Urokinase-type-plasminogen-activator (uPA) production by human breast (myo) fibroblasts in vitro: influence of transforming growth factor-beta(1) (TGF beta(1)) compared with factor(s) released by human epithelial-carcinoma cells.
The urokinase-type plasminogen activator (uPA) may be considered as a key enzyme in the processes of cancer cell invasion and metastasis. Evidence has been presented that, in breast stroma, uPA is expressed predominantly by myofibroblasts located at the invasive areas of the tumor. To examine whether transforming growth factor type-1 (TGF beta(1)) produced by breast-carcinoma cells is a candidate responsible for the induction of uPA-producing myofibroblasts, we studied in vitro the capacity of normal and tumor-derived human breast fibroblasts to express uPA and the myofibroblast marker alpha-smooth-muscle actin in response to TGF beta(1). Next, we compared these influences with those elicited by factor(s) released by epithelial-cancer cells. In all 8 fibroblast strains tested, TGF beta(1) induced a similar concentration-dependent increase in the fraction of alpha-smooth-muscle-actin-positive fibroblasts. While uPA expression was decreased by TGF beta(1) in most of the fibroblast strains, 2 strains were relatively insensitive to TGF beta(1) in this respect. Although factors present in media conditioned by non-uPA-producing epithelial-tumor cells could trigger fibroblasts to become potent producers of uPA, the TGF beta(1) content of the conditioned media were linked to the differential effects of externally added TGF beta(1) with respect to uPA expression. The data demonstrate that, although fibroblasts may utilize TGF beta(1) secreted by tumor cells to differentiate into myofibroblasts, tumor cells secrete factor(s) other than TGF beta(1) ultimately responsible for the generation of powerful uPA-producing fibroblasts.
Sieuwerts
A M
AM
Medical Oncology Department (Division of Endocrine Oncology), Rotterdam Cancer Institute (Daniel den Hoed Kliniek)/Academic Hospital Rotterdam, The Netherlands. Sieuwerts@bidh.azr.nl
Klijn
J G
JG
Henzen-Logmand
S C
SC
Bouwman
I
I
Van Roozendaal
K E
KE
Peters
H A
HA
Setyono-Han
B
B
Foekens
J A
JA
D001940:Breast / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis* / Q000235:genetics
D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014568:Urokinase-Type Plasminogen Activator