Delitto Daniel, Pham Kien, Vlada Adrian C, Sarosi George A, Thomas Ryan M, Behrns Kevin E, Liu Chen, Hughes Steven J, Wallet Shannon M, Trevino Jose G
Department of Surgery, Colleges of Medicine, Dentistry, and Public Health and Health Professions, University of Florida Health Science Center, Gainesville, Florida.
Department of Pathology, Colleges of Medicine, Dentistry, and Public Health and Health Professions, University of Florida Health Science Center, Gainesville, Florida.
Am J Pathol. 2015 May;185(5):1297-303. doi: 10.1016/j.ajpath.2015.01.016. Epub 2015 Mar 12.
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 stromal 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.
直接植入有活力的手术标本为胰腺腺癌提供了一个具有代表性的临床前平台。患者来源的异种移植瘤始终显示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未得到充分表征。这项工作专门研究了小鼠基质成分向不断扩大的患者来源的胰腺腺癌异种移植瘤中的募集和整合，确定了小鼠细胞融入侵袭性癌细胞网络的情况。此外，我们还提供了建立和维持患者来源的胰腺腺癌异种移植瘤模型的方法和观察结果。总共将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。对患者的人口统计学、分期、病理分析和结果进行了分析。肿瘤成功植入后，对取出的肿瘤进行了组织学和免疫荧光分析。25次尝试中有15次（60%）成功植入胰腺腺癌标本。成功植入似乎与临床病理因素或患者生存率无关。肿瘤形态在多次传代中得以保留，并且肿瘤保留了转移潜能。有趣的是，尽管各代之间形态相似，但人类基质成分似乎并未随着侵袭性癌细胞的生长而扩张。相反，在最初植入后，促结缔组织增生性小鼠基质在异种移植瘤微环境中占主导地位。以这种方式募集基质成分以支持和维持肿瘤生长，为研究肿瘤-基质相互作用提供了一条新途径。
