Mesenchymal stem cell homing towards cancer cells is increased by enzyme activity of cathepsin D

Exp Cell Res. 2019 Oct 1;383(1):111494. doi: 10.1016/j.yexcr.2019.07.007. Epub 2019 Jul 12.

Abstract

Mesenchymal stem cells home towards inflammatory microenvironments, such as the tumour stroma, where they have been shown to have both pro- and anti-tumorigenic effects. Here, we demonstrate that the aspartic acid protease cathepsin D is part of the chemoattraction process. Using a Boyden chamber co-culture system, the migration of the mesenchymal stem cells and their invasion through Matrigel increased in the presence of breast cancer MDA-MB-231 cells, colon cancer HT29 cells or their conditioned media. Mesenchymal stem cell movement was reduced by protease inhibitors of matrix metalloproteinases and by pepstatin A, an inhibitor of cathepsin D. We confirmed a role for cathepsin D through addition of recombinant protein, upregulation of cathepsin D release using chloroquine and knockdown of cathepsin D expression. While all cell types expressed active cathepsin D, enzymatically inactive precursor procathepsin D was expressed only at low levels by mesenchymal stem cells. Expression in mesenchymal stem cells was increased following co-culture with cancer cells. The chemoattractive effect of cathepsin D required its enzymatic activity, but not changes in mesenchymal stem cell proliferation or adhesion rates. In conclusion, cathepsin D and its precursors enhance mesenchymal stem cell homing towards tumour sites, most likely by enzymatic mechanisms.

Keywords: Cathepsin D; Invasion; Matrix metalloproteinase; Mesenchymal stem cell; Migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cathepsin D / metabolism*
  • Cell Adhesion
  • Cell Movement*
  • Cell Proliferation
  • Cells, Cultured
  • Coculture Techniques
  • Collagen
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Culture Media, Conditioned
  • Drug Combinations
  • Enzyme Precursors / metabolism*
  • Female
  • Humans
  • Laminin
  • Mesenchymal Stem Cells / metabolism
  • Mesenchymal Stem Cells / pathology*
  • Proteoglycans
  • Tumor Microenvironment*

Substances

  • Culture Media, Conditioned
  • Drug Combinations
  • Enzyme Precursors
  • Laminin
  • Proteoglycans
  • matrigel
  • Collagen
  • procathepsin D
  • Cathepsin D