Catalytically inactive human cathepsin D triggers fibroblast invasive growth.
The aspartyl-protease cathepsin D (cath-D) is overexpressed and hypersecreted by epithelial breast cancer cells and stimulates their proliferation. As tumor epithelial-fibroblast cell interactions are important events in cancer progression, we investigated whether cath-D overexpression affects also fibroblast behavior. We demonstrate a requirement of cath-D for fibroblast invasive growth using a three-dimensional (3D) coculture assay with cancer cells secreting or not pro-cath-D. Ectopic expression of cath-D in cath-D-deficient fibroblasts stimulates 3D outgrowth that is associated with a significant increase in fibroblast proliferation, survival, motility, and invasive capacity, accompanied by activation of the ras-MAPK pathway. Interestingly, all these stimulatory effects on fibroblasts are independent of cath-D proteolytic activity. Finally, we show that pro-cath-D secreted by cancer cells is captured by fibroblasts and partially mimics effects of transfected cath-D. We conclude that cath-D is crucial for fibroblast invasive outgrowth and could act as a key paracrine communicator between cancer and stromal cells, independently of its catalytic activity.
Laurent-Matha
Valérie
V
INSERM U540 Endocrinologie Moléculaire et Cellulaire des Cancers, Université de Montpellier 1, 34090 Montpellier, France.
Maruani-Herrmann
Sharon
S
Prébois
Christine
C
Beaujouin
Mélanie
M
Glondu
Murielle
M
Noël
Agnès
A
Alvarez-Gonzalez
Marie Luz
ML
Blacher
Sylvia
S
Coopman
Peter
P
Baghdiguian
Stephen
S
Gilles
Christine
C
Loncarek
Jadranka
J
Freiss
Gilles
G
Vignon
Françoise
F
Liaudet-Coopman
Emmanuelle
E
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002070:Butadienes / Q000494:pharmacology; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D049108:Cell Enlargement / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000502:physiology; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000378:metabolism / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000648:ultrastructure; D006801:Humans; D008360:Mannosephosphates / Q000494:pharmacology; D051379:Mice; D008854:Microscopy, Electron; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009375:Neoplasms, Glandular and Epithelial / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D019899:Paracrine Communication / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D014945:Wound Healing
D002070:Butadienes; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D008360:Mannosephosphates; D009570:Nitriles; D034741:RNA, Small Interfering; C113580:U 0126; C027693:mannose-6-phosphate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C058345:procathepsin D; D002402:Cathepsin D