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Vitamin D(3) suppresses morphological evolution of the cribriform cancerous phenotype
Development of cribriform morphology (CM) heralds malignant change in human colon but lack of mechanistic understanding hampers preventive therapy. This study investigated CM pathobiology in three-dimensional (3D) Caco-2 culture models of colorectal glandular architecture, assessed translational rel...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226489/ https://www.ncbi.nlm.nih.gov/pubmed/27119498 http://dx.doi.org/10.18632/oncotarget.8863 |
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author | Deevi, Ravi K. McClements, Jane McCloskey, Karen D. Fatehullah, Aliya Tkocz, Dorota Javadi, Arman Higginson, Robyn Durban, Victoria Marsh Jansen, Marnix Clarke, Alan Loughrey, Maurice B. Campbell, Frederick C. |
author_facet | Deevi, Ravi K. McClements, Jane McCloskey, Karen D. Fatehullah, Aliya Tkocz, Dorota Javadi, Arman Higginson, Robyn Durban, Victoria Marsh Jansen, Marnix Clarke, Alan Loughrey, Maurice B. Campbell, Frederick C. |
author_sort | Deevi, Ravi K. |
collection | PubMed |
description | Development of cribriform morphology (CM) heralds malignant change in human colon but lack of mechanistic understanding hampers preventive therapy. This study investigated CM pathobiology in three-dimensional (3D) Caco-2 culture models of colorectal glandular architecture, assessed translational relevance and tested effects of 1,25(OH)(2)D(3), the active form of vitamin D. CM evolution was driven by oncogenic perturbation of the apical polarity (AP) complex comprising PTEN, CDC42 and PRKCZ (phosphatase and tensin homolog, cell division cycle 42 and protein kinase C zeta). Suppression of AP genes initiated a spatiotemporal cascade of mitotic spindle misorientation, apical membrane misalignment and aberrant epithelial configuration. Collectively, these events promoted “Swiss cheese-like” cribriform morphology (CM) comprising multiple abnormal “back to back” lumens surrounded by atypical stratified epithelium, in 3D colorectal gland models. Intestinal cancer driven purely by PTEN-deficiency in transgenic mice developed CM and in human CRC, CM associated with PTEN and PRKCZ readouts. Treatment of PTEN-deficient 3D cultures with 1,25(OH)(2)D(3) upregulated PTEN, rapidly activated CDC42 and PRKCZ, corrected mitotic spindle alignment and suppressed CM development. Conversely, mutationally-activated KRAS blocked 1,25(OH)(2)D(3) rescue of glandular architecture. We conclude that 1,25(OH)(2)D(3) upregulates AP signalling to reverse CM in a KRAS wild type (wt), clinically predictive CRC model system. Vitamin D could be developed as therapy to suppress inception or progression of a subset of colorectal tumors. |
format | Online Article Text |
id | pubmed-5226489 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-52264892017-01-18 Vitamin D(3) suppresses morphological evolution of the cribriform cancerous phenotype Deevi, Ravi K. McClements, Jane McCloskey, Karen D. Fatehullah, Aliya Tkocz, Dorota Javadi, Arman Higginson, Robyn Durban, Victoria Marsh Jansen, Marnix Clarke, Alan Loughrey, Maurice B. Campbell, Frederick C. Oncotarget Research Paper Development of cribriform morphology (CM) heralds malignant change in human colon but lack of mechanistic understanding hampers preventive therapy. This study investigated CM pathobiology in three-dimensional (3D) Caco-2 culture models of colorectal glandular architecture, assessed translational relevance and tested effects of 1,25(OH)(2)D(3), the active form of vitamin D. CM evolution was driven by oncogenic perturbation of the apical polarity (AP) complex comprising PTEN, CDC42 and PRKCZ (phosphatase and tensin homolog, cell division cycle 42 and protein kinase C zeta). Suppression of AP genes initiated a spatiotemporal cascade of mitotic spindle misorientation, apical membrane misalignment and aberrant epithelial configuration. Collectively, these events promoted “Swiss cheese-like” cribriform morphology (CM) comprising multiple abnormal “back to back” lumens surrounded by atypical stratified epithelium, in 3D colorectal gland models. Intestinal cancer driven purely by PTEN-deficiency in transgenic mice developed CM and in human CRC, CM associated with PTEN and PRKCZ readouts. Treatment of PTEN-deficient 3D cultures with 1,25(OH)(2)D(3) upregulated PTEN, rapidly activated CDC42 and PRKCZ, corrected mitotic spindle alignment and suppressed CM development. Conversely, mutationally-activated KRAS blocked 1,25(OH)(2)D(3) rescue of glandular architecture. We conclude that 1,25(OH)(2)D(3) upregulates AP signalling to reverse CM in a KRAS wild type (wt), clinically predictive CRC model system. Vitamin D could be developed as therapy to suppress inception or progression of a subset of colorectal tumors. Impact Journals LLC 2016-04-20 /pmc/articles/PMC5226489/ /pubmed/27119498 http://dx.doi.org/10.18632/oncotarget.8863 Text en Copyright: © 2016 Deevi et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Deevi, Ravi K. McClements, Jane McCloskey, Karen D. Fatehullah, Aliya Tkocz, Dorota Javadi, Arman Higginson, Robyn Durban, Victoria Marsh Jansen, Marnix Clarke, Alan Loughrey, Maurice B. Campbell, Frederick C. Vitamin D(3) suppresses morphological evolution of the cribriform cancerous phenotype |
title | Vitamin D(3) suppresses morphological evolution of the cribriform cancerous phenotype |
title_full | Vitamin D(3) suppresses morphological evolution of the cribriform cancerous phenotype |
title_fullStr | Vitamin D(3) suppresses morphological evolution of the cribriform cancerous phenotype |
title_full_unstemmed | Vitamin D(3) suppresses morphological evolution of the cribriform cancerous phenotype |
title_short | Vitamin D(3) suppresses morphological evolution of the cribriform cancerous phenotype |
title_sort | vitamin d(3) suppresses morphological evolution of the cribriform cancerous phenotype |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226489/ https://www.ncbi.nlm.nih.gov/pubmed/27119498 http://dx.doi.org/10.18632/oncotarget.8863 |
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