Abstract
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.
Highlights
Pancreatic cancer carries a dismal prognosis (Coupland et al, 2012)
Our studies identify a novel role by which nuclear FGFR1 and FGF2 may regulate pancreatic stellate cells (PSCs) behaviour in pancreatic ductal adenocarcinoma (PDAC)
Understanding the role of intracrine FGF2 in PDAC has been facilitated by the isolation, and creation, of PSC cell lines
Summary
Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) carries a dismal prognosis (Coupland et al, 2012). Improved understanding of the role of the stroma in pancreatic cancer is possible due to the isolation, and in vitro culture, of pancreatic stellate cells (PSCs), the main cells responsible for desmoplasia in PDAC (Apte et al, 1998; Erkan et al, 2012; Kadaba et al, 2013). A number of in vitro and in vivo studies have shown that cross-talk between PSCs and PDAC cells facilitates local tumour growth as well as regional and distant metastatic spread of PDAC (Apte et al, 1999, 2004; Bachem et al, 2005; Hwang et al, 2008; Vonlaufen et al, 2008; Xu et al, 2010). Multiple signalling cascades are altered by retinol treatment of stellate cells; one such being the fibroblast growth factor (FGF) signalling cascade, known already to play a critical role in pancreatic organogenesis (Kim & Hebrok, 2001)
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