A short review of the literature first confirms the clinical value of
cathepsin D as a prognostic marker in
breast cancer, when using well standardized assays. We then summarize results of studies, mostly performed in our laboratory, aimed at understanding the effect of
cathepsin D overexpression on
metastasis and the molecular mechanisms involved.
Cathepsin D-
cDNA transfection increases
tumor cell proliferation in vitro and the metastatic potential of 3Y1-Ad12 embryonic rat tumorigenic cells when injected in vivo into nude mice. The mechanism by which
cathepsin D increases the incidence of clinical
metastasis involves increased cell growth and decreased contact inhibition rather than escape of
cancer cells through the basement membrane. Different mechanisms are considered to explain this mitogenic activity.
Cathepsin D could act as a
protease following its activation at an acidic pH, or as a
ligand of different membrane receptors at a more neutral pH. In this case
cathepsin D can displace IGFII from the
mannose-6-
phosphate/IGFII receptor to the IGFI receptor or activate another membrane receptor to be identified. The nature of the mechanisms involved in vivo may depend on the micro environment of the
tumor cells. These studies should guide in the development of new
therapies aimed at inhibiting the deleterious effect of overexpressed
cathepsin D.