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EMBO Mol Med. 2015 Aug;7(8):1063-76. doi: 10.15252/emmm.201404827.

Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy.

Author information

1
Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK.
2
The Garvan Institute of Medical Research, Sydney, NSW, Australia.
3
Cancer Research UK Manchester Institute, Withington Manchester, UK.
4
West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
5
Institute of Cancer Sciences University of Glasgow Garscube Estate, Glasgow, UK.
6
Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK Institute of Cancer Sciences University of Glasgow Garscube Estate, Glasgow, UK.
7
Institute of Cancer Research, London, UK.
8
Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen (UCPH), Denmark janine.erler@bric.ku.dk o.sansom@beatson.gla.ac.uk.
9
Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK janine.erler@bric.ku.dk o.sansom@beatson.gla.ac.uk.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1-Cre Kras(G12D/+) Trp53(R172H/+) (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor-free survival in KPC mice with early-stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease.

KEYWORDS:

animal models of cancer; collagen cross‐linking; lysyl oxidase; pancreatic cancer

PMID:
26077591
PMCID:
PMC4551344
DOI:
10.15252/emmm.201404827
[Indexed for MEDLINE]
Free PMC Article

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