Both p16Ink4a and the p19Arf-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse
Both p16Ink4a and the p19Arf-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse
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DOI：
10.1073/pnas.0601273103
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发表时间：
2006-04-11
影响因子：
11.1
通讯作者：
DePinho, RA
中科院分区：
文献类型：
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作者：
Bardeesy, N;Aguirre, AJ;DePinho, RA
激活KRAS突变和p16（Ink 4a）失活是人类胰腺导管腺癌（PDAC）中几乎普遍的事件。在小鼠模型中，Kras（G12 D）启动癌前胰腺导管病变的形成，Ink 4a/Arf（p16（Ink 4a）/p19（Arf））或p53的缺失使其恶性进展。由于最近的小鼠模型研究表明p16（Ink 4a）在抑制恶性进展中的作用不太突出，我们试图评估Kras（G12 D）模型中P16（Ink 4a），p19（Arf）和/或p53失活的病理学和基因组影响。在p53或p16（Ink 4a）纯合缺失的情况下观察到快速进展的PDAC，后者具有完整的生殖系p53和p19（Arf）序列。此外，Kras（G12 D）在p53 + p16（Ink 4a）或p16（Ink 4a）/p19（Arf）杂合性背景下产生的PDAC相对于p53或p16（Ink 4a）/p19（Arf）纯合缺失的小鼠具有更长的潜伏期和更大的远处转移倾向。来自双杂合队列的肿瘤显示频繁的p16（Ink 4a）失活和p53或p19（Arf）的丢失。不同的基因型与特定的组织病理学特征相关，最明显的是在纯合子p16（Ink 4a）/p19（Arf）突变模型中分化程度较低的趋势。高分辨率基因组分析显示，肿瘤抑制基因型影响这些肿瘤的特定基因组模式，并显示在小鼠和人类PDAC之间的区域染色体改变重叠。总的来说，我们的研究结果表明，p16（Ink 4a）和p19（ARF）-p53电路的中断在PDAC进展中起着关键和合作的作用，特定的肿瘤抑制基因型间接影响肿瘤生物学表型和基因组图谱。
Activating KRAS mutations and p16(Ink4a) inactivation are near universal events in human pancreatic ductal adenocarcinoma (PDAC). In mouse models, Kras(G12D) initiates formation of premalignant pancreatic ductal lesions, and loss of either Ink4a/Arf (p16(Ink4a)/p19(Arf)) or p53 enables their malignant progression. As recent mouse modeling studies have suggested a less prominent role for p16(Ink4a) in constraining malignant progression, we sought to assess the pathological and genomic impact of inactivation of P16(Ink4a), p19(Arf), and/or p53 in the Kras(G12D) model. Rapidly progressive PDAC was observed in the setting of homozygous deletion of either p53 or p16(Ink4a), the latter with intact germ-line p53 and p19(Arf) sequences. Additionally, Kras(G12D) in the context of heterozygosity either for p53 plus p16(Ink4a) or for p16(Ink4a)/p19(Arf) produced PDAC with longer latency and greater propensity for distant metastases relative to mice with homozygous deletion of p53 or p16(Ink4a)/p19(Arf). Tumors from the double-heterozygous cohorts showed frequent p16(Ink4a) inactivation and loss of either p53 or p19(Arf). Different genotypes were associated with specific histopathologic characteristics, most notably a trend toward less differentiated features in the homozygous p16(Ink4a)/p19(Arf) mutant model. High-resolution genomic analysis revealed that the tumor suppressor genotype influenced the specific genomic patterns of these tumors and showed overlap in regional chromosomal alterations between murine and human PDAC. Collectively, our results establish that disruptions of p16(Ink4a) and the p19(ARF)-p53 circuit play critical and cooperative roles in PDAC progression, with specific tumor suppressor genotypes provocatively influencing the tumor biological phenotypes and genomic profiles of the resultant tumors.