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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / pathology*
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • Humans
  • Hypoxia
  • Mice
  • Neoplasm Metastasis / prevention & control
  • Pancreatic Neoplasms / pathology*
  • Protein-Lysine 6-Oxidase / antagonists & inhibitors
  • Protein-Lysine 6-Oxidase / metabolism*
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Deoxycytidine
  • gemcitabine
  • Protein-Lysine 6-Oxidase