Cathepsin-D affects multiple tumor progression steps in vivo: Proliferation, angiogenesis and apoptosis

Guy Berchem, Murielle Glondu, Michel Gleizes, Jean Paul Brouillet, Françoise Vignon, Marcel Garcia, Emmanuelle Liaudet-Coopman

Research output: Contribution to journalArticleResearchpeer-review

190 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5951-5955
Number of pages5
JournalOncogene
Volume21
Issue number38
DOIs
Publication statusPublished - 2002
Externally publishedYes

Keywords

  • Angiogenesis
  • Apoptosis
  • Cancer
  • Cathepsin-D
  • Proliferation

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