Abstract LB-395: Hepatocyte growth factor: a potential therapeutic target in pancreatic cancer

Abstract

Abstract 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 in PC patients correlate with poor outcome. However, there is limited knowledge about the role of HGF in PC. Aims: To i) determine whether human PSCs and PC cell lines express HGF; and ii) assess the effects of HGF inhibition on PC progression in an orthotopic mouse model. Methods: i) HGF expression in PSCs and PC cells assessed by RT-PCR, immunoblotting/immunocytochemistry. ii) Orthotopic model: AsPC-1 (a human PC cell line) ± human PSCs implanted into the pancreas mice. One week later, mice divided into groups (n=8 mice/group) and treated with: HGF antibody AMG102 [(Amgen Inc.), 300 or 600μg IP biweekly] or isotype IgG (600 μg IP biweekly). Seven weeks later, tumour size and metastasis assessed. Results: i) PSCs express HGF at both mRNA and protein levels. In contrast, PC cells (MiaPaCa2, Panc-1, AsPC-1) express negligible HGF mRNA. ii) Orthotopic model: a) IgG treated AsPC-1+PSC mice showed larger tumours than mice injected with AsPC-1 alone (Table); b) 300 and 600μg AMG102 inhibited tumour growth in AsPC-1+PSC mice compared to the IgG treated group. However, AMG102 did not reduce tumour size in mice injected with AsPC-1 alone (Table). c) 600μg AMG102 inhibited metastasis (liver, diaphragm, mediastinum) in AsPC-1+PSC mice (p<0.05) compared to IgG treated mice. Conclusions: We have shown for the first time that i)human PSCs synthesise HGF; ii)HGF inhibition reduces tumour growth and metastasis of tumours representative of human PC i.e., exhibiting both tumour elements and a stromal reaction, but not in the clinically non-representative cancers formed by PC cells alone. Implication: Targeting the stromal reaction with relevant specific inhibitors may represent a novel therapeutic approach in PC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-395. doi:10.1158/1538-7445.AM2011-LB-395