Oncotarget

Research Papers:

Vitamin D3 suppresses morphological evolution of the cribriform cancerous phenotype

Ravi K. Deevi, Jane McClements, Karen D. McCloskey, Aliya Fatehullah, Dorota Tkocz, Arman Javadi, Robyn Higginson, Victoria Marsh Durban, Marnix Jansen, Alan Clarke, Maurice B. Loughrey and Frederick C. Campbell _

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Oncotarget. 2016; 7:49042-49064. https://doi.org/10.18632/oncotarget.8863

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Abstract

Ravi K. Deevi1, Jane McClements1 , Karen D. McCloskey1, Aliya Fatehullah1, Dorota Tkocz1, Arman Javadi1, Robyn Higginson1, Victoria Marsh Durban3 Marnix Jansen4, Alan Clarke3,*, Maurice B. Loughrey2 and Frederick C. Campbell1

1 Centre for Cancer Research and Cell Biology, Queen’s University of Belfast, Belfast, UK

2 Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queens University Belfast and Belfast Health and Social Care Trust, Belfast, UK

3 European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK

4 Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, UK

* Deceased

Correspondence to:

Frederick C. Campbell, email:

Keywords: colorectal cancer, molecular oncology, vitamin D receptor gene, morphology, prognosis

Received: February 25, 2016 Accepted: February 28, 2016 Published: April 20, 2016

Abstract

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)2D3,theactive 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)2D3 upregulated PTEN, rapidly activated CDC42 and PRKCZ, corrected mitotic spindle alignment and suppressed CM development. Conversely, mutationally-activated KRAS blocked1,25(OH)2D3 rescue of glandular architecture. We conclude that 1,25(OH)2D3 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.


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