文章：

胰腺癌生物学和遗传学

Pancreatic cancer biology and genetics

原文发布日期：2002-12-01

DOI: 10.1038/nrc949

类型: Review Article

开放获取: 否

要点：

1. Pancreatic adenocarcinoma is a highly aggressive malignancy that shows profound resistance to extant treatments.
2. Genetic studies identified a signature molecular profile of this malignancy, consisting of mutations in KRAS, CDKN2A, TP53 and SMAD4/DPC4.
3. Pancreatic adenocarcinomas seem to arise from the progression of lesions that occur in the pancreatic ducts (pancreatic intraepithelial neoplasia, PanIN). Although the mutations listed above seem to occur in a temporal sequence in progressive PanIN stages, the specific biochemical and cellular events resulting from the mutations are not known.
4. This tumour type shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in TP53 and BRCA2 are likely to contribute to these phenotypes.
5. There is ongoing study of the cell of origin in pancreatic adenocarcinoma. Although there is general agreement that the pancreatic ductal epithelial cell gives rise to this malignancy, there is evidence that transdifferentiation of other pancreatic cell types, such as acinar cells, might serve as an alternative route to pancreatic adenocarcinoma.
6. These tumours show an extensive proliferation of stromal fibroblasts and deposition of extracellular-matrix components (desmoplasia) that seem to promote growth and invasiveness. The molecular basis of this phenotype is not resolved, although TGF-β is thought to have a role.
7. Engineered mouse models have recapitulated some of the genetic and histological features of the human disease. The use of refined methodologies, such as tissue-specific mouse knockouts, should give insight into the biological and biochemical impact of tumour-suppressor gene loss or oncogene activation in pancreatic neoplasia.

要点翻译：

1. 胰腺腺癌是一种高度侵袭性恶性肿瘤，对现有治疗方法表现出极强的抵抗性。
2. 基因研究确定了该恶性肿瘤的特征性分子谱系，包括KRAS、CDKN2A、TP53和SMAD4/DPC4基因突变。
3. 胰腺腺癌似乎源于胰腺导管内病变（胰腺上皮内瘤变，PanIN）的进展。虽然上述突变似乎按时间顺序发生在PanIN进展阶段，但这些突变导致的具体生化和细胞事件尚未明确。
4. 此类肿瘤表现出广泛的基因组不稳定性与非整倍性。端粒缩短以及TP53和BRCA2基因突变可能促成这些表型。
5. 关于胰腺腺癌起源细胞的研究仍在进行中。虽然学界普遍认为胰腺导管上皮细胞是此恶性肿瘤的起源，但有证据表明其他胰腺细胞类型（如腺泡细胞）的转分化可能成为胰腺腺癌形成的替代途径。
6. 这些肿瘤呈现显著的基质成纤维细胞增殖和细胞外基质成分沉积（促纤维结缔组织增生），这些现象似乎促进肿瘤生长和侵袭性。虽然TGF-β被认为在此过程中发挥作用，但该表型的分子基础尚未明确。
7. 工程化小鼠模型已成功复现人类疾病的部分遗传学和组织学特征。通过应用组织特异性基因敲除小鼠等精密技术手段，将有助于深入理解抑癌基因缺失或癌基因激活在胰腺肿瘤发生中的生物学和生化效应。

英文摘要：

Pancreatic ductal adenocarcinoma is an aggressive and devastating disease, which is characterized by invasiveness, rapid progression and profound resistance to treatment. Advances in pathological classification and cancer genetics have improved our descriptive understanding of this disease; however, important aspects of pancreatic cancer biology remain poorly understood. What is the pathogenic role of specific gene mutations? What is the cell of origin? And how does the stroma contribute to tumorigenesis? A better understanding of pancreatic cancer biology should lead the way to more effective treatments.

摘要翻译： 

胰腺导管腺癌是一种侵袭性强、破坏力大的疾病，其特征是侵袭性、快速进展和对治疗的深度抵抗。病理分类和癌症遗传学的进展提高了我们对该疾病的描述性理解；然而，胰腺癌生物学的重要方面仍知之甚少。特定基因突变的致病作用是什么？起源细胞是什么？基质如何促进肿瘤发生？对胰腺癌生物学的更好理解应为更有效的治疗开辟道路。

原文链接：

Pancreatic cancer biology and genetics