Blocking Surgically Induced Lysyl Oxidase Activity Reduces the Risk of Lung Metastases

Cell Rep. 2017 Apr 25;19(4):774-784. doi: 10.1016/j.celrep.2017.04.005.

Abstract

Surgery remains the most successful curative treatment for cancer. However, some patients with early-stage disease who undergo surgery eventually succumb to distant metastasis. Here, we show that in response to surgery, the lungs become more vulnerable to metastasis due to extracellular matrix remodeling. Mice that undergo surgery or that are preconditioned with plasma from donor mice that underwent surgery succumb to lung metastases earlier than controls. Increased lysyl oxidase (LOX) activity and expression, fibrillary collagen crosslinking, and focal adhesion signaling contribute to this effect, with the hypoxic surgical site serving as the source of LOX. Furthermore, the lungs of recipient mice injected with plasma from post-surgical colorectal cancer patients are more prone to metastatic seeding than mice injected with baseline plasma. Downregulation of LOX activity or levels reduces lung metastasis after surgery and increases survival, highlighting the potential of LOX inhibition in reducing the risk of metastasis following surgery.

Keywords: breast cancer; host response; hypoxia; lysyl oxidase; metastasis; pre-metastatic niche; surgery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / immunology
  • Antibodies / therapeutic use
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Breast Neoplasms / surgery
  • Cell Line, Tumor
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / surgery*
  • Disease Models, Animal
  • Extracellular Matrix / metabolism
  • Female
  • Focal Adhesions / metabolism
  • Humans
  • Kaplan-Meier Estimate
  • Lung / pathology
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Protein-Lysine 6-Oxidase / blood
  • Protein-Lysine 6-Oxidase / immunology
  • Protein-Lysine 6-Oxidase / metabolism*
  • Risk
  • Signal Transduction
  • Transplantation, Homologous

Substances

  • Antibodies
  • Protein-Lysine 6-Oxidase