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

Abstract

To determine how toremifene, an anti-oestrogen triphenylethylene derivate, reduces tumour mass, we investigated its modulation of TGF-␤1 and TNF-␣ 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-␤1 was increased in fibroma fibroblasts compared to healthy cells. The increase in TGF-␤1 secretion into the medium was associated with a parallel increase in TGF-␤1 gene expression and receptor number. Receptor cross-linking studies using radiolabelled TGF-␤1 revealed more receptors, particularly types I and II, in fibroma fibroblasts than in normal cells. Normal and fibroma fibroblasts did not synthesise TNF-␣, but they had TNF-␣ membrane receptors, as shown by TNF-␣ assay. TNF-␣ 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-␤1 treatment. Both growth factors increased angiogenesis, as shown by the CAM assay. Toremifene reduced TGF-␤1 secretion by fibroma fibroblasts and TNF-␣ secretion by monocytes, thus downregulating cell proliferation, ECM macromolecule accumulation and angiogenic progression. We hypothesise that increased TGF-␤1 gene expression and TGF-␤1 secretion in fibroma fibroblasts as well as the subsequent rise in TNF-␣ production by monocytes may facilitate fibroma growth and that toremifene inhibits autocrine and paracrine growth factor production.

Interleukin-10 Suppresses Proliferation and Remodeling of Extracellular Matrix of Cultured Human Skin Fibroblasts

“…TGFß1 stimulates fibroblast proliferation [19] and Van Vlasselaer et al [20] have reported that IL-10 inhibits TGFß1 synthesis in mouse bone marrow cells. In our study, the concentration of TGFß1 in cell culture supernatants incubated with TNF· alone was almost 2.5-fold higher than that in supernatants from cells incubated with both IL-10 and TNF·, suggesting that IL-10 reduced TNF·-induced fibroblast proliferation by decreasing TGFß1 production.…”

Role of tissue stroma in cancer cell invasion

“…The fibroblastoid morphotype is associated with nuclear β-catenin and decreased E-cadherin protein expression. Interestingly, myofibroblasts isolated from desmoid tumours, which are locally invasive soft tissue tumours in which β-catenin-mediated TCF-dependent transcription is activated [114], show increased TGF-β production in comparison with fibroblasts from normal fascia [115]. This suggests a possible cooperation between Wnt/β-catenin and TGF-β signalling making desmoid myofibroblasts invasive.…”

“…Small organic molecules that fine-tune TGF-β production and activation offer another therapeutic strategy. Such molecules are Tranilast [237,238], Pirfenidone [239], Pentoxifylline [240], Toremifene [115], angiotensin-converting enzyme inhibitors [241], and Triptolide and derivatives [242]. MMP inhibitors might also have an effect on TGF-β activation.…”

The Acute Stress Reaction to Major Thoracic Surgery

“…The loss of integrity of PGs reflects the sustained increase in parenchymal stresses, the weakening of the non-covalent bonds due to increased water binding, and the activation of tissue metalloproteases (32 Miserocchi et al, 2001a). The hypothesis that the activation of tissue metalloproteases leads to the loss of integrity of PGs faces to new therapeutic approachs by drugs able to control this family of proteinases [33,34,35].…”