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The proline TP53 variant stimulates likely lymphangiogenesis in an orthotopic mouse model of pancreatic cancer

BACKGROUND: Pancreatic cancer is a deadly disease characterised by high incidence of TP53 mutations. Restoration of TP53 function is perceived as a highly attractive therapeutic strategy, whose effects are not well characterised. METHODS: The current work adapted an inducible strategy of stage-speci...

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Autores principales: Otto, N, Schulz, P, Scholz, A, Hauff, P, Schlegelberger, B, Detjen, K M, Wiedenmann, B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261666/
https://www.ncbi.nlm.nih.gov/pubmed/22146521
http://dx.doi.org/10.1038/bjc.2011.521
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author Otto, N
Schulz, P
Scholz, A
Hauff, P
Schlegelberger, B
Detjen, K M
Wiedenmann, B
author_facet Otto, N
Schulz, P
Scholz, A
Hauff, P
Schlegelberger, B
Detjen, K M
Wiedenmann, B
author_sort Otto, N
collection PubMed
description BACKGROUND: Pancreatic cancer is a deadly disease characterised by high incidence of TP53 mutations. Restoration of TP53 function is perceived as a highly attractive therapeutic strategy, whose effects are not well characterised. METHODS: The current work adapted an inducible strategy of stage-specific reexpression of wild-type (wt) TP53 in an in vivo orthotopic mouse model of pancreatic cancer. RESULTS: The reconstitution of wt TP53 function in TP53-mutant DanG and MiaPaCa-2 cells caused G1 cell cycle arrest but no evidence of apoptosis induction. Consistent with subcutaneous xenograft models, we found that wt TP53 reduced primary tumour growth. Wt TP53 reexpression during early tumour growth led to significant increase in vascularisation. This correlated with an unexpectedly high rate of micro-metastases in lymph nodes of animals with wt TP53 induction, despite the 90% decrease in median primary tumour weight. Reexpression of wt TP53 later in tumour development did not significantly affect the number of CD31-reactive vessels, but increased lymphatic vessel density. CONCLUSION: The increased number of lymphatic vessels and micro-metastases suggests that wt TP53 induction complexly affected the biology of different tumour constituents of pancreatic cancer. Our observation suggests that combination of the inducible system with an orthotopic model can yield important insights into in vivo pancreatic cancer biology.
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spelling pubmed-32616662013-01-17 The proline TP53 variant stimulates likely lymphangiogenesis in an orthotopic mouse model of pancreatic cancer Otto, N Schulz, P Scholz, A Hauff, P Schlegelberger, B Detjen, K M Wiedenmann, B Br J Cancer Molecular Diagnostics BACKGROUND: Pancreatic cancer is a deadly disease characterised by high incidence of TP53 mutations. Restoration of TP53 function is perceived as a highly attractive therapeutic strategy, whose effects are not well characterised. METHODS: The current work adapted an inducible strategy of stage-specific reexpression of wild-type (wt) TP53 in an in vivo orthotopic mouse model of pancreatic cancer. RESULTS: The reconstitution of wt TP53 function in TP53-mutant DanG and MiaPaCa-2 cells caused G1 cell cycle arrest but no evidence of apoptosis induction. Consistent with subcutaneous xenograft models, we found that wt TP53 reduced primary tumour growth. Wt TP53 reexpression during early tumour growth led to significant increase in vascularisation. This correlated with an unexpectedly high rate of micro-metastases in lymph nodes of animals with wt TP53 induction, despite the 90% decrease in median primary tumour weight. Reexpression of wt TP53 later in tumour development did not significantly affect the number of CD31-reactive vessels, but increased lymphatic vessel density. CONCLUSION: The increased number of lymphatic vessels and micro-metastases suggests that wt TP53 induction complexly affected the biology of different tumour constituents of pancreatic cancer. Our observation suggests that combination of the inducible system with an orthotopic model can yield important insights into in vivo pancreatic cancer biology. Nature Publishing Group 2012-01-17 2011-12-06 /pmc/articles/PMC3261666/ /pubmed/22146521 http://dx.doi.org/10.1038/bjc.2011.521 Text en Copyright © 2012 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Molecular Diagnostics
Otto, N
Schulz, P
Scholz, A
Hauff, P
Schlegelberger, B
Detjen, K M
Wiedenmann, B
The proline TP53 variant stimulates likely lymphangiogenesis in an orthotopic mouse model of pancreatic cancer
title The proline TP53 variant stimulates likely lymphangiogenesis in an orthotopic mouse model of pancreatic cancer
title_full The proline TP53 variant stimulates likely lymphangiogenesis in an orthotopic mouse model of pancreatic cancer
title_fullStr The proline TP53 variant stimulates likely lymphangiogenesis in an orthotopic mouse model of pancreatic cancer
title_full_unstemmed The proline TP53 variant stimulates likely lymphangiogenesis in an orthotopic mouse model of pancreatic cancer
title_short The proline TP53 variant stimulates likely lymphangiogenesis in an orthotopic mouse model of pancreatic cancer
title_sort proline tp53 variant stimulates likely lymphangiogenesis in an orthotopic mouse model of pancreatic cancer
topic Molecular Diagnostics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261666/
https://www.ncbi.nlm.nih.gov/pubmed/22146521
http://dx.doi.org/10.1038/bjc.2011.521
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