Journal
BRITISH JOURNAL OF CANCER
Volume 114, Issue 3, Pages 269-280Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2015.478
Keywords
pancreatic cancer; stromal-tumour interactions; pancreatic stellate cells; HGF inhibition; HGF/c-MET pathway; orthotopic model
Categories
Funding
- Cancer Council of New South Wales [RG-13-01]
- Cancer Research UK [17263] Funding Source: researchfish
- Chief Scientist Office [SGP/1] Funding Source: researchfish
- Medical Research Council [MC_PC_15080] Funding Source: researchfish
- Pancreatic Cancer UK [FLF2015_04_Glasgow] Funding Source: researchfish
- MRC [MC_PC_15080] Funding Source: UKRI
Ask authors/readers for more resources
Background: 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. Methods: 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. Results: 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. Conclusions: 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available