Pancreatic stellate cells (PSCs, which produce the desmoplastic reaction of pancreatic cancer) interact with pancreatic cancer (PC) cells to potentiate PC progression. A candidate factor that may mediate this interaction is the hepatocyte growth factor (HGF). High serum HGF levels correlate with poor clinical outcome, yet little is known about the role of HGF in PC.
Aims: To i) determine whether human PSCs (hPSCs) and PC cell lines express HGF; ii) assess the effects of HGF inhibition on PC progression in vitro; and iii) in vivo.
Methods: i) HGF expression in PSCs and PC cells was assessed by RT-PCR, immunoblotting/immunocytochemistry; ii) Proliferation of PC cells incubated in PSC secretions pre-treated with or without anti-HGF monoclonal antibody rilotumumab [AMG 102, Amgen Inc.] was assessed; iii) Orthotopic model: AsPC-1 (human PC cell line) + hPSCs were implanted into mouse pancreas, and mice were treated with AMG 102 or IgG. Seven weeks later, tumour and metastasis were assessed.
Results: i) At mRNA and protein levels, hPSCs express HGF, while PC cells exhibit negligible expression. On the other hand, the receptor for HGF (c-Met) is expressed by cancer cells but not by hPSCs. ii) PSC-induced cancer cell proliferation (29.3±5.1% over basal level) was significantly inhibited by HGF antibody to 12.1±3.9% over basal level (p<0.03;n=3). iii) Orthotopic model: a) 300 and 600μg AMG 102 treatments significantly inhibited tumour growth compared to IgG treatment (1312.63±175.27mm3 vs 532.47±91.83* and 382.85±42.70* respectively, *p<0.001;n=8/group); b) The number of proliferating cancer cells in AMG 102-treated tumours was significantly reduced to 79.3±6.4% and 66.5±1.1% of that in IgG-treated tumours (p<0.005;n=4); c) 600μg AMG 102 significantly inhibited metastasis (liver, diaphragm, mediastinum, p<0.05) in mice compared to IgG treatment.
Conclusions: We have shown for the first time that i) human PSCs synthesise HGF, but do not express its receptor; ii) HGF inhibition reduces cancer cells proliferation in vitro, the growth and metastasis of cancer in vivo. Implication: Targeting the stromal reaction with relevant specific inhibitors may represent a novel therapeutic approach PC.