Imperial College London
Alternate

DrFiekeFroeling

Faculty of Medicine, Department of Surgery & Cancer

Honorary Clinical Senior Lecturer
 
 
 
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f.froeling

 
 
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Location

 

Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Froeling:2011:10.1053/j.gastro.2011.06.047,
author = {Froeling, FEM and Feig, C and Chelala, C and Dobson, R and Mein, CE and Tuveson, DA and Clevers, H and Hart, IR and Kocher, HM},
doi = {10.1053/j.gastro.2011.06.047},
journal = {Gastroenterology},
pages = {1486--1497.14},
title = {Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-β-catenin signaling to slow tumor progression.},
url = {http://dx.doi.org/10.1053/j.gastro.2011.06.047},
volume = {141},
year = {2011}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - BACKGROUND & AIMS: Patients with pancreatic ductal adenocarcinoma are deficient in vitamin A, resulting in activation of pancreatic stellate cells (PSCs). We investigated whether restoration of retinol to PSCs restores their quiescence and affects adjacent cancer cells. METHODS: PSCs and cancer cell lines (AsPc1 and Capan1) were exposed to doses and isoforms of retinoic acid (RA) in 2-dimensional and 3-dimensional culture conditions (physiomimetic organotypic culture). The effects of all-trans retinoic acid (ATRA) were studied in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre mice, a model of human pancreatic ductal adenocarcinoma. RESULTS: After incubation with ATRA, PSCs were quiescent and had altered expression of genes that regulate proliferation, morphology, and motility; genes that encode cytoskeletal proteins and cytokines; and genes that control other functions, irrespective of culture conditions or dosage. In the organotypic model, and in mice, ATRA induced quiescence of PSCs and thereby reduced cancer cell proliferation and translocation of β-catenin to the nucleus, increased cancer cell apoptosis, and altered tumor morphology. ATRA reduced the motility of PSCs, so these cells created a "wall" at the junction between the tumor and the matrix that prevented cancer cell invasion. Restoring secreted frizzled-related protein 4 (sFRP4) secretion to quiescent PSCs reduced Wnt-β-catenin signaling in cancer cells and their invasive ability. Human primary and metastatic pancreatic tumor tissues stained strongly for cancer cell nuclear β-catenin but had low levels of sFRP4 (in cancer cells and PSCs). CONCLUSIONS: RA induces quiescence and reduces motility of PSCs, leading to reduced proliferation and increased apoptosis of surrounding pancreatic cancer cells. RA isoforms might be developed as therapeutic reagents for pancreatic cancer.
AU  - Froeling,FEM
AU  - Feig,C
AU  - Chelala,C
AU  - Dobson,R
AU  - Mein,CE
AU  - Tuveson,DA
AU  - Clevers,H
AU  - Hart,IR
AU  - Kocher,HM
DO  - 10.1053/j.gastro.2011.06.047
EP  - 1497
PY  - 2011///
SP  - 1486
TI  - Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-β-catenin signaling to slow tumor progression.
T2  - Gastroenterology
UR  - http://dx.doi.org/10.1053/j.gastro.2011.06.047
UR  - https://www.ncbi.nlm.nih.gov/pubmed/21704588
VL  - 141
ER  -
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