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

胰腺十二指肠同源异型盒基因1（pdx-1）具有双重功能，在成人胰腺器官发生和β细胞功能维持中起关键调节作用。Pdx-1被认为是去分化细胞的标志物，具有再分化成几种胰腺细胞类型的能力。在这个项目中，我们分析了pdx-1在人胰腺癌标本以及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效果。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表达来分析肝脏的可塑性，43%的胰腺癌中pdx-1表达阳性，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阳性患者的预后显著差于pdx-1阴性患者（p=0.02）。因波尔 ...更多信息 pdx-1是影响总生存率的独立变量（p=0.03）。胰腺癌细胞系中没有pdx-1表达。Ad-pdx-1和Ad-lacZ感染的Panc-1细胞在增殖和形态学上均无显著差异。然而，Ad-pdx-1感染的Panc-1细胞确实显示出比Ad-lacZ感染的Panc-1细胞显著更高的迁移率。在小鼠实验中，大多数Ad-pdx-1感染小鼠的肝细胞通过免疫组织化学检测呈pdx-1阳性表达。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。与此相反，胰岛素和生长抑素在STZ治疗的小鼠中表达，并且在STZ + HX治疗的小鼠中表达更多的细胞。在STZ治疗的小鼠和STZ加HX治疗的小鼠中，高血压得到改善。STZ处理组和STZ + HX处理组小鼠血清和肝提取物的IRI增加。STZ + HX治疗组小鼠肝脏胰岛素阳性面积大于未治疗组和STZ治疗组小鼠。从目前的项目来看，pdx-1的重新表达可能代表了更具侵袭性的胰腺癌向更去分化状态的回归，也可能代表了这些侵袭性癌症的重要新肿瘤标志物。我们观察到的pdx-1表达模式也有力地表明，特定的胚胎分化途径可能在胰腺癌的肿瘤进展中是活跃的。从该项目的后半部分来看，异位pdx-1表达本身可能不足以诱导肝脏中的胰岛素产生细胞。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可能刺激肝细胞转分化为胰岛素产生细胞。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