Department of Pathology, Stanford University, Palo Alto, California, USA.
Clin Cancer Res. 2010 Jul 15;16(14):3684-95. doi: 10.1158/1078-0432.CCR-09-2384. Epub 2010 Jun 9.
The most common preclinical models of pancreatic adenocarcinoma utilize human cells or tissues that are xenografted into immunodeficient hosts. Several immunocompetent, genetically engineered mouse models of pancreatic cancer exist; however, tumor latency and disease progression in these models are highly variable. We sought to develop an immunocompetent, orthotopic mouse model of pancreatic cancer with rapid and predictable growth kinetics.
Cell lines with epithelial morphology were derived from liver metastases obtained from Kras(G12D/+);LSL-Trp53(R172H/+);Pdx-1-Cre mice. Tumor cells were implanted in the pancreas of immunocompetent, histocompatible B6/129 mice, and the mice were monitored for disease progression. Relevant tissues were harvested for histologic, genomic, and immunophenotypic analysis.
All mice developed pancreatic tumors by two weeks. Invasive disease and liver metastases were noted by six to eight weeks. Histologic examination of tumors showed cytokeratin-19-positive adenocarcinoma with regions of desmoplasia. Genomic analysis revealed broad chromosomal changes along with focal gains and losses. Pancreatic tumors were infiltrated with dendritic cells, myeloid-derived suppressor cells, macrophages, and T lymphocytes. Survival was decreased in RAG(-/-) mice, which are deficient in T cells, suggesting that an adaptive immune response alters the course of disease in wild-type mice.
We have developed a rapid, predictable orthotopic model of pancreatic adenocarcinoma in immunocompetent mice that mimics human pancreatic cancer with regard to genetic mutations, histologic appearance, and pattern of disease progression. This model highlights both the complexity and relevance of the immune response to invasive pancreatic cancer and may be useful for the preclinical evaluation of new therapeutic agents.
最常见的胰腺腺癌临床前模型利用异种移植到免疫缺陷宿主的人细胞或组织。存在几种免疫活性的、基因工程小鼠胰腺癌模型；然而，这些模型中的肿瘤潜伏期和疾病进展差异很大。我们试图开发一种具有快速和可预测生长动力学的免疫活性的胰腺腺癌原位小鼠模型。
从 Kras(G12D/+);LSL-Trp53(R172H/+);Pdx-1-Cre 小鼠的肝转移中获得具有上皮形态的细胞系。将肿瘤细胞植入免疫活性的、组织相容性的 B6/129 小鼠的胰腺中，并监测疾病进展。采集相关组织进行组织学、基因组和免疫表型分析。
所有小鼠在两周内均发展为胰腺肿瘤。六到八周时出现侵袭性疾病和肝转移。肿瘤的组织学检查显示具有间皮样区域的细胞角蛋白 19 阳性腺癌。基因组分析显示广泛的染色体变化以及局灶性增益和缺失。胰腺肿瘤浸润有树突状细胞、髓系来源的抑制细胞、巨噬细胞和 T 淋巴细胞。在缺乏 T 细胞的 RAG(-/-) 小鼠中，存活率降低，这表明适应性免疫反应改变了野生型小鼠的疾病进程。
我们已经在免疫活性小鼠中开发了一种快速、可预测的胰腺腺癌原位模型，该模型在遗传突变、组织学表现和疾病进展模式方面模拟了人类胰腺癌。该模型突出了侵袭性胰腺癌中免疫反应的复杂性和相关性，并且可能对新治疗药物的临床前评估有用。
