR31-4肿瘤植入Cav1缺陷型小鼠体内时，其生长速度更快。与来自Cav1野生型动物的肿瘤相比，Cav1缺陷型小鼠体内肿瘤生长增加与平滑肌细胞整合到新形成血管壁中的减少有关，因此血管表型不太稳定。然而，与在野生型小鼠体内生长的肿瘤相比，在Cav1基因敲除小鼠体内生长的MPR31-4肿瘤对单次20格雷高剂量照射的生长延迟更为明显。Cav1缺陷型小鼠中辐射诱导的肿瘤生长延迟增加与内皮细胞凋亡增加有关。使用培养的内皮细胞（ECs）进行的体外研究证实，Cav1表达的缺失增加了ECs对辐射诱导凋亡的敏感性，并降低了其照射后的克隆存活能力。对人体组织标本的免疫组织化学分析进一步显示，尽管在晚期和转移性前列腺癌的肿瘤基质中Cav1表达大多降低，但血管部分仍表达高水平的Cav1。总之，MPR31-4前列腺肿瘤的辐射反应受到肿瘤脉管系统中Cav1表达的关键调节。因此，Cav1可能是在肿瘤脉管系统水平上对抗前列腺癌辐射抗性的联合治疗的一个有前景的治疗靶点。
