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Uncoupling protein 2 deficiency of non-cancerous tissues inhibits the progression of pancreatic cancer in mice |
Denis Revskij a , Jakob Runst a , Camilla Umstatter a , Luise Ehlers a , Sarah Rohde a , Dietmar Zechner b , Manuela Bastian c , Brigitte Muller-Hilke d , Georg Fuellen e , Larissa Henze f , Hugo Murua Escobar f , Christian Junghanss f , Axel Kowald e , Uwe Walter g , Rudiger Kohling h , Olaf Wolkenhauer i , Robert Jaster a , ∗ |
a Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany
b Rudolf-Zenker-Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany
c Institute of Clinical Chemistry and Laboratory Medicine, Rostock University Medical Center, Rostock, Germany
d Facility for Cell Sorting and Cell Analysis and Institute of Immunology, Rostock University Medical Center, Rostock, Germany
e Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany
f Department of Medicine, Clinic III, Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock, Germany
g Department of Neurology, Rostock University Medical Center, Rostock, Germany
h Oscar LangendorffInstitute of Physiology, Rostock University Medical Center, Rostock, Germany
i Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany
∗Corresponding author.
E-mail address: robert.jaster@med.uni-rostock.de (R. Jaster). |
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Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a disease of the elderly mostly because its development from preneoplastic lesions depends on the accumulation of gene mutations and epigenetic alterations over time. How aging of non-cancerous tissues of the host affects tumor progression, however, remains largely unknown.
Methods: We took advantage of a model of accelerated aging, uncoupling protein 2-deficient ( Ucp2 knockout, Ucp2 KO) mice, to investigate the growth of orthotopically transplanted Ucp2 wild-type (WT) PDAC cells (cell lines Panc02 and 6606PDA) in vivo and to study strain-dependent differences of the PDAC microenvironment.
Results: Measurements of tumor weights and quantification of proliferating cells indicated a significant growth advantage of Panc02 and 6606PDA cells in WT mice compared to Ucp2 KO mice. In tumors in the knockout strain, higher levels of interferon-γ mRNA despite similar numbers of tumor-infiltrating T cells were observed. 6606PDA cells triggered a stronger stromal reaction in Ucp2 KO mice than in WT animals. Accordingly, pancreatic stellate cells from Ucp2 KO mice proliferated at a higher rate than cells of the WT strain when they were incubated with conditioned media from PDAC cells.
Conclusions: Ucp2 modulates PDAC microenvironment in a way that favors tumor progression and implicates an altered stromal response as one of the underlying mechanisms.
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