The ARF tumor suppressor inhibits tumor cell colonization independent of p53 in a novel mouse model of pancreatic ductal adenocarcinoma metastasis.
The ARF tumor suppressor inhibits tumor cell colonization independent of p53 in a novel mouse model of pancreatic ductal adenocarcinoma metastasis.
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DOI：
10.1158/1541-7786.mcr-10-0475
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发表时间：
2011-07
期刊：
影响因子：
--
通讯作者：
Quelle DE
中科院分区：
文献类型：
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作者：
Muniz VP;Barnes JM;Paliwal S;Zhang X;Tang X;Chen S;Zamba KD;Cullen JJ;Meyerholz DK;Meyers S;Davis JN;Grossman SR;Henry MD;Quelle DE
胰腺导管腺癌(PDAC)是一种无法治愈的高转移性疾病，对现有的治疗方法大多具有抵抗力。更好地了解PDAC转移的遗传基础应该有助于改进治疗方法的发展。为此，我们开发了一种新的小鼠PDAC转移的异种移植模型，以加快与该疾病相关的候选基因的测试。建立稳定表达荧光素酶的人PDAC细胞系BxPC-3、MiaPaCa-2和PANC-1，并通过心内注射的方法将其导入免疫缺陷小鼠体内，建立癌细胞血行播散模型。通过生物发光成像(BLI)监测肿瘤生长情况。生物发光的MiaPaCa-2细胞最有效地再现了PDAC肿瘤在体内的发展和转移分布。肿瘤在近90%的小鼠和多种组织中形成，包括PDAC转移的正常部位。为了验证该模型，对已知的PDAC抑制因子p14ARF的作用进行了测试。在体外，p14ARF通过CtBP2依赖、P53不依赖的途径抑制MiaPaCa-2侵袭表型，这与体内肿瘤细胞定植减少相关。这些发现建立了一种新的生物发光小鼠肿瘤模型，用于快速评估可疑的PDAC转移基因的生物学意义。该系统还可能为测试创新疗法提供一个有价值的平台。
Pancreatic ductal adenocarcinoma (PDAC) is an incurable, highly metastatic disease that is largely resistant to existing treatments. A better understanding of the genetic basis of PDAC metastasis should facilitate development of improved therapies. To that end, we developed a novel mouse xenograft model of PDAC metastasis to expedite testing of candidate genes associated with the disease. Human PDAC cell lines BxPC-3, MiaPaCa-2 and Panc-1 stably expressing luciferase were generated and introduced by intracardiac injections into immunodeficient mice to model hematogenous dissemination of cancer cells. Tumor development was monitored by bioluminescence imaging (BLI). Bioluminescent MiaPaCa-2 cells most effectively recapitulated PDAC tumor development and metastatic distribution in vivo. Tumors formed in nearly 90% of mice and in multiple tissues, including normal sites of PDAC metastasis. Effects of p14ARF, a known suppressor of PDAC, were tested to validate the model. In vitro, p14ARF acted through a CtBP2-dependent, p53-independent pathway to inhibit MiaPaCa-2 invasive phenotypes, which correlated with reduced tumor cell colonization in vivo. These findings establish a new bioluminescent mouse tumor model for rapidly assessing the biological significance of suspected PDAC metastasis genes. This system may also provide a valuable platform for testing innovative therapies.