Cathepsin S from both tumour and tumour-associated cells promote cancer growth and neovascularisation

Donna M. Small, Roberta E. Burden, Jakub Jaworski, Shauna M. Hegarty, Shaun Spence, James F. Burrows, Cheryl McFarlane, Adrien Kissenpfennig, Helen O. McCarthy, James A. Johnston, Brian Walker, Christopher J. Scott

Research output: Contribution to journalArticle

48 Citations (Scopus)
285 Downloads (Pure)

Abstract

Recent murine studies have demonstrated that tumour-associated macrophages in the tumour microenvironment are a key source of the pro-tumourigenic cysteine protease, cathepsin S. We now show in a syngeneic colorectal carcinoma murine model that both tumour and tumour-associated cells contribute cathepsin S to promote neovascularisation and tumour growth. Cathepsin S depleted and control colorectal MC38 tumour 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 tumour, tumour-associated host cells, or both. Parallel analysis of these conditions showed that deletion of cathepsin S inhibited tumour growth and development, and revealed a clear contribution of both tumour and tumour-associated cell derived cathepsin S. The most significant impact on tumour development was obtained when the protease was depleted from both sources. Further characterisation revealed that the loss of cathepsin S led to impaired tumour vascularisation, which was complemented by a reduction in proliferation and increased apoptosis, consistent with reduced tumour growth. Analysis of cell types showed that in addition to the tumour cells, tumour-associated macrophages and endothelial cells can produce cathepsin S within the microenvironment. Taken together, these findings clearly highlight a manner by which tumour-associated cells can positively contribute to developing tumours and highlight cathepsin S as a therapeutic target in cancer.
Original languageEnglish
Pages (from-to)2102-2112
Number of pages11
JournalInternational Journal of Cancer
Volume133
Issue number9
Early online date29 May 2013
DOIs
Publication statusPublished - Nov 2013

    Fingerprint

Keywords

  • proteases
  • cathepsin S
  • angiogenesis
  • tumorigenesis
  • stroma

Cite this