Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution

Oncotarget. 2016 May 31;7(22):32100-12. doi: 10.18632/oncotarget.8527.

Abstract

Solid tumors often display chemotherapy resistance. Pancreatic ductal adenocarcinoma (PDAC) is the archetype of resistant tumors as current chemotherapies are inefficient. The tumor stroma and extracellular matrix (ECM) are key contributors to PDAC aggressiveness and to limiting the efficacy of chemotherapy. Lysyl oxidase (LOX) family members mediate collagen cross-linking and thus promote ECM stiffening. Our data demonstrate increased LOX, LOXL1, and LOXL2 expression in PDAC, and that the level of fibrillar collagen, which is directly dependent of LOX family activity, is an independent predictive biomarker of adjuvant "Gemcitabine-based chemotherapy" benefit. Experimentally in mice, increased LOX family activity through LOXL2 promotes chemoresistance. This effect of LOX family activity seems to be due to decreased gemcitabine intra-tumoral diffusion. This observation might be explained by increased fibrillar collagen and decreased vessel size observed in tumors with increased LOX family activity. In conclusion, our data support that LOX family activity is both a novel target to improve chemotherapy as well as a novel biomarker to predict gemcitabine benefit in PDAC. Beyond the PDAC, it is possible that targeting LOX family activity might improve efficacy of chemotherapies against different kinds of solid tumors.

Keywords: biomarker; chemoresistance; collagen; lysyl oxidase; survival.

MeSH terms

  • Amino Acid Oxidoreductases / genetics
  • Amino Acid Oxidoreductases / metabolism
  • Animals
  • Antimetabolites, Antineoplastic / pharmacokinetics
  • Antimetabolites, Antineoplastic / pharmacology*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / enzymology
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacokinetics
  • Deoxycytidine / pharmacology
  • Diffusion
  • Drug Resistance, Neoplasm*
  • Female
  • Fibrillar Collagens / metabolism
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice, Nude
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Protein-Lysine 6-Oxidase / genetics
  • Protein-Lysine 6-Oxidase / metabolism*
  • Tissue Distribution
  • Up-Regulation
  • Xenograft Model Antitumor Assays

Substances

  • Antimetabolites, Antineoplastic
  • Biomarkers, Tumor
  • Fibrillar Collagens
  • Deoxycytidine
  • gemcitabine
  • Amino Acid Oxidoreductases
  • LOXL1 protein, human
  • LOXL2 protein, human
  • Protein-Lysine 6-Oxidase