Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion

Pancreatic cancer is characterised by desmoplasia, driven by activated pancreatic stellate cells (PSCs). Over-expression of FGFs and their receptors is a feature of pancreatic cancer and correlates with poor prognosis, but whether their expression impacts on PSCs is unclear. At the invasive front of...

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Main Authors:	Coleman, Stacey J, Chioni, Athina-Myrto, Ghallab, Mohammed, Anderson, Rhys K, Lemoine, Nicholas R, Kocher, Hemant M, Grose, Richard P
Format:	Online
Language:	English
Published:	Backwell Publishing Ltd 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992074/

id	pubmed-3992074
recordtype	oai_dc
spelling	pubmed-39920742014-04-22 Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion Coleman, Stacey J Chioni, Athina-Myrto Ghallab, Mohammed Anderson, Rhys K Lemoine, Nicholas R Kocher, Hemant M Grose, Richard P Research Articles Pancreatic cancer is characterised by desmoplasia, driven by activated pancreatic stellate cells (PSCs). Over-expression of FGFs and their receptors is a feature of pancreatic cancer and correlates with poor prognosis, but whether their expression impacts on PSCs is unclear. At the invasive front of human pancreatic cancer, FGF2 and FGFR1 localise to the nucleus in activated PSCs but not cancer cells. In vitro, inhibiting FGFR1 and FGF2 in PSCs, using RNAi or chemical inhibition, resulted in significantly reduced cell proliferation, which was not seen in cancer cells. In physiomimetic organotypic co-cultures, FGFR inhibition prevented PSC as well as cancer cell invasion. FGFR inhibition resulted in cytoplasmic localisation of FGFR1 and FGF2, in contrast to vehicle-treated conditions where PSCs with nuclear FGFR1 and FGF2 led cancer cells to invade the underlying extra-cellular matrix. Strikingly, abrogation of nuclear FGFR1 and FGF2 in PSCs abolished cancer cell invasion. These findings suggest a novel therapeutic approach, where preventing nuclear FGF/FGFR mediated proliferation and invasion in PSCs leads to disruption of the tumour microenvironment, preventing pancreatic cancer cell invasion. Backwell Publishing Ltd 2014-04 2014-02-06 /pmc/articles/PMC3992074/ /pubmed/24503018 http://dx.doi.org/10.1002/emmm.201302698 Text en © 2014 The Authors. http://creativecommons.org/licenses/by/3.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Coleman, Stacey J Chioni, Athina-Myrto Ghallab, Mohammed Anderson, Rhys K Lemoine, Nicholas R Kocher, Hemant M Grose, Richard P
spellingShingle	Coleman, Stacey J Chioni, Athina-Myrto Ghallab, Mohammed Anderson, Rhys K Lemoine, Nicholas R Kocher, Hemant M Grose, Richard P Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion
author_facet	Coleman, Stacey J Chioni, Athina-Myrto Ghallab, Mohammed Anderson, Rhys K Lemoine, Nicholas R Kocher, Hemant M Grose, Richard P
author_sort	Coleman, Stacey J
title	Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion
title_short	Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion
title_full	Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion
title_fullStr	Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion
title_full_unstemmed	Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion
title_sort	nuclear translocation of fgfr1 and fgf2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion
description	Pancreatic cancer is characterised by desmoplasia, driven by activated pancreatic stellate cells (PSCs). Over-expression of FGFs and their receptors is a feature of pancreatic cancer and correlates with poor prognosis, but whether their expression impacts on PSCs is unclear. At the invasive front of human pancreatic cancer, FGF2 and FGFR1 localise to the nucleus in activated PSCs but not cancer cells. In vitro, inhibiting FGFR1 and FGF2 in PSCs, using RNAi or chemical inhibition, resulted in significantly reduced cell proliferation, which was not seen in cancer cells. In physiomimetic organotypic co-cultures, FGFR inhibition prevented PSC as well as cancer cell invasion. FGFR inhibition resulted in cytoplasmic localisation of FGFR1 and FGF2, in contrast to vehicle-treated conditions where PSCs with nuclear FGFR1 and FGF2 led cancer cells to invade the underlying extra-cellular matrix. Strikingly, abrogation of nuclear FGFR1 and FGF2 in PSCs abolished cancer cell invasion. These findings suggest a novel therapeutic approach, where preventing nuclear FGF/FGFR mediated proliferation and invasion in PSCs leads to disruption of the tumour microenvironment, preventing pancreatic cancer cell invasion.
publisher	Backwell Publishing Ltd
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992074/
_version_	1612079989154381824

Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion

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