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

胰腺十二指肠同源盒基因-1 （pdx-1）作为胰腺器官发生和成人β细胞功能维持的关键调节因子具有双重任务。Pdx-1被认为是去分化细胞的标志物，具有重新分化为几种胰腺细胞类型的能力。在本项目中，我们分析了pdx-1在人胰腺癌标本和胰腺癌细胞系中的表达，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增强pdx-1的表达来分析肝脏的可塑性。43%的胰腺癌患者pdx-1表达呈阳性，57%为阴性。淋巴结转移（p=0.02）和组织学分级（p=0.04）与pdx-1表达显著相关。pdx-1阳性患者的预后明显差于pdx-1阴性患者（p=0.02）。更重要的是，pdx-1是影响总生存率的独立变量（p=0.03）。胰腺癌细胞系无pdx-1表达。Ad-pdx-1和Ad-lacZ感染的Panc-1细胞在细胞增殖和形态上无显著差异。然而，Ad-pdx-1感染的Panc-1细胞的迁移率明显高于Ad-lacZ感染的Panc-1细胞。在小鼠实验中，大多数感染Ad-pdx-1的小鼠肝细胞免疫组化显示pdx-1表达阳性。在未接受治疗的小鼠中，很少有细胞表达胰岛素和其他激素。相比之下，胰岛素和生长抑素在STZ处理的小鼠中表达，并且STZ + hx处理的小鼠中表达的细胞越多。STZ治疗小鼠和STZ + hx治疗小鼠的高血糖得到改善。STZ处理小鼠和STZ + hx处理小鼠血清和肝脏提取物IRI均升高。STZ + hx治疗组小鼠肝脏胰岛素阳性面积大于未治疗组和STZ治疗组。从目前的项目来看，pdx-1的重新表达可能代表着侵袭性更强的胰腺癌恢复到更加去分化的状态，也可能代表着这些侵袭性癌症的一个重要的新的肿瘤标志物。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很活跃。从项目的后半部分来看，单独的异位pdx-1表达可能不足以诱导肝脏中产生胰岛素的细胞。stz诱导的高血糖加上部分肝切除术导致的糖尿病状态和肝脏再生可能刺激肝细胞向胰岛素生成细胞的转分化。少

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