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Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer

The Kras(G12D/+);LSL-Trp53(R172H/+);Pdx-1-Cre (KPC) mouse model is frequently employed for preclinical therapeutic testing, in particular in regard to antistromal therapies. Here, we investigate the prognostic implications of histopathological features that may guide preclinical trial design. Pancre...

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Autores principales: Hasselluhn, Marie C., Klein, Lukas, Patzak, Melanie S., Buchholz, Sören M., Ströbel, Philipp, Ellenrieder, Volker, Maisonneuve, Patrick, Neesse, Albrecht
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017324/
https://www.ncbi.nlm.nih.gov/pubmed/31878349
http://dx.doi.org/10.3390/cells9010058
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author Hasselluhn, Marie C.
Klein, Lukas
Patzak, Melanie S.
Buchholz, Sören M.
Ströbel, Philipp
Ellenrieder, Volker
Maisonneuve, Patrick
Neesse, Albrecht
author_facet Hasselluhn, Marie C.
Klein, Lukas
Patzak, Melanie S.
Buchholz, Sören M.
Ströbel, Philipp
Ellenrieder, Volker
Maisonneuve, Patrick
Neesse, Albrecht
author_sort Hasselluhn, Marie C.
collection PubMed
description The Kras(G12D/+);LSL-Trp53(R172H/+);Pdx-1-Cre (KPC) mouse model is frequently employed for preclinical therapeutic testing, in particular in regard to antistromal therapies. Here, we investigate the prognostic implications of histopathological features that may guide preclinical trial design. Pancreatic tumor tissue from n = 46 KPC mice was quantitatively analyzed using immunohistochemistry and co-immunofluorescence for proliferation (Ki67), mitotic rate (phospho-Histone 3, PHH3), apoptosis (cleaved caspase-3, CC3), collagen content, secreted protein acidic and rich in cysteine (SPARC), hyaluronic acid (HA), and α-smooth muscle actin (α-SMA). Furthermore, mean vessel density (MVD), mean lumen area (MLA), grading, activated stroma index (ASI), and fibroblast-proliferation rate (α-SMA/Ki67) were assessed. Univariate analysis using the Kaplan–Meier estimator and Cox regression model for continuous variables did not show association between survival and any of the analyzed parameters. Spearman correlation demonstrated that desmoplasia was inversely correlated with differentiated tumor grade (ρ = −0.84). Ki67 and PHH3 synergized as proliferation markers (ρ = 0.54), while SPARC expression was positively correlated with HA content (ρ = 0.37). MVD and MLA were correlated with each other (ρ = 0.31), while MLA positively correlated with CC3 (ρ = 0.45). Additionally, increased MVD was correlated with increased fibroblast proliferation rate (α-SMA + Ki67; ρ = 0.36). Our pilot study provides evidence that individual histopathological parameters of the primary tumor of KPC mice are not associated with survival, and may hint at the importance of systemic tumor-related effects such as cachexia.
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spelling pubmed-70173242020-02-28 Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer Hasselluhn, Marie C. Klein, Lukas Patzak, Melanie S. Buchholz, Sören M. Ströbel, Philipp Ellenrieder, Volker Maisonneuve, Patrick Neesse, Albrecht Cells Article The Kras(G12D/+);LSL-Trp53(R172H/+);Pdx-1-Cre (KPC) mouse model is frequently employed for preclinical therapeutic testing, in particular in regard to antistromal therapies. Here, we investigate the prognostic implications of histopathological features that may guide preclinical trial design. Pancreatic tumor tissue from n = 46 KPC mice was quantitatively analyzed using immunohistochemistry and co-immunofluorescence for proliferation (Ki67), mitotic rate (phospho-Histone 3, PHH3), apoptosis (cleaved caspase-3, CC3), collagen content, secreted protein acidic and rich in cysteine (SPARC), hyaluronic acid (HA), and α-smooth muscle actin (α-SMA). Furthermore, mean vessel density (MVD), mean lumen area (MLA), grading, activated stroma index (ASI), and fibroblast-proliferation rate (α-SMA/Ki67) were assessed. Univariate analysis using the Kaplan–Meier estimator and Cox regression model for continuous variables did not show association between survival and any of the analyzed parameters. Spearman correlation demonstrated that desmoplasia was inversely correlated with differentiated tumor grade (ρ = −0.84). Ki67 and PHH3 synergized as proliferation markers (ρ = 0.54), while SPARC expression was positively correlated with HA content (ρ = 0.37). MVD and MLA were correlated with each other (ρ = 0.31), while MLA positively correlated with CC3 (ρ = 0.45). Additionally, increased MVD was correlated with increased fibroblast proliferation rate (α-SMA + Ki67; ρ = 0.36). Our pilot study provides evidence that individual histopathological parameters of the primary tumor of KPC mice are not associated with survival, and may hint at the importance of systemic tumor-related effects such as cachexia. MDPI 2019-12-24 /pmc/articles/PMC7017324/ /pubmed/31878349 http://dx.doi.org/10.3390/cells9010058 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hasselluhn, Marie C.
Klein, Lukas
Patzak, Melanie S.
Buchholz, Sören M.
Ströbel, Philipp
Ellenrieder, Volker
Maisonneuve, Patrick
Neesse, Albrecht
Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer
title Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer
title_full Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer
title_fullStr Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer
title_full_unstemmed Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer
title_short Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer
title_sort stromal features of the primary tumor are not prognostic in genetically engineered mice of pancreatic cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017324/
https://www.ncbi.nlm.nih.gov/pubmed/31878349
http://dx.doi.org/10.3390/cells9010058
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