Direct evidence of the importance of stromal urokinase plasminogen activator (uPA) in the growth of an experimental human breast cancer using a combined uPA gene-disrupted and immunodeficient xenograft model.
Several studies have indicated an interaction between tumor cells and infiltrating stromal cells regarding the urokinase plasminogen activation (uPA) system. By developing combined uPA gene-disrupted and immunodeficient mice, we have studied the role of stromal uPA for the growth of the MDA-MB-435 BAG human tumor xenograft. Subcutaneous tumor growth and lung metastasis were compared between wild-type immunodeficient mice and mice with the combined deficiencies. Tumor growth was evaluated by volume measurements and plasma beta-galactosidase activity and metastasis was evaluated by counting lung surface metastases. Although no differences appeared in primary tumor take between the two groups of mice, a significant difference was observed in primary tumor growth, with tumors in uPA-/- mice growing significantly more slowly. In addition, a nonsignificant trend toward fewer lung metastases in uPA-/- mice was observed. The present data points to a critical role of stromal-derived uPA in the primary tumor growth of MDA-MB-435 BAG xenografts, whereas only a trend toward fewer lung metastases in uPA gene-disrupted mice was found.
Frandsen
T L
TL
The Fintsen Laboratory, Copenhagen University Hospital, Denmark.
Holst-Hansen
C
C
Nielsen
B S
BS
Christensen
I J
IJ
Nyengaard
J R
JR
Carmeliet
P
P
Brünner
N
N
D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002455:Cell Division / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D016513:Mice, SCID; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D018952:Antigens, CD34; D012333:RNA, Messenger; D014568:Urokinase-Type Plasminogen Activator