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Combined changes in Wnt signaling response and contact inhibition induce altered proliferation in radiation-treated intestinal crypts

Curative intervention is possible if colorectal cancer is identified early, underscoring the need to detect the earliest stages of malignant transformation. A candidate biomarker is the expanded proliferative zone observed in crypts before adenoma formation, also found in irradiated crypts. However,...

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Autores principales: Dunn, S.-J., Osborne, J. M., Appleton, P. L., Näthke, I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884076/
https://www.ncbi.nlm.nih.gov/pubmed/27053661
http://dx.doi.org/10.1091/mbc.E15-12-0854
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author Dunn, S.-J.
Osborne, J. M.
Appleton, P. L.
Näthke, I.
author_facet Dunn, S.-J.
Osborne, J. M.
Appleton, P. L.
Näthke, I.
author_sort Dunn, S.-J.
collection PubMed
description Curative intervention is possible if colorectal cancer is identified early, underscoring the need to detect the earliest stages of malignant transformation. A candidate biomarker is the expanded proliferative zone observed in crypts before adenoma formation, also found in irradiated crypts. However, the underlying driving mechanism for this is not known. Wnt signaling is a key regulator of proliferation, and elevated Wnt signaling is implicated in cancer. Nonetheless, how cells differentiate Wnt signals of varying strengths is not understood. We use computational modeling to compare alternative hypotheses about how Wnt signaling and contact inhibition affect proliferation. Direct comparison of simulations with published experimental data revealed that the model that best reproduces proliferation patterns in normal crypts stipulates that proliferative fate and cell cycle duration are set by the Wnt stimulus experienced at birth. The model also showed that the broadened proliferation zone induced by tumorigenic radiation can be attributed to cells responding to lower Wnt concentrations and dividing at smaller volumes. Application of the model to data from irradiated crypts after an extended recovery period permitted deductions about the extent of the initial insult. Application of computational modeling to experimental data revealed how mechanisms that control cell dynamics are altered at the earliest stages of carcinogenesis.
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spelling pubmed-48840762016-08-16 Combined changes in Wnt signaling response and contact inhibition induce altered proliferation in radiation-treated intestinal crypts Dunn, S.-J. Osborne, J. M. Appleton, P. L. Näthke, I. Mol Biol Cell Articles Curative intervention is possible if colorectal cancer is identified early, underscoring the need to detect the earliest stages of malignant transformation. A candidate biomarker is the expanded proliferative zone observed in crypts before adenoma formation, also found in irradiated crypts. However, the underlying driving mechanism for this is not known. Wnt signaling is a key regulator of proliferation, and elevated Wnt signaling is implicated in cancer. Nonetheless, how cells differentiate Wnt signals of varying strengths is not understood. We use computational modeling to compare alternative hypotheses about how Wnt signaling and contact inhibition affect proliferation. Direct comparison of simulations with published experimental data revealed that the model that best reproduces proliferation patterns in normal crypts stipulates that proliferative fate and cell cycle duration are set by the Wnt stimulus experienced at birth. The model also showed that the broadened proliferation zone induced by tumorigenic radiation can be attributed to cells responding to lower Wnt concentrations and dividing at smaller volumes. Application of the model to data from irradiated crypts after an extended recovery period permitted deductions about the extent of the initial insult. Application of computational modeling to experimental data revealed how mechanisms that control cell dynamics are altered at the earliest stages of carcinogenesis. The American Society for Cell Biology 2016-06-01 /pmc/articles/PMC4884076/ /pubmed/27053661 http://dx.doi.org/10.1091/mbc.E15-12-0854 Text en © 2016 Dunn, Osborne, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Dunn, S.-J.
Osborne, J. M.
Appleton, P. L.
Näthke, I.
Combined changes in Wnt signaling response and contact inhibition induce altered proliferation in radiation-treated intestinal crypts
title Combined changes in Wnt signaling response and contact inhibition induce altered proliferation in radiation-treated intestinal crypts
title_full Combined changes in Wnt signaling response and contact inhibition induce altered proliferation in radiation-treated intestinal crypts
title_fullStr Combined changes in Wnt signaling response and contact inhibition induce altered proliferation in radiation-treated intestinal crypts
title_full_unstemmed Combined changes in Wnt signaling response and contact inhibition induce altered proliferation in radiation-treated intestinal crypts
title_short Combined changes in Wnt signaling response and contact inhibition induce altered proliferation in radiation-treated intestinal crypts
title_sort combined changes in wnt signaling response and contact inhibition induce altered proliferation in radiation-treated intestinal crypts
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884076/
https://www.ncbi.nlm.nih.gov/pubmed/27053661
http://dx.doi.org/10.1091/mbc.E15-12-0854
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