FGF7/KGF triggers cell transformation and invasion on immortalised human prostatic epithelial PNT1A cells

Abstract

Fibroblast growth factor 7 (FGF7/KGF) is synthesized exclusively by fibroblasts in normal tissues; it acts as a potent mitogen on epithelial cells, through interaction with the FGF7‐specific receptor FGFR2/IIIb. To examine the importance of this growth factor both to prostate physiology and to prostate‐cancer progression, we have tested the exogenous effect of FGF7. Thus, by mimicking the paracrine pathway (on proliferation, growth in soft agar and invasion) on the human prostatic epithelial cell line PNT1A positively checked for FGFR2/IIIb expression, FGF7 significantly enhanced cell proliferation at an optimal concentration of 7.5 × 10−11 M, but no significant invasion or growth in soft agar were observed. To confirm FGF7 properties on human prostatic epithelial cells, we constitutively expressed FGF7 by transfecting PNT1A cells with FGF7‐cDNA. The FGF7‐transfected clones, PNT1A/FGF7‐T5 and PNT1A/FGF7‐T6, were stable and expressed FGF7. Analysis of the FGF7‐autocrine loop on the non‐tumorigenic epithelial cells PNT1A showed acquired invasive potential in in vitro extracellular‐matrix migration assays, specifically inhibited by an FGF7‐neutralizing antibody, and over‐expressed factors implicated in the migration process: the metalloproteinase MMP‐1 and the plasminogen activator uPA. Taken together, these results demonstrate a role for FGF7 in triggering invasion of human prostatic epithelial cells. Furthermore, these FGF7‐transfected clones exhibited functional and physiological differences from the original PNT1A cell line: anchorage‐independent growth, growth in serum‐free media and increased proliferation. These data confirm the oncogenic function of FGF7 in prostate progression potentially acting through paracrine and/or autocrine regulatory pathways. Int. J. Cancer 82:237–243, 1999. © 1999 Wiley‐Liss, Inc.

HPV16 Down-Regulates the Insulin-Like Growth Factor Binding Protein 2 to Promote Epithelial Invasion in Organotypic Cultures

“…Therefore, we next investigated whether IGFBP2 could alter these effects. We treated late-passage E6/7-HFKs with KGF in the presence or absence of IGFBP2 and showed that IGFBP2 was sufficient to inhibit KGF induction of ETS2 and MMP1, known modulators of the invasive process ( Fig 6E ) [ 40 , 41 ]. This implied a crucial role for the IGF pathway in the regulation of invasion.…”

Role and expression of FRS2 and FRS3 in prostate cancer

“…The reason for differences in this pattern is not clear but may represent cell and tumour specific differential utilisation of the FRS proteins. Despite the lack of over-expression we did observe that FRS2 and FRS3 suppression had a significant and specific inhibitory effect in cancer cell lines whereas it had no discernible effect on PNT2 benign prostate cells which are known to express FGF receptors and respond to FGF stimulation [32,33]. Wang et al have previously shown that the quantity and quality of FRS2 phosphorylation is dependent on the cellular context and type of activating FGFR [34].…”

The RNA-binding protein ESRP1 promotes human colorectal cancer progression

“…Culture media used are described in supplementary methods. Cells were treated with 10 -9 M FGF7 (Peprotech) [49], 5μM of the FGFR inhibitor, AZD4547 (Selleck Chemicals) or 1μM of the PI3K inhibitor, ZST K474 (kind gift from E. Ciraolo).…”