title: Cathepsin S from both tumor and tumor-associated cells promote cancer growth and neovascularization.
abstract: 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.
authors: School of Pharmacy, Queen's University Belfast, Lisburn Road, Belfast, BT9 7BL, United Kingdom.
authors: Donna M
authors: DM
authors: Small
authors: Roberta E
authors: RE
authors: Burden
authors: Jakub
authors: J
authors: Jaworski
authors: Shauna M
authors: SM
authors: Hegarty
authors: Shaun
authors: S
authors: Spence
authors: James F
authors: JF
authors: Burrows
authors: Cheryl
authors: C
authors: McFarlane
authors: Adrien
authors: A
authors: Kissenpfennig
authors: Helen O
authors: HO
authors: McCarthy
authors: James A
authors: JA
authors: Johnston
authors: Brian
authors: B
authors: Walker
authors: Christopher J
authors: CJ
authors: Scott
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D002403:Cathepsins / Q000502:physiology*; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059016:Tumor Microenvironment
chemical_list: D012333:RNA, Messenger; D002403:Cathepsins; C028217:cathepsin S
keywords: angiogenesis; cathepsin S; proteases; stroma; tumorigenesis