Mapping proteolytic processing in the secretome of gastric cancer-associated myofibroblasts reveals activation of MMP-1, MMP-2, and MMP-3

Christopher Holmberg, Bart Ghesquière, Francis Impens, Kris Gevaert, J. Dinesh Kumar, Nicole Cash, Sandhir Kandola, Peter Hegyi, Timothy C. Wang, Graham J. Dockray, Andrea Varro

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Cancer progression involves changes in extracellular proteolysis, but the contribution of stromal cell secretomes to the cancer degradome remains uncertain. We have now defined the secretome of a specific stromal cell type, the myofibroblast, in gastric cancer and its modification by proteolysis. SILAC labeling and COFRADIC isolation of methionine containing peptides allowed us to quantify differences in gastric cancer-derived myofibroblasts compared with myofibroblasts from adjacent tissue, revealing increased abundance of several proteases in cancer myofibroblasts including matrix metalloproteinases (MMP)-1 and -3. Moreover, N-terminal COFRADIC analysis identified cancer-restricted proteolytic cleavages, including liberation of the active forms of MMP-1, -2, and -3 from their inactive precursors. In vivo imaging confirmed increased MMP activity when gastric cancer cells were xenografted in mice together with gastric cancer myofibroblasts. Western blot and enzyme activity assays confirmed increased MMP-1, -2, and -3 activity in cancer myofibroblasts, and cancer cell migration assays indicated stimulation by MMP-1, -2, and -3 in cancer-associated myofibroblast media. Thus, cancer-derived myofibroblasts differ from their normal counterparts by increased production and activation of MMP-1, -2, and -3, and this may contribute to the remodelling of the cancer cell microenvironment.

Original languageEnglish
Pages (from-to)3413-3422
Number of pages10
JournalJournal of Proteome Research
Volume12
Issue number7
DOIs
Publication statusPublished - Jul 5 2013

Keywords

  • COFRADIC
  • degradome
  • myofibroblast
  • neo-N-termini
  • secretome

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)

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    Holmberg, C., Ghesquière, B., Impens, F., Gevaert, K., Kumar, J. D., Cash, N., Kandola, S., Hegyi, P., Wang, T. C., Dockray, G. J., & Varro, A. (2013). Mapping proteolytic processing in the secretome of gastric cancer-associated myofibroblasts reveals activation of MMP-1, MMP-2, and MMP-3. Journal of Proteome Research, 12(7), 3413-3422. https://doi.org/10.1021/pr400270q