Effects of transforming growth factor‐β1 and tumour necrosis factor‐α on cultured fibroblasts from skin fibroma as modulated by toremifene

Abstract

Abstract To determine how toremifene, an anti‐oestrogen triphenylethylene derivate, reduces tumour mass, we investigated its modulation of TGF‐β1 and TNF‐α in fibroma fibroblasts. Normal and fibroma fibroblasts, isolated from patients affected by Gardner's syndrome without or with fibroma manifestation, were cultured in vitro. Secretion of GAG, collagen and TGF‐β1 was increased in fibroma fibroblasts compared to healthy cells. The increase in TGF‐β1 secretion into the medium was associated with a parallel increase in TGF‐β1 gene expression and receptor number. Receptor cross‐linking studies using radiolabelled TGF‐β1 revealed more receptors, particularly types I and II, in fibroma fibroblasts than in normal cells. Normal and fibroma fibroblasts did not synthesise TNF‐α, but they had TNF‐α membrane receptors, as shown by TNF‐α assay. TNF‐α secreted by human monocytes, which may be present in the peritumoral area, increased cell proliferation and GAG accumulation and was, in turn, enhanced by TGF‐β1 treatment. Both growth factors increased angiogenesis, as shown by the CAM assay. Toremifene reduced TGF‐β1 secretion by fibroma fibroblasts and TNF‐α secretion by monocytes, thus downregulating cell proliferation, ECM macromolecule accumulation and angiogenic progression. We hypothesise that increased TGF‐β1 gene expression and TGF‐β1 secretion in fibroma fibroblasts as well as the subsequent rise in TNF‐α production by monocytes may facilitate fibroma growth and that toremifene inhibits autocrine and paracrine growth factor production. © 2002 Wiley‐Liss, Inc.