Department of Medicine, Center for Translational Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Oncogene. 2012 Oct 11;31(41):4484-9. doi: 10.1038/onc.2011.574. Epub 2011 Dec 12.
Pancreatic ductal adenocarcinoma (PDA) is often detected at a late stage, hence the identification of new therapies that have potential to block tumor progression is critical for this lethal disease. N-cadherin upregulation has been observed in many cancers including PDA, however, a causal role for this cell adhesion receptor in disease progression has yet to be defined. The concomitant expression of oncogenic Kras(G12D) and mutant p53 (Trp53(R172H)) in the murine pancreas results in metastatic PDA that recapitulates the cognate features of human pancreatic cancer providing an excellent animal model to identify genes required for tumor progression. Here we determine the consequences of genetically manipulating N-cadherin expression in a mouse model of PDA. Remarkably, mice with reduced N-cadherin expression (that is, Ncad(-/+)) survived 25% longer (177 vs 142 days, P<0.05) than animals expressing two wild-type N-cadherin (Cdh2) alleles. The survival benefit is likely due to a cumulative effect of N-cadherin's role in different aspects of tumorigenesis including tumor-cell survival, growth, migration and invasion. Interestingly, reduced hedgehog signaling may contribute to the better prognosis for the Ncad(-/+) mice. Moreover, the matrix metalloproteinase MMP-7, associated with poor prognosis in PDA, was reduced in Ncad(-/+) tumors. Finally, Ncad(-/+) tumor cells exhibited decreased FGF-stimulated ERK1/2 activation consistent with N-cadherin's ability to promote FGFR signaling. These data support a critical role for N-cadherin in PDA and its potential prognostic value. Additionally, this study provides in vivo genetic evidence that the cell-surface protein N-cadherin represents a promising therapeutic target for the treatment of pancreatic cancer.
胰腺导管腺癌（PDA）通常在晚期被发现，因此，鉴定出有潜力阻断肿瘤进展的新疗法对于这种致命疾病至关重要。N-钙黏蛋白上调已在许多癌症中观察到，包括 PDA，然而，这种细胞黏附受体在疾病进展中的因果作用尚未确定。在小鼠胰腺中同时表达致癌性 Kras（G12D）和突变型 p53（Trp53（R172H））会导致转移性 PDA，该模型重现了人类胰腺癌的特征，为鉴定肿瘤进展所需的基因提供了一个极好的动物模型。在这里，我们确定了在 PDA 的小鼠模型中遗传操纵 N-钙黏蛋白表达的后果。值得注意的是，N-钙黏蛋白表达降低的小鼠（即 Ncad（-/-））的存活时间比表达两个野生型 N-钙黏蛋白（Cdh2）等位基因的动物长 25%（177 天对 142 天，P<0.05）。生存获益可能是由于 N-钙黏蛋白在肿瘤发生的不同方面的作用，包括肿瘤细胞的存活、生长、迁移和侵袭。有趣的是，降低的 Hedgehog 信号可能有助于 Ncad（-/-）小鼠的更好预后。此外，与 PDA 预后不良相关的基质金属蛋白酶 MMP-7 在 Ncad（-/-）肿瘤中减少。最后，Ncad（-/-）肿瘤细胞表现出降低的 FGF 刺激的 ERK1/2 激活，这与 N-钙黏蛋白促进 FGFR 信号的能力一致。这些数据支持 N-钙黏蛋白在 PDA 中的关键作用及其潜在的预后价值。此外，本研究提供了体内遗传证据，表明细胞表面蛋白 N-钙黏蛋白是治疗胰腺癌的有前途的治疗靶点。
