Activated mesothelial cells produce heparin-binding growth factors: implications for tumour metastases

Curative surgery for gastrointestinal malignancy is commonly thwarted by lo cal tumour recurrence. The heparin-binding growth factors, basic fibroblast growth factor (bFGF), heparin-binding epidermal growth factor-like growth factor (HB-EGF) and vascular epidermal growth factor (VEGF) are all implica ted in the metastatic process, but whether or not these essential growth fa ctors are produced by the activated peritoneum is unknown. This study revea ls that peritoneal mesothelial cells constitutively express mRNA for bFGF, HB-EGF and two VEGF spliced variants, VEGF(121) and VEGF(165). Mesothelial activation with interleukin (IL)-1b or tumour necrosis factor (TNF)-a produ ced an up-regulation of mRNA for HB-EGF and VEGF, but not bFGF expression. IL-6 failed to stimulate growth factor expression, whereas IL-2 produced a marked suppression in HB-EGF and bFGF, but not VEGF expression. Mesothelial cells were shown to predominantly express mRNA for the intermediate affini ty (bg(c)) IL-2 receptor. Cytokine-induced growth factor up-regulation was confirmed at the protein level using Western blotting of mesothelial cell l ysates for HB-EGF and culture supernatant enzyme-linked immunosorbent assay for VEGF. The production of these growth factors by human mesothelial cell s may play a significant role in post-operative peritoneal tumour recurrenc e. Their common heparin-binding property offers a potential therapeutic tar get for manipulating the growth factor environment of the human peritoneum. (C) 2000 Cancer Research Campaign.