Fibroblast growth factor 7, secreted by breast fibroblasts, is an interleukin-1beta-induced paracrine growth factor for human breast cells

Abstract

Keratinocyte growth factor/fibroblast growth factor 7 (KGF/FGF7) is known to be a potent growth factor for mammary cells but its origin, cellular targets and mode of action in the breast are unclear. In this study, we carried out studies to determine the localisation of FGF7 and its receptor, and the related growth factor FGF10. We also determined the factors that regulate FGF7 release from stromal cells and the effects of FGF7 on normal and neoplastic breast cells. Using an FGF7-specific antibody which does not react with the FGF7 heparan sulphate proteoglycan (HSPG)-binding site, we showed epithelial and myoepithelial immunohistochemical staining in normal breast sections, and epithelial staining in breast carcinomas. Stromal staining was also detected in some lobular carcinomas as well as a subset of invasive ductal carcinomas. FGF10 and FGF receptor (FGFR)2 immunostaining showed a similar epithelial expression pattern, whereas no stromal staining was observed. We purified normal breast stromal, epithelial and myoepithelial cells and showed that FGF7 stimulated proliferation of both epithelial cell types, but not stromal fibroblasts. We also examined the effects of FGF7 on Matrigel-embedded organoids, containing both epithelial and myoepithelial cells, and showed FGF7 induced an increase in cellular proliferation. Furthermore, conditioned medium derived from stromal cells was shown to increase the proliferation of normal and neoplastic breast epithelial cells, which could be abolished by a neutralising antibody to FGF7. Finally, we showed that interleukin-1 , but not oestradiol or other oestrogen receptor ligands, caused a dose-related FGF7 release. Further results also indicate that the epithelial localisation of FGF7 and FGF10 in breast tissue sections is likely to be due to their binding to their cognate receptor. In summary, our findings suggest that FGF7 is a paracrine growth factor in the breast. FGF7 is produced by the breast stromal fibroblasts and has profound proliferative and morphogenic roles on both epithelial and myoepithelial cells.

The expression of oestrogen receptor (ER)-beta and its variants, but not ERalpha, in adult human mammary fibroblasts

“…6.). Consistent with previous reports (Palmieri et al 2003), treatment with IL-1 induced a significant increase in the release of FGF7 (t-test, P<0·001), indicating that these human breast fibroblasts were capable of producing FGF7. When fibroblasts in culture were treated with various physiological concentrations of oestradiol (10 10 , 10 9 , 10 8 ), there was no significant increase in release of FGF7 into the culture medium.…”

“…Fibroblast growth factor (FGF7) (also termed keratinocyte growth factor (KGF)) is also another important mesenchymal-derived epithelial growth factor that has been shown to be regulated by oestrogen; however, there are species differences in its function on epithelial cells and its regulation by oestrogen. In humans, FGF7 stimulates both normal and malignant breast cancer epithelial cell proliferation (Palmieri et al 2003). One report has indicated that the expression of FGF7 is not affected by oestrogen in normal breast stromal cells but is stimulated by oestrogen in stromal cells from breast cancers (Zhang et al 1998).…”

Available human feeder cells for the maintenance of human embryonic stem cells

“…In this process, hUECs express various factors including cell adhesion molecules, growth factors and cytokines that have critical roles in embryo proliferation, attachment and invasion (Aplin 1997, Lessey 2000, Selam et al 2002, Nardo et al 2003. Many factors that regulate the growth of cells are also expressed from not only hUECs but also hBPCs (Imagawa et al 2002, Palmieri et al 2003 and hEFs (Ellis et al 1997, Chang et al 2002. The various factors expressed in each cell type may have an important role in inducing the growth and inhibiting the differentiation of hESCs.…”

Essential role of gastric gland mucin in preventing gastric cancer in mice

“…Notably, Palmieri et al (24) demonstrated that IL-1β induces FGF7 release from breast fibroblasts, and Tu et al (25) reported that IL-1β overexpressed in mouse gastric mucosa promotes spontaneous gastric inflammation and cancer by recruiting myeloid-derived suppressor cells. In human gastric adenocarcinoma, Kai et al (26) demonstrated that tumor IL-1β expression levels are elevated more than 50 fold over those seen in normal gastric mucosa and that levels were significantly higher in nonscirrhous carcinomas compared with those in scirrhous carcinomas.…”