NO• and Pancreatic Cancer: A Complex Interaction with Therapeutic Potential.
NO• and Pancreatic Cancer: A Complex Interaction with Therapeutic Potential.
复制标题
DOI：
10.1089/ars.2016.6809
复制
发表时间：
2017-06
影响因子：
6.6
通讯作者：
Jian Wang;S. Hussain
中科院分区：
文献类型：
--
作者：
Jian Wang;S. Hussain
意义胰腺肿瘤表达高水平的一氧化氮合酶(NOS)，尤其是诱导型(iNOS/NOS2)和内皮型(eNOS/NOS3)。然而，一氧化氮(NO·)在胰腺癌发生发展中的作用尚不清楚。阐明NO·诱导的信号在胰腺癌中的作用及其在疾病侵袭性中的潜在作用可能为提高这种致命恶性肿瘤的存活率提供治疗靶点。最新进展：NOS2/iNOS在肿瘤中的表达增加与早期胰腺导管腺癌(PDAC)切除患者的生存不良有关。此外，NOS2的基因缺失提高了自发性PDAC小鼠的存活率。此外，靶向NOS3/eNOS降低了小鼠体内前体病变的丰度，这有提高存活率的趋势。胰腺癌预后极差的原因是晚期胰腺癌的诊断较晚，缺乏有效的治疗方法。最关键的问题之一是破译疾病侵袭性和治疗耐药性的潜在机制，以确定潜在的治疗靶点和有效的治疗方法。有证据表明炎症和胰腺癌之间有很强的相关性，临床证据表明NOS2和疾病侵袭性之间存在关联，因此确定NO·信号在这种致命恶性肿瘤中的作用是至关重要的。最近的临床前和临床证据表明，靶向NO·信号转导在胰腺癌中具有潜在的治疗意义。随着新的临床前模型的出现，包括患者衍生的有机化合物，需要使用经过临床测试的NOS抑制剂进行进一步的临床前评估，以设计未来的临床研究。抗氧化剂。氧化还原信号。26,1000-1008。
SIGNIFICANCE Pancreatic tumors express high level of nitric oxide synthases (NOSs) in particular inducible (iNOS/NOS2) and endothelial (eNOS/NOS3) forms. However, the role of nitric oxide (NO•) in the development and progression of pancreatic cancer is not clearly defined. Delineating the NO•-induced signaling in pancreatic cancer and its potential contribution in disease aggressiveness may provide therapeutic targets to improve survival in this lethal malignancy. Recent Advances: An increased expression of NOS2/iNOS in tumors is associated with poorer survival in early stage resected patients with pancreatic ductal adenocarcinoma (PDAC). Furthermore, genetic deletion of NOS2 enhanced survival in mice with autochthonous PDAC. Additionally, targeting NOS3/eNOS reduced the abundance of precursor lesions in mice, which trended toward improved survival. CRITICAL ISSUES The extremely poor prognosis in pancreatic cancer is due to the late diagnosis and lack of effective therapy in advanced disease. One of the most critical issues is to decipher the underlying mechanism of disease aggressiveness and therapeutic resistance for identifying potential therapeutic target and effective treatment. Given the evidence of a strong association between inflammation and pancreatic cancer and clinical evidence, which suggests an association between NOS2 and disease aggressiveness, it is critical to define the role of NO• signaling in this lethal malignancy. FUTURE DIRECTIONS Recent preclinical and clinical evidences indicate a potential therapeutic significance of targeting NO• signaling in pancreatic cancer. With the emergence of new preclinical models, including the patient-derived organoids, further preclinical evaluation using clinically tested NOS inhibitors is needed for designing future clinical investigation. Antioxid. Redox Signal. 26, 1000-1008.