The effect of fibroblast growth factor 8, isoform b, on the biology of prostate carcinoma cells and their interaction with stromal cells

Fibroblast growth factor 8, isoform b (FGF8b), has been implicated in the o ncogenesis of the prostate and mammary epithelia. We examined whether overe xpression of FGF8b in a weakly tumorigenic prostate carcinoma cell line, LN CaP, could alter the growth and tumorigenic properties of these cells. LNCa P cells were infected with a lentivirus vector carrying FGF8b cDNA and the green fluorescent protein (GFP) cDNA in the same construct, and the infecte d cell population was sorted on the basis of GFP protein expression. It was demonstrated that, in comparison with the cells transduced with GFP-vector alone, LNCaP cells with FGF8b-GFP expression manifested an increased growt h rate, higher soft agar clonogenic efficiency, enhanced in vitro invasion, and increased in vivo tumorigenesis. Most strikingly, whereas parental or vector-control LNCaP cells failed to grow at all in an in vivo tumorigenesi s/diaphragm invasion assay in nude mice, the cells overexpressing FGF8b pro liferated as deposits of tumor cells on the diaphragm, frequently with indi cations of tumor cell invasion into the diaphragm. Coculturing of primary p rostatic or non-prostatic stromal cells with the infected LNCaP cells led u s to observe that: (a) stromal cells, irrespective of tissue origin, strong ly suppressed LNCaP cell growth; (b) FGF8b producing LNCaP cells could part ially evade the stromal inhibition, perhaps from the autocrine stimulatory effect of FGF8b; and (c) production of FGF8b in the coculture had a stimula tory effect on the proliferation of the stromal cells, prostatic or non-pro static. This stimulation was not attributable to the direct action of FGF8b on stromal cells. Instead, it appears that epithelial-stromal cell-cell co ntact and some unknown soluble factors secreted by LNCaP cells upon stimula tion of FGF8b are required for the maximal effect. Together, these results suggest that the growth rate and biological behavior of prostatic cancer ce lls can be altered to a more aggressive phenotype by up-regulation of FGF8b expression. These changes in phenotype also influence the interaction of t he affected cells with stromal cells. The data obtained may have direct rel evance to the progression of prostate cancer, recognizing that FGF8b is nat urally overexpressed in advanced disease.