Patient-Derived Xenograft Models for Pancreatic Adenocarcinoma Demonstrate Retention of Tumor Morphology through Incorporation of Murine Stromal Elements
Patient-Derived Xenograft Models for Pancreatic Adenocarcinoma Demonstrate Retention of Tumor Morphology through Incorporation of Murine Stromal Elements
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DOI：
10.1016/j.ajpath.2015.01.016
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发表时间：
2015-05-01
影响因子：
6
通讯作者：
Trevino, Jose G.
中科院分区：
文献类型：
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作者：
Delitto, Daniel;Pham, Kien;Trevino, Jose G.
直接植入可行的手术标本为胰腺癌提供了代表性的临床前平台。患者来源的异种移植物始终表现出保留的肿瘤形态和遗传稳定性。然而，在这些模型中，肿瘤微环境随时间的演变仍然很少被描述。这项工作专门解决了将小鼠基质元素招募和掺入扩大的患者来源的胰腺腺癌异种移植物中，建立小鼠细胞与入侵癌细胞网络的整合。此外，我们还提供建立和维持患者来源的胰腺腺癌异种移植模型的方法和观察结果。将总共25个经组织学证实的胰腺腺癌标本皮下植入非肥胖糖尿病严重联合免疫缺陷小鼠体内。对患者人口统计、分期、病理分析和结果进行了分析。肿瘤成功植入后，对移植的肿瘤进行组织学和免疫荧光分析。 25 次尝试中，有 15 次 (60%) 成功移植胰腺癌标本。成功的植入似乎与临床病理因素或患者存活率无关。肿瘤形态通过多次传代得以保留，并且肿瘤保留了转移潜力。有趣的是，尽管各代之间的形态相似，但人类造口成分似乎并没有随着癌细胞的入侵而扩张。相反，在初次植入后，促结缔组织增生性小鼠基质在异种移植物微环境中占主导地位。以这种方式募集基质成分来支持和维持肿瘤生长代表了研究肿瘤基质相互作用的新途径。
Direct implantation of viable surgical specimens provides a representative preclinical platform in pancreatic adenocarcinoma. Patient-derived xenografts consistently demonstrate retained tumor morphology and genetic stability. However, the evolution of the tumor microenvironment over time remains poorly characterized in these models. This work specifically addresses the recruitment and incorporation of murine stromal elements into expanding patient-derived pancreatic adenocarcinoma xenografts, establishing the integration of murine cells into networks of invading cancer cells. In addition, we provide methods and observations in the establishment and maintenance of a patient-derived pancreatic adenocarcinoma xenograft model. A total of 25 histologically confirmed pancreatic adenocarcinoma specimens were implanted subcutaneously into nonobese diabetic severe combined immunodeficiency mice. Patient demographics, staging, pathological analysis, and outcomes were analyzed. After successful engraftment of tumors, histological and immunofluorescence analyses were performed on explanted tumors. Pancreatic adenocarcinoma specimens were successfully engrafted in 15 (60%) of 25 attempts. Successful engraftment does not appear to correlate with clinicopathologic factors or patient survival. Tumor morphology is conserved through multiple passages, and tumors retain metastatic potential. Interestingly, despite morphological similarity between passages, human stomal elements do not appear to expand with invading cancer cells. Rather, desmoplastic murine stroma dominates the xenograft microenvironment after the initial implantation. Recruitment of stromal elements in this manner to support and maintain tumor growth represents a novel avenue for investigation into tumor-stromal interactions.