Expression of gemcitabine metabolizing enzymes and stromal components reveal complexities of preclinical pancreatic cancer models for therapeutic testing.

Autor:	Knoll L; Department of Nephrology and Hypertension, University Hospital Hannover, Carl-Neuberg-Straße 1, 30625 Hannover, Germany., Hamm J; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Centre Goettingen, Robert-Koch-Straße 40, 37075 Goettingen, Germany., Stroebel P; Institute of Pathology, University Medical Center Goettingen, Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany., Jovan T; Institute of Pathology, University Medical Center Goettingen, Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany., Goetze R; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Centre Goettingen, Robert-Koch-Straße 40, 37075 Goettingen, Germany., Singh S; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Centre Goettingen, Robert-Koch-Straße 40, 37075 Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany., Hessmann E; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Centre Goettingen, Robert-Koch-Straße 40, 37075 Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany., Ellenrieder V; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Centre Goettingen, Robert-Koch-Straße 40, 37075 Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany., Ammer-Herrmenau C; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Centre Goettingen, Robert-Koch-Straße 40, 37075 Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany., Neesse A; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Centre Goettingen, Robert-Koch-Straße 40, 37075 Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany. Electronic address: albrecht.neesse@med.uni-goettingen.de.
Jazyk:	angličtina
Zdroj:	Neoplasia (New York, N.Y.) [Neoplasia] 2024 Jul; Vol. 53, pp. 101002. Date of Electronic Publication: 2024 May 13.
DOI:	10.1016/j.neo.2024.101002
Abstrakt:	Background: Pancreatic ductal adenocarcinoma (PDAC) poorly responds to antineoplastic agents. Discrepancies between preclinical success and clinical failure of compounds has been a continuous challenge and major obstacle in PDAC research. Aim: To investigate the association of the tumor microenvironment (TME) composition and gemcitabine metabolizing enzyme (GME) expression in vitro and several in vivo models. Methods: mRNA expression and protein levels of GME (cytosolic 5'-nucleotidase 1 A; NT5C1A, cytidine deaminase; CDA, deoxycytidine kinase; DCK), gemcitabine transporters (ENT1, ENT2, RRM1, RRM2) and stromal components (hyaluroninc acid, podoplanin, masson trichrome, picrosirius) were assessed by qRT-PCR and immunohistochemistry in murine LSL-Kras G12D/+ ;LSL-Trp53 R172 H/+ ; Pdx-1-Cre (KPC), orthotopically transplanted mice (OTM), human primary resected PDAC tissue (hPRT), corresponding patient-derived xenograft (PDX) mice, and KPC-SPARC -/- mice. mRNA expression of GME was analyzed in PDAC cell lines (Panc-1, MIA PaCa, BXPC3 and L3.6) upon incubation on collagen or pancreatic stellate cell (PSC) conditioned media by qRT-PCR. Results: Endogenous KPC tumors exhibited significantly higher levels of GME compared to OTM. However, GME levels did not differ between hPRT and corresponding PDX mice. Using Kendalls Tau correlation coefficient we did not show a significant correlation of GME and components of the TME except for NT5C1A and hyaluronic acid in PDX mice (p=0.029). GME were not significantly altered upon SPARC depletion in vivo, and upon treatment with PSC-conditioned media or incubation on collagen plated dishes in vitro. Conclusions: Our findings suggest that the expression of GME is independent from the deposition of stromal components. KPC mice are most appropriate to study stromal composition whereas PDX mice maintain GME expression of the corresponding hPRT and could be best suited for pharmacokinetic studies. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024. Published by Elsevier Inc.)
Databáze:	MEDLINE
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