转化性胰腺癌研究：患者来源异种移植模型的比较研究。

Translational pancreatic cancer research: A comparative study on patient-derived xenograft models.

机构信息

Department of Hepatobiliary and Pancreatic Surgery, Virgen del Rocio University Hospital, Seville 41013, Spain.

Oncology Surgery, Cell Therapy, and Organ Transplantation Group, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital, University of Seville, Seville 41013, Spain.

出版信息

World J Gastroenterol. 2018 Feb 21;24(7):794-809. doi: 10.3748/wjg.v24.i7.794.

DOI:10.3748/wjg.v24.i7.794

PMID:29467550

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5807938/

Abstract

AIM

To assess the viability of orthotopic and heterotopic patient-derived pancreatic cancer xenografts implanted into nude mice.

METHODS

This study presents a prospective experimental analytical follow-up of the development of tumours in mice upon implantation of human pancreatic adenocarcinoma samples. Specimens were obtained surgically from patients with a pathological diagnosis of pancreatic adenocarcinoma. Tumour samples from pancreatic cancer patients were transplanted into nude mice in three different locations (intraperitoneal, subcutaneous and pancreatic). Histological analysis (haematoxylin-eosin and Masson's trichrome staining) and immunohistochemical assessment of apoptosis (TUNEL), proliferation (Ki-67), angiogenesis (CD31) and fibrogenesis (α-SMA) were performed. When a tumour xenograft reached the target size, it was re-implanted in a new nude mouse. Three sequential tumour xenograft generations were generated (F1, F2 and F3).

RESULTS

The overall tumour engraftment rate was 61.1%. The subcutaneous model was most effective in terms of tissue growth (69.9%), followed by intraperitoneal (57.6%) and pancreatic (55%) models. Tumour development was faster in the subcutaneous model (17.7 ± 2.6 wk) compared with the pancreatic (23.1 ± 2.3 wk) and intraperitoneal (25.0 ± 2.7 wk) models ( = 0.064). There was a progressive increase in the tumour engraftment rate over successive generations for all three models (F1 28.1% F2 71.4% F3 80.9%, < 0.001). There were no significant differences in tumour xenograft differentiation and cell proliferation between human samples and the three experimental models among the sequential generations of tumour xenografts. However, a progressive decrease in fibrosis, fibrogenesis, tumour vascularisation and apoptosis was observed in the three experimental models compared with the human samples. All three pancreatic patient-derived xenograft models presented similar histological and immunohistochemical characteristics.

CONCLUSION

In our experience, the faster development and greatest number of viable xenografts could make the subcutaneous model the best option for experimentation in pancreatic cancer.

摘要

目的

评估将同种异体和异种患者来源的胰腺癌异种移植物植入裸鼠体内的可行性。

方法

本研究前瞻性地分析了将人胰腺腺癌样本植入裸鼠后肿瘤的发展情况。标本取自经病理诊断为胰腺腺癌的患者手术中获得。将来自胰腺癌患者的肿瘤样本分别移植到裸鼠的三个不同部位（腹腔内、皮下和胰腺内）。进行组织学分析（苏木精-伊红和 Masson 三色染色）和凋亡（TUNEL）、增殖（Ki-67）、血管生成（CD31）和纤维化（α-SMA）的免疫组织化学评估。当肿瘤异种移植物达到目标大小，将其重新植入新的裸鼠中。生成了三个连续的肿瘤异种移植物代（F1、F2 和 F3）。

结果

总体肿瘤植入率为 61.1%。皮下模型在组织生长方面最有效（69.9%），其次是腹腔内（57.6%）和胰腺内（55%）模型。皮下模型中肿瘤的生长速度更快（17.7 ± 2.6 周），而胰腺内（23.1 ± 2.3 周）和腹腔内（25.0 ± 2.7 周）模型较慢（ = 0.064）。所有三种模型的肿瘤植入率在连续几代中均逐渐增加（F1 28.1%、F2 71.4%、F3 80.9%，<0.001）。在肿瘤异种移植物的连续几代中，人类样本与三种实验模型之间的肿瘤异种移植物分化和细胞增殖没有差异。然而，在三种实验模型中，纤维化、纤维发生、肿瘤血管生成和凋亡逐渐减少。所有三种胰腺患者来源的异种移植模型均表现出相似的组织学和免疫组织化学特征。