Genes&Dev：新型胰腺癌动物模型被建立

    生物谷报道：最近，Vanderbilt-Ingram癌症中心研究者们研制出一种新的胰腺癌的动物模型，该模型与人的胰腺癌具有很高的相似性。该项研究发表于11月15日《基因和发育杂志》上，来自于遗传基因工程鼠的研究结果表明这种小鼠能为研究胰腺癌靶向化疗和检查方法提供新的机遇，而胰腺癌是大多数最易致死性癌症中的一种。
    胰腺癌预后很差，5年生存率不到5％大多数胰腺癌诊断时已经是处于晚期。因此建立一种胰腺癌动物模型对识别新的治疗方法和检查方法非常必需的，但这方面的进展非常缓慢。第一个理想的胰腺癌模型于2003年报道，涉及到一个名为Kras基因的突变。这个基因的突变是人类胰腺癌中最早期的基因改变，然而，这个动物模型与人类胰腺癌不很相同。Kras突变被认为是一个“肿瘤启动”事件，但需要其他基因的另外突变才可能进展为临床相关的肿瘤。过去多年来，研究者们正在寻找一种联合基因突变的胰腺癌动物模型。
    在以前动物模型的基础上，Moses和其合作者们将Kras突变与Ⅱ型TGFB受体的“敲除”结合起来，后者是抑制细胞生长的一种信号途径的一个成分。TGFB信号的丧失能除去分子“检查和平衡”对细胞生长的影响，导致没有抑制的细胞增殖和肿瘤形成。研究者们使用基因操作方法仅调控胰腺细胞中这些基因改变。形成的肿瘤局限于胰腺内，其他组织无肿瘤形成。Kras突变和TGFBR2敲除的结合导致了进展性肿瘤中有100％外显率，肿瘤组织学和临床上非常类似于人类疾病。

Figure 1. Normal pancreas development in Tgfbr2 knockout mice.

 (A) PCR detected Tgfbr2 allele recombination in the pancreas tissues of 1-d to 24-wk-old mice. (Top) PCR to detect Tgfbr2 allele recombination. The recombined allele was detected in the Ptf1acre/+;Tgfbr2flox/flox and Ptf1acre/+;Tgfbr2flox/f+ mice throughout the ages examined. (Bottom) Genotyping PCR to detect floxed and wild-type Tgfbr2 alleles. Some floxed alleles appeared to be diminished in those mice that showed the allele recombination. (Rec) Recombined allele; (fl) floxed allele; (wt) wild-type allele of Tgfbr2 gene; (fl/fl) Ptf1acre/+;Tgfbr2flox/flox mice; (fl/+) Ptf1acre/+;Tgfbr2flox/f+ mice; (+/+) Tgfbr2flox/flox mice. (B,C) -Galactosidase in situ staining. Cre recombination was homogeneously observed all through the pancreas of Ptf1acre/+;Tgfbr2flox/flox;Rosa26r mice (B), but not in that of Tgfbr2flox/flox;Rosa26r mice (C). (D) H&E staining of 1.5-yr-old pancreas of the Ptf1acre/+;Tgfbr2flox/flox mouse. The pancreas was normally developed and has no abnormal findings in Tgfbr2 knockout mice. (E) Immunohistochemistry of endocrine and exocrine pancreas markers at 7 wk of age. Insulin, glucagon, and amylase staining showed no difference. Somatostatin expression was more prominent in the Tgfbr2 knockout mice at this stage. (Control) Tgfbr2flox/flox mice; (Tgfbr2 KO) Ptf1acre/+;Tgfbr2flox/flox mice. Bars: B,C,E 250 µm; D, 500 µm.