Abstract
Patient-derived xenograft models reportedly represent original tumor morphology and gene mutation profiles. In addition, patient-derived xenografts are expected to recapitulate the parental tumor drug responses. In this study, we analyzed the pathways involved in gemcitabine resistance using patient-derived xenograft models of pancreatic cancer. The patient-derived xenograft models were established using samples from patients with pancreatic cancer. The models were treated with gemcitabine to better understand the mechanism of resistance to this anti-cancer drug. We performed comparative gene analysis through the next-generation sequencing of tumor tissues from gemcitabine-treated or non-treated patient-derived xenograft mice and gene set enrichment analysis to analyze mRNA profiling data. Pathway analysis of gemcitabine-treated patient-derived xenografts disclosed the upregulation of multiple gene sets and identified several specific gene pathways that could potentially be related to gemcitabine resistance in pancreatic cancer. Further, we conducted an in vitro analysis to validate these results. The mRNA expression of cytochrome P450 1B1 and cytochrome P450 2A6 was upregulated in a concentration-dependent manner following gemcitabine treatment. Moreover, the sensitivity to gemcitabine increased, and viable cells were decreased by the cytochrome P450 1B1 inhibitor, indicating that the cytochrome P450 1B1 pathway may be related to gemcitabine resistance in pancreatic cancer.
Highlights
We referred to the mice engrafted with a patient-derived tissue as a “G1 mouse” and mice engrafted with G1 mouse-derived tumor pieces as a “G2 mouse” Our results showed that morphology had even been preserved in G6 mice
Seven Patient-derived xenograft (PDX) mouse lines were treated with GEM after tumor engraftment to identify chemoresistant genes according to a previously described protocol [16]
GEM resistance in pancreatic cancer, activity, genes within the red lines were upregulated in the is shown we examined the proliferation of pancreatic cancer cell lines #1–#7 in vitro
Summary
A myriad of cancer cell lines has already been used in biomedical research. These cell lines are cultured under artificial conditions and do not necessarily reflect physiological cancer cell kinetics. Xenografts such as cell line-derived xenografts (CDX). Cancer cell line xenografts (CCLX), which can be transplanted into immunodeficient mice, are widely used in cancer research [1]. CDX provides the advantage of studying disease progression in the physiological environment of mice. This system has the disadvantage that the cell lines used to establish CDX have already adapted to in vitro
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