This study reports on the effects of
heparin, basic and acidic
fibroblast growth factors (bFGF and aFGF, respectively), and
transforming growth factor type-e (
TGFe) on the growth of a human
adrenocortical carcinoma cell line, SW-13.
Heparin has previously been shown to inhibit growth in several cell types, including smooth muscle cells, certain fibroblasts, and epithelial cells, and to modulate the effects of
fibroblast growth factors. Whereas bFGF and aFGF bind tightly to
heparin and elute from a
heparin-Sepharose column with 2 M NaCl and 1.6 M NaCl, respectively,
TGFe binds to
heparin with lower affinity and can be eluted from
heparin-Sepharose column with 0.5 M NaCl.
TGFe is a
polypeptide unrelated to FGF, is present in neoplastic and nonneoplastic tissues, and stimulates the growth of certain epithelial cells and fibroblasts in soft
agar and monolayer. Since the growth of SW-13 cells is stimulated by
TGFe and by bFGF, we hypothesized that
heparin would inhibit the growth of SW-13 cells by binding to these
growth factors and that the effects of
heparin could be overcome with the addition of either
growth factor. Our experiments confirmed that
heparin inhibits the growth of SW-13 cells. A dose-dependent growth inhibition was observed in both monolayer and soft
agar. The inhibition in monolayer was partially reversed upon
heparin withdrawal. The effects of
heparin in both monolayer and soft
agar were at least partially overcome by
TGFe and by basic or acidic FGF. Overall
protein synthesis does not appear to be affected by
heparin as measured by [35S]
methionine uptake. In contrast,
epidermal growth factor (
EGF) and
insulin-like growth factor I (
IGF-I) were unable to overcome
heparin-induced inhibition both in monolayer and in soft
agar.
Heparin also inhibited [3H]
thymidine incorporation in AKR-2B and partially inhibited AKR-2B cell stimulation by
TGFe; however, it further potentiated the already potent stimulation by bFGF. We propose that
heparin,
TGFe, bFGF, and aFGF modulate the growth of SW-13 cells and possibly of other epithelial cells in complex ways and that
heparin-like substances present in the extracellular matrix play an important role in the control of epithelial growth.