Vitamin D3 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 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.
Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, UK.
Ravi K
RK
Deevi
Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, UK.
Jane
J
McClements
Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, UK.
Karen D
KD
McCloskey
Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, UK.
Aliya
A
Fatehullah
Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, UK.
Dorota
D
Tkocz
Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, UK.
Arman
A
Javadi
Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, UK.
Robyn
R
Higginson
European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK.
Victoria
V
Marsh Durban
Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, UK.
Marnix
M
Jansen
European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK.
Alan
A
Clarke
Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queens University Belfast and Belfast Health and Social Care Trust, Belfast, UK.
Maurice B
MB
Loughrey
Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, UK.
Frederick C
FC
Campbell
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology*; D000818:Animals; D018938:Caco-2 Cells; D018929:Cell Culture Techniques; D002471:Cell Transformation, Neoplastic; D002762:Cholecalciferol / Q000494:pharmacology*; D015331:Cohort Studies; D003106:Colon / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011493:Protein Kinase C / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D000099221:Protein Kinase C zeta
D002762:Cholecalciferol; D051059:PTEN Phosphohydrolase; D011493:Protein Kinase C; D018167:Receptors, Calcitriol; D020764:cdc42 GTP-Binding Protein; D000099221:Protein Kinase C zeta; C579457:VDR protein, human; C494929:PTEN protein, human; C487757:Pten protein, mouse
colorectal cancer; molecular oncology; morphology; prognosis; vitamin D receptor gene