Cathepsin-D affects multiple tumor progression steps in vivo: proliferation, angiogenesis and apoptosis.
Cathepsin-D is an independent marker of poor prognosis in human breast cancer. We previously showed that human wild-type cathepsin-D, as well as its mutated form devoid of proteolytic activity stably transfected in 3Y1-Ad12 cancer cells, stimulated tumor growth. To investigate the mechanisms by which human cathepsin-D and its catalytically-inactive counterpart promoted tumor growth in vivo, we quantified the expression of proliferating cell nuclear antigen, the number of blood vessels and of apoptotic cells in 3Y1-Ad12 tumor xenografts. We first verified that both human wild-type and mutated cathepsin-D were expressed at a high level in cathepsin-D xenografts, whereas no human cathepsin-D was detected in control xenografts. Our immunohistochemical studies then revealed that both wild-type cathepsin-D and catalytically-inactive cathepsin-D, increased proliferating cell nuclear antigen expression and tumor angiogenesis. Interestingly, wild-type cathepsin-D significantly inhibited tumor apoptosis, whereas catalytically-inactive cathepsin-D did not. We therefore propose that human cathepsin-D stimulates tumor growth by acting-directly or indirectly-as a mitogenic factor on both cancer and endothelial cells independently of its catalytic activity. Our overall results provide the first mechanistic evidences on the essential role of cathepsin-D at multiple tumor progression steps, affecting cell proliferation, angiogenesis and apoptosis.
Laboratoire d'Hémato-Cancérologie, Centre Hospitalier de Luxembourg 4, rue Barblé.
Guy
G
Berchem
Murielle
M
Glondu
Michel
M
Gleizes
Jean-Paul
JP
Brouillet
Françoise
F
Vignon
Marcel
M
Garcia
Emmanuelle
E
Liaudet-Coopman
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002402:Cathepsin D / Q000502:physiology*; D002455:Cell Division; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009389:Neovascularization, Pathologic; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D018809:Proliferating Cell Nuclear Antigen; D002402:Cathepsin D