Pancreatic cancer is characterised by a prominent desmoplastic/stromal reaction that has received little attention until recent times. Given that treatments focusing on pancreatic cancer cells alone have failed to significantly improve patient outcome over many decades, research efforts have now moved to understanding the pathophysiology of the stromal reaction and its role in cancer progression. In this regard, our Group was the first to identify the cells (pancreatic stellate cells, PSCs) that produced the collagenous stroma of pancreatic cancer and to demonstrate that these cells interacted closely with cancer cells to facilitate local tumour growth and distant metastasis. Evidence is accumulating to indicate that stromal PSCs may also mediate angiogenesis, immune evasion and the well known resistance of pancreatic cancer to chemotherapy and radiotherapy. This review will summarise current knowledge regarding the critical role of pancreatic stellate cells and the stroma in pancreatic cancer biology and the therapeutic approaches being developed to target the stroma in a bid to improve the outcome of this devastating disease.

Pancreatic stellate cells (PSCs, which produce the stroma of pancreatic cancer (PC)) interact with cancer cells to facilitate PC growth. A candidate growth factor pathway that may mediate this interaction is the HGF–c-MET pathway. Effects of HGF inhibition (using a neutralising antibody AMG102) alone or in combination with gemcitabine were assessed (i) in vivo using an orthotopic model of PC, and (ii) in vitro using cultured PC cells (AsPC-1) and human PSCs. We have shown that human PSCs (hPSCs) secrete HGF but do not express the receptor c-MET, which is present predominantly on cancer cells. HGF inhibition was as effective as standard chemotherapy in inhibiting local tumour growth but was significantly more effective than gemcitabine in reducing tumour angiogenesis and metastasis. HGF inhibition has resulted in reduced metastasis; however, interestingly this antimetastatic effect was lost when combined with gemcitabine. This suggests that gemcitabine treatment selects out a subpopulation of cancer cells with increased epithelial–mesenchymal transition (EMT) and stem-cell characteristics, as supported by our findings of increased expression of EMT and stem-cell markers in tumour sections from our animal model. In vitro studies showed that hPSC secretions induced proliferation and migration, but inhibited apoptosis, of cancer cells. These effects were countered by pretreatment of hPSC secretions with a HGF-neutralising antibody but not by gemcitabine, indicating a key role for HGF in PSC–PC interactions. Our studies suggest that targeted therapy to inhibit stromal–tumour interactions mediated by the HGF–c-MET pathway may represent a novel therapeutic approach in PC that will require careful modelling for optimal integration with existing treatment modalities.

Activated cancer-associated human pancreatic stellate cells (CAhPSCs, which produce the collagenous stroma of pancreatic cancer [PC]) are known to play a major role in PC progression. Apart from inducing cancer cell proliferation and migration, CAhPSCs have also been implicated in neoangiogenesis in PC. However, the mechanisms mediating the observed angiogenic effects of CAhPSCs are unknown. A candidate pathway that may be involved in this process is the hepatocyte growth factor (HGF)/c-MET pathway and its helper molecule, urokinase-type plasminogen activator (uPA). This study investigated the effects of CAhPSC secretions on endothelial cell function in the presence and absence of HGF, c-MET and uPA inhibitors. HGF levels in CAhPSC secretions were quantified using ELISA. CAhPSC secretions were then incubated with human microvascular endothelial cells (HMEC-1) and angiogenesis assessed by quantifying HMEC-1 tube formation and proliferation. CAhPSC-secreted HGF significantly increased HMEC-1 tube formation and proliferation; notably, these effects were downregulated by inhibition of HGF, its receptor c-MET and uPA. Phosphorylation of p38 mitogen-activated protein kinase was downregulated during inhibition of the HGF/c-MET pathway, whereas phosphatidylinositol-3 kinase and ERK1/2 remained unaffected. Our studies have shown for the first time that CAhPSCs induce proliferation and tube formation of HMEC-1 and that the HGF/c-MET pathway plays a major role in this induction. Given that standard antiangiogenic treatment targeting vascular endothelial growth factor has had limited success in the clinical setting, the findings of the current study provide strong support for a novel, alternative antiangiogenic approach targeting the HGF/c-MET and uPA pathways in PC.

Pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC/PC)) has been an aggressive disease that is associated with early metastases. It is characterized by dense and collagenous desmoplasia/stroma, predominantly produced by pancreatic stellate cells (PSCs). PSCs interact with cancer cells as well as other stromal cells, facilitating disease progression. A candidate growth factor pathway that may mediate this interaction is the hepatocyte growth factor (HGF)/c-MET pathway. HGF is produced by PSCs and its receptor c-MET is expressed on pancreatic cancer cells and endothelial cells. The current review discusses the role of the MET/HGF axis in tumour progression and dissemination of pancreatic cancer. Therapeutic approaches that were developed targeting either the ligand (HGF) or the receptor (c-MET) have not been shown to translate well into clinical settings. We discuss a two-pronged approach of targeting both the components of this pathway to interrupt the stromal–tumour interactions, which may represent a potential therapeutic strategy to improve outcomes in PC.