Kanai Tomoya, Ito Zensho, Oji Yusuke, Suka Machi, Nishida Sumiyuki, Takakura Kazuki, Kajihara Mikio, Saruta Masayuki, Fujioka Shuichi, Misawa Takeyuki, Akiba Tadashi, Yanagisawa Hiroyuki, Shimodaira Shigetaka, Okamoto Masato, Sugiyama Haruo, Koido Shigeo
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan.
Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Oncol Lett. 2018 Aug;16(2):2682-2692. doi: 10.3892/ol.2018.8961. Epub 2018 Jun 13.
The only current curative treatment for patients with pancreatic ductal adenocarcinoma (PDA) is surgical resection, and certain patients still succumb to disease shortly after complete surgical resection. Wilms' tumor 1 (WT1) serves an oncogenic role in various types of tumors; therefore, in the present study, WT1 protein expression in patients with PDA was analyzed and the association with overall survival (OS) and disease-free survival (DFS) time in patients with PDA was assessed following surgical resection. A total of 50 consecutive patients with PDA who received surgical resection between January 2005 and December 2015 at the Jikei University Kashiwa Hospital (Kashiwa, Chiba, Japan) were enrolled. WT1 protein expression in PDA tissue was measured using immunohistochemical staining. Furthermore, laboratory parameters were measured within 2 weeks of surgery, and systemic inflammatory response markers were evaluated. WT1 protein expression was detected in the nucleus and cytoplasm of all PDA cells and in tumor vessels. WT1 exhibited weak staining in the nuclei of all PDA cells; however, the cytoplasmic expression of WT1 levels was classified into four groups: Negative (n=0), weak (n=19), moderate (n=23) and strong (n=8). In patients with PDA, it was demonstrated that the OS and DFS times of patients with weak cytoplasmic WT1 expression were significantly prolonged compared with those of patients with moderate-to-strong cytoplasmic WT1 expression, as determined by log-rank test (P=0.0005 and P=0.0001, respectively). Furthermore, an association between the density of WT1-expressing tumor vessels and worse OS/DFS times was detected. Multivariate analysis also indicated a significant association between the overexpression of WT1 in PDA tissue and worse OS/DFS times. To the best of our knowledge, the present study is the first to demonstrate that moderate-to-strong overexpression of WT1 in the cytoplasm of PDA cells is significantly associated with worse OS/DFS times. Therefore, overexpression of WT1 in the cytoplasm of PDA cells may impact the recurrence and prognosis of patients with PDA following surgical resection. The results further support the development of WT1-targeted therapies to prolong survival in all patients with PDA.
目前，胰腺导管腺癌（PDA）患者唯一的治愈性治疗方法是手术切除，然而部分患者在完全手术切除后不久仍会死于该疾病。威尔姆斯瘤1（WT1）在多种肿瘤中发挥致癌作用；因此，在本研究中，分析了PDA患者中WT1蛋白的表达情况，并评估了手术切除后其与PDA患者总生存期（OS）和无病生存期（DFS）的关系。选取了2005年1月至2015年12月期间在日本千叶县柏市的慈惠会医科大学柏医院接受手术切除的50例连续PDA患者。采用免疫组织化学染色法检测PDA组织中WT1蛋白的表达。此外，在术后2周内检测实验室参数，并评估全身炎症反应标志物。在所有PDA细胞的细胞核和细胞质以及肿瘤血管中均检测到WT1蛋白表达。WT1在所有PDA细胞核中呈弱阳性染色；然而，WT1的细胞质表达水平分为四组：阴性（n = 0）、弱阳性（n =
19）、中度阳性（n = 23）和强阳性（n = 8）。通过对数秩检验确定，在PDA患者中，细胞质WT1表达为弱阳性的患者的OS和DFS时间明显长于细胞质WT1表达为中度至强阳性的患者（分别为P = 0.0005和P = 0.0001）。此外，检测到表达WT1的肿瘤血管密度与较差的OS/DFS时间之间存在关联。多因素分析还表明，PDA组织中WT1的过表达与较差的OS/DFS时间之间存在显著关联。据我们所知，本研究首次表明，PDA细胞细胞质中WT1的中度至强过表达与较差的OS/DFS时间显著相关。因此，PDA细胞细胞质中WT1的过表达可能会影响PDA患者手术切除后的复发和预后。这些结果进一步支持了开发靶向WT1的疗法以延长所有PDA患者生存期的研究。
