N-cadherin haploinsufficiency increases survival in a mouse model of pancreatic cancer.
N-cadherin haploinsufficiency increases survival in a mouse model of pancreatic cancer.
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DOI：
10.1038/onc.2011.574
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发表时间：
2012-10-11
期刊：
影响因子：
8
通讯作者：
Radice GL
中科院分区：
文献类型：
--
作者：
Su Y;Li J;Witkiewicz AK;Brennan D;Neill T;Talarico J;Radice GL
胰腺导管腺癌（PDA）通常在晚期才被发现，因此确定有可能阻止肿瘤进展的新疗法对这种致命疾病至关重要。在包括PDA在内的许多癌症中已经观察到N-钙粘蛋白上调，然而这种细胞粘附受体在疾病进展中的因果作用尚未确定。致癌基因KrasG 12 D和突变型p53（Trp 53 R172 H）在鼠胰腺中的伴随表达导致重现人胰腺癌的同源特征的转移性PDA，提供了鉴定肿瘤进展所需基因的极好动物模型。在这里，我们确定的后果，遗传操纵N-钙粘蛋白的表达在PDA的小鼠模型。值得注意的是，N-cadherin表达减少的小鼠（即N-cad-/+）比表达两种野生型N-cadherin（Cdh 2）等位基因的动物存活时间长25%（177对142天，p <0.05）。存活益处可能是由于N-钙粘蛋白在肿瘤发生的不同方面（包括肿瘤细胞存活、生长、迁移和侵袭）中的作用的累积效应。有趣的是，Hedgehog信号的减少可能有助于N-cad −/+小鼠更好的预后。此外，与PDA预后不良相关的基质金属蛋白酶MMP-7在N-cad −/+肿瘤中降低。最后，N-cad −/+肿瘤细胞表现出FGF刺激的ERK 1/2活化减少，这与N-cadherin促进FGFR信号传导的能力一致。这些数据支持N-钙粘蛋白在PDA中的关键作用及其潜在的预后价值。此外，这项研究提供了体内遗传学证据，表明细胞表面蛋白N-钙粘蛋白是治疗胰腺癌的一个有前途的治疗靶点。
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 KrasG12D and mutant p53 (Trp53R172H) 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 (i.e. N-cad −/+) 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 N-cad −/+ mice. Moreover, the matrix metalloproteinase MMP-7, associated with poor prognosis in PDA, was reduced in N-cad −/+ tumors. Finally, N-cad −/+ 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.
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影响因子：
2.5
作者：
Luo, Y;Kostetskii, I;Radice, GL
通讯作者：
Radice, GL
FGF10/FGFR2信号诱导胰腺癌细胞迁移和侵袭。
影响因子：
8.8
作者：
Nomura, S.;Yoshitomi, H.;Takano, S.;Shida, T.;Kobayashi, S.;Ohtsuka, M.;Kimura, F.;Shimizu, H.;Yoshidome, H.;Kato, A.;Miyazaki, M.
通讯作者：
Miyazaki, M.
N-钙粘着蛋白在乳腺癌细胞中的外源表达会诱导细胞迁移，侵袭和转移。
影响因子：
7.8
作者：
Hazan, R B;Phillips, G R;Qiao, R F;Norton, L;Aaronson, S A
通讯作者：
Aaronson, S A
影响因子：
6.4
作者：
Shintani，Yasushi;Fukumoto，Yuri;Johnson，Keith R.
通讯作者：
Johnson，Keith R.
影响因子：
11.8
作者：
Tenzen, Toyoaki;Allen, Benjamin L.;McMahon, Andrew P.
通讯作者：
McMahon, Andrew P.