Disruption of p16 and activation of Kras in pancreas increase ductal adenocarcinoma formation and metastasis in vivo.
Disruption of p16 and activation of Kras in pancreas increase ductal adenocarcinoma formation and metastasis in vivo.
复制标题
DOI：
10.18632/oncotarget.357
复制
发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Su GH
中科院分区：
文献类型：
--
作者：
Qiu W;Sahin F;Iacobuzio-Donahue CA;Garcia-Carracedo D;Wang WM;Kuo CY;Chen D;Arking DE;Lowy AM;Hruban RH;Remotti HE;Su GH
抑癌基因p16/INK 4A的失活和KRAS的致癌激活几乎发生在所有胰腺癌中。为了更好地了解p16在胰腺肿瘤发生中的作用，我们建立了一个条件性p16基因敲除小鼠系（p16 flox/flox），其中p16以组织特异性方式被特异性破坏，而不影响p19/ARF表达。p16flox/flox; LSL-KrasG12D; Pdx 1-Cre小鼠发生全谱胰腺上皮内瘤变（mPanIN）病变、胰腺导管腺癌（PDA），并在所有小鼠中观察到转移。在这里，我们报告了一个小鼠模型，模拟人类胰腺肿瘤发生在遗传和组织学水平，是理想的转移研究。在从原发性肿瘤进展到转移的过程中，在p16 flox/flox; LSL-KrasG 12 D; Pdx 1-Cre小鼠中，Kras的野生型等位基因逐渐丢失（Kras处的杂合性丢失或Kras处的洛）。这些观察结果表明Kras的作用超出了肿瘤起始的范围。对这些小鼠的原发性胰腺肿瘤来源的癌细胞系进行的体外测定显示，Kras处具有洛的癌细胞表现出比保留野生型Kras等位基因的癌细胞更具侵袭性的表型，表明Kras处的洛可以提供癌细胞功能性生长优势并促进转移。在人胰腺原发性肿瘤向转移的进展中也观察到KRAS处的洛缺失增加，再次支持KRAS基因在癌症转移中的作用。这一发现具有潜在的翻译意义-未来的KRAS靶向治疗可能需要考虑特异性靶向致癌KRAS而不抑制野生型KRAS功能。
Inactivation of tumor suppressor gene p16/INK4A and oncogenic activation of KRAS occur in almost all pancreatic cancers. To better understand the roles of p16 in pancreatic tumorigenesis, we created a conditional p16 knockout mouse line (p16flox/flox), in which p16 is specifically disrupted in a tissue-specific manner without affecting p19/ARF expression. p16flox/flox; LSL-KrasG12D; Pdx1-Cre mice developed the full spectrum of pancreatic intraepithelial neoplasia (mPanIN) lesions, pancreatic ductal adenocarcinoma (PDA), and metastases were observed in all the mice. Here we report a mouse model that simulates human pancreatic tumorigenesis at both genetic and histologic levels and is ideal for studies of metastasis. During the progression from primary tumors to metastases, the wild-type allele of Kras was progressively lost (loss of heterozygosity at Kras or LOH at Kras) in p16flox/flox; LSL- KrasG12D; Pdx1-Cre mice. These observations suggest a role for Kras beyond tumor initiation. In vitro assays performed with cancer cell lines derived from primary pancreatic tumors of these mice showed that cancer cells with LOH at Kras exhibited more aggressive phenotypes than those retained the wild-type Kras allele, indicating that LOH at Kras can provide cancer cells functional growth advantages and promote metastasis. Increased LOH at KRAS was also observed in progression of human pancreatic primary tumors to metastases, again supporting a role for the KRAS gene in cancer metastasis. This finding has potential translational implications- future KRAS target therapies may need to consider targeting oncogenic KRAS specifically without inhibiting wild-type KRAS function.