Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy.
AffiliationCancer Research UK Beatson Institute Garscube Estate, Glasgow, UK
MetadataShow full item record
AbstractPancreatic 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.
CitationTargeting 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
JournalEMBO Molecular Medicine
- Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution.
- Authors: Le Calvé B, Griveau A, Vindrieux D, Maréchal R, Wiel C, Svrcek M, Gout J, Azzi L, Payen L, Cros J, de la Fouchardière C, Dubus P, Guitton J, Bartholin L, Bachet JB, Bernard D
- Issue date: 2016 May 31
- Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells With Activated KRAS in Response to Hypoxia.
- Authors: McDonald PC, Chafe SC, Brown WS, Saberi S, Swayampakula M, Venkateswaran G, Nemirovsky O, Gillespie JA, Karasinska JM, Kalloger SE, Supuran CT, Schaeffer DF, Bashashati A, Shah SP, Topham JT, Yapp DT, Li J, Renouf DJ, Stanger BZ, Dedhar S
- Issue date: 2019 Sep
- Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma.
- Authors: Carapuça EF, Gemenetzidis E, Feig C, Bapiro TE, Williams MD, Wilson AS, Delvecchio FR, Arumugam P, Grose RP, Lemoine NR, Richards FM, Kocher HM
- Issue date: 2016 Jul
- PG545, an angiogenesis and heparanase inhibitor, reduces primary tumor growth and metastasis in experimental pancreatic cancer.
- Authors: Ostapoff KT, Awasthi N, Cenik BK, Hinz S, Dredge K, Schwarz RE, Brekken RA
- Issue date: 2013 Jul
- GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine.
- Authors: Ferro R, Adamska A, Lattanzio R, Mavrommati I, Edling CE, Arifin SA, Fyffe CA, Sala G, Sacchetto L, Chiorino G, De Laurenzi V, Piantelli M, Sansom OJ, Maffucci T, Falasca M
- Issue date: 2018 Dec