Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Barrett AJ . 1970 Biochem. J. 117: 601–607
Briozzo P, Badet J, Capony F, Pieri I, Montcourrier P, Barritault D, Rochefort H . 1991 Exp. Cell Res. 194: 252–259
Deiss LP, Galinka H, Berissi H, Cohen O, Kimchi A . 1996 EMBO J. 15: 3861–3870
Ferrandina G, Scambia G, Bardelli F, Panici B, Mancuso S, Messori A . 1997 Br. J. Cancer 76: 661–666
Foekens JA, Look MP, Bolt-de Vries J, Meijer-van Gelder ME, van Putten WLJ, Klijn JGM . 1999 Br. J. Cancer 79: 300–307
Folkman J . 1972 Ann. Surg. 175: 409–416
Garcia M, Capony F, Derocq D, Simon D, Pau B, Rochefort H . 1985 Cancer Res. 45: 709–716
Garcia M, Derocq D, Pujol P, Rochefort H . 1990 Oncogene 5: 1809–1814
Glondu M, Coopman JP, Laurent-Matha V, Garcia M, Rochefort H, Liaudet-Coopman E . 2001 Oncogene 20: 6920–6929
Gonzalez-Vela MC, Garijo MF, Fernandez F, Buelta L, Val-Bernal JF . 1999 Histopathology 34: 35–42
Kagedal K, Johansson U, Ollinger K . 2001 FASEB J. 15: 1592–1594
Liaudet E, Garcia M, Rochefort H . 1994 Oncogene, 9: 1145–1154
Liaudet E, Derocq D, Rochefort H, Garcia M . 1995 Cell Growth Differ. 6: 1045–1052
Liaudet-Coopman E, Berchem G, Wellstein A . 1997 Clin. Cancer Res. 3: 179–184
Morikawa W, Yamamoto K, Ishikawa S, Takemoto S, Ono M, Fukushi J, Naito S, Nozaki C, Iwanaga S, Kuwano M . 2000 J. Biol. Chem. 275: 38912–38920
Pepper MS . 2001 Arterioscler. Thromb. Vasc. Biol. 21: 1104–1117
Rochefort H, Capony F, Garcia M, Cavaillès V, Freiss G, Chambon M, Morisset M, Vignon F . 1987 J. Cell. Biochem. 35: 17–29
Rochefort H . 1992 Eur. J. Cancer. 28A: 1780–1783
Rochefort H, Liaudet-Coopman E . 1999 APMIS 107: 86–95
Roger P, Montcourrier P, Maudelonde T, Brouillet JP, Pages A, Laffargue F, Rochefort H . 1994 Hum. Pathol. 25: 863–871
Saftig P, Hetman M, Schmahl W, Weber K, Heine L, Mossmann H, Koster A, Hess B, Evers M, Von Figura K, Peters C . 1995 EMBO J. 14: 3599–3608
Tsukuba T, Okamoto K, Yasuda Y, Morikawa W, Nakanishi H, Yamamoto K . 2000 Mol. Cells 10: 601–611
Vignon F, Capony F, Chambon M, Freiss G, Garcia M, Rochefort H . 1986 Endocrinology 118: 1537–1545
Wu GS, Saftig P, Peters C, El-Deiry WS . 1998 Oncogene 16: 2177–2183
Acknowledgements
We thank Dr T Maudelonde for helpful discussions and suggestions, Dr P Roger for pathology advice, JY Cance for photographs and illustrations, and N Kerdjadj for secretarial assistance. This work was supported by the University of Montpellier I, the ‘Institut National de la Santé et de la Recherche Médicale’, the ‘Association pour la Recherche sur le Cancer’, and the ‘Ligue Départementale and Régionale contre le Cancer’.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Berchem, G., Glondu, M., Gleizes, M. et al. Cathepsin-D affects multiple tumor progression steps in vivo: proliferation, angiogenesis and apoptosis. Oncogene 21, 5951–5955 (2002). https://doi.org/10.1038/sj.onc.1205745
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1205745
Keywords
This article is cited by
-
Itch and autophagy-mediated NF-κB activation contributes to inhibition of cathepsin D-induced sensitizing effect on anticancer drugs
Cell Death & Disease (2022)
-
Cathepsin D as a potential therapeutic target to enhance anticancer drug-induced apoptosis via RNF183-mediated destabilization of Bcl-xL in cancer cells
Cell Death & Disease (2022)
-
The noncanonical role of the protease cathepsin D as a cofilin phosphatase
Cell Research (2021)
-
Pro-cathepsin D as a diagnostic marker in differentiating malignant from benign pleural effusion: a retrospective cohort study
BMC Cancer (2020)
-
Immunotherapy of triple-negative breast cancer with cathepsin D-targeting antibodies
Journal for ImmunoTherapy of Cancer (2019)