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

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    Authors
    Miller, B
    Morton, J
    Pinese, M
    Saturno, Grazia
    Jamieson, N
    McGhee, E
    Timpson, Paul
    Leach, J
    McGarry, L
    Shanks, E
    Bailey, P
    Chang, D
    Oien, K
    Karim, S
    Au, A
    Steele, C
    Carter, C
    McKay, C
    Anderson, K
    Evans, T
    Marais, Richard
    Springer, C
    Biankin, A
    Erler, J
    Sansom, O
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    Affiliation
    Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK
    Issue Date
    2015-06-15
    
    Metadata
    Show full item record
    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.
    Citation
    Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. 2015: EMBO Mol Med
    Journal
    EMBO Molecular Medicine
    URI
    http://hdl.handle.net/10541/561254
    DOI
    10.15252/emmm.201404827
    PubMed ID
    26077591
    Type
    Article
    Language
    en
    ISSN
    1757-4684
    ae974a485f413a2113503eed53cd6c53
    10.15252/emmm.201404827
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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