Cathepsin S from both tumor and tumor-associated cells promote cancer growth and neovascularization

Int J Cancer. 2013 Nov;133(9):2102-12. doi: 10.1002/ijc.28238. Epub 2013 May 29.


Recent murine studies have demonstrated that tumor-associated macrophages in the tumor microenvironment are a key source of the pro-tumorigenic cysteine protease, cathepsin S. We now show in a syngeneic colorectal carcinoma murine model that both tumor and tumor-associated cells contribute cathepsin S to promote neovascularization and tumor growth. Cathepsin S depleted and control colorectal MC38 tumor cell lines were propagated in both wild type C57Bl/6 and cathepsin S null mice to provide stratified depletion of the protease from either the tumor, tumor-associated host cells, or both. Parallel analysis of these conditions showed that deletion of cathepsin S inhibited tumor growth and development, and revealed a clear contribution of both tumor and tumor-associated cell derived cathepsin S. The most significant impact on tumor development was obtained when the protease was depleted from both sources. Further characterization revealed that the loss of cathepsin S led to impaired tumor vascularization, which was complemented by a reduction in proliferation and increased apoptosis, consistent with reduced tumor growth. Analysis of cell types showed that in addition to the tumor cells, tumor-associated macrophages and endothelial cells can produce cathepsin S within the microenvironment. Taken together, these findings clearly highlight a manner by which tumor-associated cells can positively contribute to developing tumors and highlight cathepsin S as a therapeutic target in cancer.

Keywords: angiogenesis; cathepsin S; proteases; stroma; tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Carcinoma, Lewis Lung / blood supply
  • Carcinoma, Lewis Lung / genetics
  • Carcinoma, Lewis Lung / pathology*
  • Cathepsins / physiology*
  • Cell Adhesion
  • Cell Cycle
  • Cell Movement*
  • Cell Proliferation*
  • Cells, Cultured
  • Colorectal Neoplasms / blood supply
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Humans
  • Immunoenzyme Techniques
  • Macrophages / cytology
  • Macrophages / metabolism
  • Melanoma, Experimental / blood supply
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Pathologic*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Microenvironment


  • RNA, Messenger
  • Cathepsins
  • cathepsin S