Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 21, 2018; 24(7): 794-809
Published online Feb 21, 2018. doi: 10.3748/wjg.v24.i7.794
Translational pancreatic cancer research: A comparative study on patient-derived xenograft models
Mercedes Rubio-Manzanares Dorado, Luis Miguel Marín Gómez, Daniel Aparicio Sánchez, Sheila Pereira Arenas, Juan Manuel Praena-Fernández, Juan Jose Borrero Martín, Francisco Farfán López, Miguel Ángel Gómez Bravo, Jordi Muntané Relat, Javier Padillo Ruiz
Mercedes Rubio-Manzanares Dorado, Luis Miguel Marín Gómez, Daniel Aparicio Sánchez, Miguel Ángel Gómez Bravo, Javier Padillo Ruiz, Department of Hepatobiliary and Pancreatic Surgery, Virgen del Rocio University Hospital, Seville 41013, Spain
Sheila Pereira Arenas, Jordi Muntané Relat, 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
Juan Manuel Praena-Fernández, Statistics, Methodology and Evaluation of Research Unit, Virgen del Rocio University Hospital, Seville 41013, Spain
Juan Jose Borrero Martín, Francisco Farfán López, Pathology Department, Virgen del Rocio University Hospital, Seville 41013, Spain
Author contributions: Rubio-Manzanares Dorado M, Marín Gómez LM, Aparicio Sánchez D, and Pereira Arenas S contributed substantially to the conception and design of the study and the acquisition of data; Praena-Fernández JM analysed and interpreted the data; Farfán López F and Borrero Martín JJ analysed the anatomopathological samples; Rubio-Manzanares Dorado M wrote the manuscript; and Padillo Ruiz J, Gómez Bravo MÁ and Muntané Relat J drafted the article and made critical revisions related to the intellectual content of the manuscript. All authors approved the final version of the manuscript to be published.
Supported by the Andalusian Public Foundation for the Management of Health Research in Seville (FISEVI).
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of The Seville University of Medicine, Virgen del Rocío Universitary Hospital, Protocol number: CEEA-US2014-013/5.
Conflict-of-interest statement: To the best of our knowledge, no conflict of interest exist.
Data sharing statement: Datasets are available from the corresponding author via email. Participants gave informed consent for data sharing.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Mercedes Rubio-Manzanares Dorado, MD, PhD, Staff Physician, Department of Hepatobiliary and Pancreatic Surgery, Virgen del Rocio University Hospital, Manuel Siurot St., Seville 41013, Spain. mercedesrmd@gmail.com
Telephone: +34-609-074420 Fax: +34-955-012317
Received: December 2, 2017
Peer-review started: December 2, 2017
First decision: December 20, 2017
Revised: January 14, 2018
Accepted: January 18, 2018
Article in press: January 18, 2018
Published online: February 21, 2018
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 (P = 0.064). There was a progressive increase in the tumour engraftment rate over successive generations for all three models (F1 28.1% vs F2 71.4% vs F3 80.9%, P < 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.

Keywords: Immunohistological analysis, Pancreatic cancer, Patient-derived xenograft, Animal model, Nude mice

Core tip: Several investigations have established patient-derived xenograft models for breast, renal, head and neck cancer, and hepatocellular tumours. Some of these models have predicted the clinical response of a specific type of tumour to different chemotherapeutic agents. However, the morphological and histological features of human pancreatic cancer xenografts in experimental models have been poorly studied. In the present study, the effectiveness of three experimental models based on the implantation of patient pancreatic cancer in three different locations (subcutaneous, intraperitoneal and pancreatic) have been assessed for the first time.