Fundamental research on the treatment for pancreatic cancer based on developmental biology of the pancreas

基于胰腺发育生物学的胰腺癌治疗基础研究

• 批准号: 15390395
• 负责人: DOI Ryuichiro
• 金额: $ 9.41万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390395/
• 关键词: Pancreatic duodenal homeobox gene-1; Pancreatic ductal carcinoma; Invasion; Insulin; Streptozocin

Pancreatic duodenal homeobox gene-1 (pdx-1) has a dual task as a key regulator in pancreatic organogenesis and in functional maintenance of beta cells in adults. Pdx-1 is thought to be a marker of de-differentiated cells with the capacity to re-differentiate into several pancreatic cell types. In this project, we analyzed pdx-1 expression in human pancreatic cancer specimens, as well as pancreatic cancer cell lines, and also analyzed the effects of forced expression of pdx-1 in pancreatic cancer cells. In addition, we analyzed the plasticity of the liver by enforced expression of pdx-1 in streptozotocin(STZ)-treated mice under the condition of hepatic regeneration.Forty-three percent of pancreatic cancers were positive for pdx-1 expression and 57% were negative. Lymph node metastasis (p=0.02) and histological grade (p=0.04) were significantly correlated with pdx-1 expression. Patients with positive pdx-1 had a significantly worse prognosis than those with negative pdx-1 (p=0.02). Impor … More tantly, pdx-1 was an independent variable that affected overall survival (p=0.03). Pancreatic cancer cell lines showed no pdx-1 expression. There were no significant differences in cell proliferation or morphology between Ad-pdx-1 and Ad-lacZ infected Panc-1 cells. However, Ad-pdx-1 infected Panc-1 cells did show a significantly higher migration rate than Ad-lacZ infected Panc-1 cells. In experiments in mice, most hepatocytes of Ad-pdx-1 infected mice were positive for pdx-1 expression by immunohistochemistry. In non-treated mice, very few cells expressed insulin and other hormones. In contrast, insulin and somatostatin were expressed in STZ treated-mice, and the more cells expressed in STZ plus Hx-treated mice. Hyperglycemia was improved in STZ-treated mice and STZ plus Hx-treated mice. IRI of serum and liver extract was increased in STZ-treated mice and STZ plus Hx-treated mice. The insulin positive area of the liver in STZ plus Hx-treated mice was larger than that in non-treated and STZ-treated mice.From the current project, re-expression of pdx-1 may represent a return to a more de-differentiated state by more aggressive pancreatic cancers, and may also represent an important new tumor marker for these aggressive cancers. The pdx-1 expression pattern that we observed also strongly suggests that specific embryonic differentiation pathways may be active in tumor progression of pancreatic cancers. From the latter part of the project, ectopic pdx-1 expression alone may be insufficient to induce insulin-producing cells in the liver. STZ-induced hyperglycemia plus partial hepatectomy that leads to diabetic state and hepatic regeneration may stimulate the transdifferentiation of liver cells into insulin-producing cells. Less

胰腺十二指肠同源框基因-1 (pdx-1) 具有双重作用，作为成人胰腺器官发生和 β 细胞功能维持的关键调节因子。 Pdx-1 被认为是去分化细胞的标志物，具有重新分化为多种胰腺细胞类型的能力。在这个项目中，我们分析了人胰腺癌标本以及胰腺癌细胞系中pdx-1的表达，并分析了pdx-1在胰腺癌细胞中强制表达的影响。此外，我们通过链脲佐菌素（STZ）处理的小鼠在肝再生条件下强制表达pdx-1来分析肝脏的可塑性。43％的胰腺癌pdx-1表达呈阳性，57％呈阴性。淋巴结转移（p=0.02）和组织学分级（p=0.04）与pdx-1表达显着相关。 pdx-1 阳性患者的预后明显比 pdx-1 阴性患者差 (p=0.02)。更重要的是，pdx-1 是影响总生存率的自变量 (p=0.03)。胰腺癌细胞系未显示 pdx-1 表达。 Ad-pdx-1 和 Ad-lacZ 感染的 Panc-1 细胞之间的细胞增殖或形态没有显着差异。然而，Ad-pdx-1感染的Panc-1细胞确实表现出比Ad-lacZ感染的Panc-1细胞显着更高的迁移率。在小鼠实验中，免疫组化显示Ad-pdx-1感染小鼠的大多数肝细胞pdx-1表达呈阳性。在未经治疗的小鼠中，很少有细胞表达胰岛素和其他激素。相比之下，STZ 治疗的小鼠中表达胰岛素和生长抑素，而 STZ 加 Hx 治疗的小鼠中表达的细胞更多。 STZ 治疗的小鼠和 STZ 加 Hx 治疗的小鼠的高血糖得到改善。 STZ 处理的小鼠和 STZ 加 Hx 处理的小鼠的血清和肝脏提取物的 IRI 增加。 STZ加Hx治疗的小鼠肝脏胰岛素阳性区域比未治疗和STZ治疗的小鼠更大。从目前的项目来看，pdx-1的重新表达可能代表更具侵袭性的胰腺癌恢复到更加去分化的状态，也可能代表这些侵袭性癌症的重要新肿瘤标志物。我们观察到的 pdx-1 表达模式也强烈表明特定的胚胎分化途径可能在胰腺癌的肿瘤进展中活跃。从该项目的后半部分来看，仅异位 pdx-1 表达可能不足以诱导肝脏中产生胰岛素的细胞。 STZ 诱导的高血糖加上导致糖尿病状态和肝再生的部分肝切除术可能会刺激肝细胞转分化为产生胰岛素的细胞。较少的

项目成果

Hand-assisted laparoscopic resection of serous cystadenoma of the pancreas.

手助腹腔镜胰腺浆液性囊腺瘤切除术。

• 发表时间: 2003
• 期刊: Surg Endosc 17(12)
• 作者: Doi;R.
• 通讯作者: R.

Hosotani, R.: "Expression of pancreatic duodenal hoemobox-1 in pancreatic islet neogenesis after surgical wrapping in rats"Surgery. 135・3. 297-306 (2004)

Hosotani, R.：“大鼠手术包裹后胰岛新生中胰腺十二指肠 hoemobox-1 的表达”Surgery 135・3 (2004)。

CXCR4 antagonist inhibits stromal cell-derived factor 1-induced migration and invasion of human pancreatic cancer.

• DOI: 10.1158/1535-7163.29.3.1
• 发表时间: 2004-01
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Tomohiko Mori;R. Doi;M. Koizumi;E. Toyoda;D. Ito;K. Kami;T. Masui;K. Fujimoto;H. Tamamura;K. Hiramatsu;N. Fujii;M. Imamura

Survivin expression is a prognostic marker in pancreatic cancer patients

• DOI: 10.1016/j.surg.2004.05.023
• 发表时间: 2004-08-01
• 期刊: SURGERY
• 影响因子: 3.8
• 作者: Kami, K;Doi, R;Imamura, M
• 通讯作者: Imamura, M

All-trans retinoic acid induces differentiation of ducts and endocrine cells by mesenchymal/epithelial interactions in embryonic pancreas.

• DOI: 10.2337/diabetes.52.1.76
• 发表时间: 2003
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: S. Tulachan;R. Doi;Y. Kawaguchi;S. Tsuji;S. Nakajima;T. Masui;M. Koizumi;E. Toyoda;Tomohiko Mori;D. Ito;K. Kami;K. Fujimoto;M. Imamura