Synergistic enhancement of EGF, but not HGF, stimulated hepatocyte motility by TGF-beta 1 in vitro.
The ability of TGF-beta 1 (transforming growth factor-beta 1) to suppress growth factor induced proliferation of many cell types in vitro is well documented; however, TGF-beta 1 increases within a similar time frame as the hepatocyte mitogens HGF (hepatocyte growth factor), EGF (epidermal growth factor), and TGF-alpha (transforming growth factor-alpha) prior to hepatocyte proliferation during liver regeneration. This has raised the issue that TGF-beta 1 may have effects on hepatocytes additional to mito-inhibition and that these effects may be relevant to the regenerative process. To this end, we examined the effect of TGF-beta 1 on both the mitogenesis and the motility of growth factor stimulated primary rat hepatocytes and the hepatoblastoma cell line HepG2 in vitro. TGF-beta 1 significantly enhanced the chemotactic motility of EGF or TGF-alpha, and not HGF, stimulated hepatocytes on a collagen I substratum. TGF-beta 1 was not chemotactic when added alone and decreased the DNA synthesis of all hepatocyte cultures to near control levels. HepG2 cells were chemotactic toward HGF, EGF, and TGF-beta 1 alone and displayed an additive chemotactic response when TGF-beta 1 was added to either HGF or EGF. Additionally, HepG2 cells were refractory to the growth stimulatory effects of HGF or EGF and the growth inhibitory effects of TGF-beta 1. Hepatocytes plated onto other collagen-containing substrates (collagen IV, Matrigel, or ECL, an entactin-collagen IV-laminin matrix), but not on fibronectin or laminin alone, also displayed enhanced EGF stimulated motility by TGF-beta 1. The data indicate that an additional, novel role for TGF-beta 1 during liver tissue remodeling following PHx may include the synergistic enhancement EGF stimulated hepatocyte motility responses, and this enhancement is observed only on collagen-containing extracellular matrices.
Stolz
D B
DB
Department of Pathology, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.
Michalopoulos
G K
GK
D000818:Animals; D006528:Carcinoma, Hepatocellular; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects*; D003094:Collagen / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D008115:Liver Regeneration / Q000502:physiology; D009362:Neoplasm Metastasis / Q000503:physiopathology; D051381:Rats; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects
D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D003094:Collagen; D004247:DNA