Antibody-mediated inhibition of cathepsin S blocks colorectal tumor invasion and angiogenesis.
OBJECTIVE
Cathepsin S is a cysteine protease that promotes the invasion of tumor and endothelial cells during cancer progression. Here we investigated the potential to target cathepsin S using an antagonistic antibody, Fsn0503, to block these tumorigenic effects.


METHODS
A panel of monoclonal antibodies was raised to human cathepsin S. The effects of a selected antibody were subsequently determined using invasion and proteolysis assays. Endothelial cell tube formation and aorta sprouting assays were done to examine antiangiogenic effects. In vivo effects were also evaluated using HCT116 xenograft studies.


RESULTS
A selected cathepsin S antibody, Fsn0503, significantly blocked invasion of a range of tumor cell lines, most significantly HCT116 colorectal carcinoma cells, through inhibition of extracellular cathepsin S-mediated proteolysis. We subsequently found enhanced expression of cathepsin S in colorectal adenocarcinoma biopsies when compared with normal colon tissue. Moreover, Fsn0503 blocked endothelial cell capillary tube formation and aortic microvascular sprouting. We further showed that administration of Fsn0503 resulted in inhibition of tumor growth and neovascularization of HCT116 xenograft tumors.


CONCLUSIONS
These results show that blocking the invasive and proangiogenic effects of cathepsin S with antibody inhibitors may have therapeutic utility upon further preclinical and clinical evaluation.
School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom.
Roberta E
RE
Burden
Julie A
JA
Gormley
Thomas J
TJ
Jaquin
Donna M
DM
Small
Derek J
DJ
Quinn
Shauna M
SM
Hegarty
Claire
C
Ward
Brian
B
Walker
James A
JA
Johnston
Shane A
SA
Olwill
Christopher J
CJ
Scott
D000230:Adenocarcinoma / Q000098:blood supply / Q000473:pathology* / Q000628:therapy; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000473:pathology* / Q000628:therapy; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002403:Cathepsins; C028217:cathepsin S