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

Abstract

AIMTo assess the viability of orthotopic and heterotopic patient-derived pancreatic cancer xenografts implanted into nude mice.METHODSThis 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).RESULTSThe 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.CONCLUSIONIn our experience, the faster development and greatest number of viable xenografts could make the subcutaneous model the best option for experimentation in pancreatic cancer.

Validation of a Patient-Derived Xenograft Model for Cervical Cancer Based on Genomic and Phenotypic Characterization

“…PDX models reproduce the clinicopathological characteristics of the original tumor and are used as experimental models for drug evaluation, biomarker identification, and precision medicine strategies [ 6 ]. Several PDX models have been established successfully, including colon [ 9 ], stomach [ 10 ], breast [ 11 ], pancreas [ 12 ], lung [ 13 ], liver [ 14 ], kidney [ 15 ], bladder [ 16 ], uterus [ 17 ], and ovary [ 18 ]. However, a limited number of studies have reported PDX models of cervical cancer.…”

Establishment and Characterisation by Expression Microarray of Patient-Derived Xenograft Panel of Human Pancreatic Adenocarcinoma Patients

“…Dorado et al examined three experimental techniques for the establishment of pancreatic PDX models, subcutaneous, orthotopic and intraperitoneal. Of the bank of 11 samples collected in that study, one had received neo-adjuvant therapy and formed a sub-cutaneous tumour, but did not form a tumour intraperitoneal nor at the orthotopic site [29].…”

Complete loss of ATM function augments replication catastrophe induced by ATR inhibition and gemcitabine in pancreatic cancer models

“…Subcutaneous xenografts of MIA PaCa-2 cells were formed by implanting 5 × 10 6 cells (in 0.2 mL 1:1 Matrigel: PBS) in the flank of 7–9-week-old female NSG mice (Charles River, 5 mice per cage). Despite some limitations (lack of intratumoural heterogeneity, absence of immune responses, reduced ability to recapitulate the tumour microenvironment), subcutaneous xenografts can offer some advantages over orthotopic models, as previously reported, 25 including ease of use, reproducibility and earlier tumour detection. Mice with established tumours (average 242 mm 3 ) were randomised into treatment groups using the “spiral” randomisation method (see Supplementary Material ).…”