Isayeva Tatyana, Chanda Diptiman, Kallman Lisa, Eltoum Isam-Eldin A, Ponnazhagan Selvarangan
Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama 35294-0007, USA.
Cancer Res. 2007 Jun 15;67(12):5789-97. doi: 10.1158/0008-5472.CAN-06-3637.
Antiangiogenic therapy is a promising alternative for prostate cancer growth and metastasis and holds great promise as an adjuvant therapy. The present study evaluated the potential of stable expression of angiostatin and endostatin before the onset of neoplasia and during the early and late stages of prostate cancer progression in transgenic adenocarcinoma of mouse prostate (TRAMP) mice. Groups of 5-, 10-, and 18-week-old male TRAMP mice received recombinant adeno-associated virus-6 encoding mouse endostatin plus angiostatin (E+A) by i.m. injection. The effects of therapy were determined by sacrificing groups of treated mice at defined stages of tumor progression and following cohorts of similarly treated mice for long-term survival. Results indicated remarkable survival after recombinant adeno-associated virus-(E+A) therapy only when the treatment was given at an earlier time, before the onset of high-grade neoplasia, compared with treatment given for invasive cancer. Interestingly, early-stage antiangiogenic therapy arrested the progression of moderately differentiated carcinoma to poorly differentiated state and distant metastasis. Immunohistochemical analysis of the prostate from treated mice indicated significantly lower endothelial cell proliferation and increased tumor cell apoptosis. Vascular endothelial growth factor receptor (VEGFR)-2 expression was significantly down-regulated in tumor endothelium after treatment but not VEGFR-1. Analysis of the neuroendocrine marker synaptophysin expression indicated that antiangiogenic therapy given at an early-stage disease reduced neuroendocrine transition of the epithelial tumors. These studies indicate that stable endostatin and angiostatin gene therapy may be more effective for minimally invasive tumors rather than advanced-stage disease.
抗血管生成疗法是一种治疗前列腺癌生长和转移的有前景的替代方法，作为辅助疗法也具有很大潜力。本研究评估了在小鼠前列腺转基因腺癌（TRAMP）小鼠肿瘤形成前以及前列腺癌进展的早期和晚期稳定表达血管抑素和内皮抑素的潜力。将5周龄、10周龄和18周龄的雄性TRAMP小鼠分组，通过肌肉注射给予编码小鼠内皮抑素加血管抑素（E+A）的重组腺相关病毒-6。通过在肿瘤进展的特定阶段处死治疗组小鼠并跟踪类似治疗小鼠的长期存活情况来确定治疗效果。结果表明，与侵袭性癌症治疗相比，仅在高级别肿瘤形成前的早期给予重组腺相关病毒-（E+A）治疗时，小鼠有显著的存活期。有趣的是，早期抗血管生成疗法阻止了中度分化癌向低分化状态和远处转移的进展。对治疗小鼠前列腺的免疫组织化学分析表明，内皮细胞增殖显著降低，肿瘤细胞凋亡增加。治疗后肿瘤内皮中的血管内皮生长因子受体（VEGFR）-2表达显著下调，但VEGFR-1未下调。对神经内分泌标志物突触素表达的分析表明，疾病早期给予抗血管生成疗法可减少上皮肿瘤的神经内分泌转变。这些研究表明，稳定的内皮抑素和血管抑素基因疗法对微侵袭性肿瘤可能比对晚期疾病更有效。
