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

Autor: Bryan W Miller, Jennifer P Morton, Mark Pinese, Grazia Saturno, Nigel B Jamieson, Ewan McGhee, Paul Timpson, Joshua Leach, Lynn McGarry, Emma Shanks, Peter Bailey, David Chang, Karin Oien, Saadia Karim, Amy Au, Colin Steele, Christopher Ross Carter, Colin McKay, Kurt Anderson, Thomas R Jeffry Evans, Richard Marais, Caroline Springer, Andrew Biankin, Janine T Erler, Owen J Sansom
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 7, Iss 8, Pp 1063-1076 (2015)
Druh dokumentu: article
ISSN: 1757-4676
1757-4684
DOI: 10.15252/emmm.201404827
Popis: 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 KrasG12D/+Trp53R172H/+ (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.
Databáze: Directory of Open Access Journals
Externí odkaz: