Stimulatory effects of EGF and TGF-alpha on invasive activity and 5'-deoxy-5-fluorouridine sensitivity in uterine cervical-carcinoma SKG-IIIb cells.
We investigated the effects of epidermal growth factor (EGF) and transforming growth factor (TGF)-alpha on migration, invasion and matrix metalloproteinase (MMP) expression of uterine cervical-carcinoma SKG-IIIb cells, and whether these growth factors affect pyrimidine-nucleoside-phosphorylase (PyNPase) activity and 5'-deoxy-5-fluorouridine (5'-dFUrd) sensitivity of tumor cells. Tumor-cell migration along a gradient of substratum-bound fibronectin and invasion into reconstituted basement membrane were stimulated by 0.1 to 100 ng/ml of EGF and TGF-alpha in a concentration-dependent manner. The zymography of tumor-conditioned medium showed that the treatment of tumor cells with EGF and TGF-alpha resulted in an increase of the 92-kDa type-IV collagenase (MMP-9), which was confirmed by immunoblot analysis. These growth factors also up-regulated the expression of PyNPase activity of tumor cells and consequently enhanced the anti-proliferative action of 5'-dFUrd, a cytostatic that is biotransformed to 5-fluorouracil (5-FUra) by PyNPase. However, EGF and TGF-alpha did not have significant effects on the 5-FUra sensitivity of tumor cells. These results suggest that EGF and TGF-alpha, tumor environmental factors, simultaneously up-regulate the potential of uterine cervical-carcinoma cells to invade extracellular matrices and their PyNPase activity, which are subsequently associated with the specific action of 5'-dFUrd selectively killing tumor cells of gynecological origin with high invasive and metastatic potential.
Ueda
M
M
Department of Obstetrics and Gynecology, Osaka Medical College, Japan.
Ueki
M
M
Terai
Y
Y
Morimoto
A
A
Fujii
H
H
Yoshizawa
K
K
Yanagihara
T
T
D001485:Basement Membrane; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002633:Chemotaxis / Q000187:drug effects; D003094:Collagen; D017364:Collagenases / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005260:Female; D005353:Fibronectins; D005467:Floxuridine / Q000633:toxicity*; D005780:Gelatin; D006801:Humans; D007797:Laminin; D020780:Matrix Metalloproteinase 9; D009361:Neoplasm Invasiveness; D010430:Pentosyltransferases / Q000096:biosynthesis; D011509:Proteoglycans; D057845:Pyrimidine Phosphorylases; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000473:pathology*
D004338:Drug Combinations; D005353:Fibronectins; D007797:Laminin; D011509:Proteoglycans; D016211:Transforming Growth Factor alpha; D005467:Floxuridine; C059485:matrigel; D004815:Epidermal Growth Factor; D005780:Gelatin; D003094:Collagen; D010430:Pentosyltransferases; D057845:Pyrimidine Phosphorylases; D017364:Collagenases; D020780:Matrix Metalloproteinase 9