Changes in gene expression of growth factors and their receptors during castration‐induced involution and androgen‐induced regrowth of rat prostates

Abstract

ABSTRACT:To find candidates for the mediator of the growth-promoting action of androgen in rat prostates, the changes in the steady-state levels of mRNAs coding for several growth factors and their receptors were examined by Northern blot analysis during castration-induced involution, and subsequent regrowth induced by androgen in the ventral and dorsolateral lobes. The changes in the growth factor systems and a typical secretory protein in the ventral lobe were similar to, but more prominent than, those in the dorsolateral lobe, showing the higher androgen dependency of the ventral lobe. Among the growth factors and their receptors investigated, only epidermal growth factor (EGF) showed apparent positive androgen dependency: EGF mRNA content in the ventral lobe decreased to about 30% of the normal level within 24 hr after castration, and increased, attaining about 200-300% of the normal level 3-5 days after androgen administration to castrated rats. mRNAs coding for all other factors examined, i.e., transforming growth factor-a (TGF-a), EGF receptor, basic fibroblast growth factor (bFGF), keratinocyte growth factor (KGF), FGF receptor 1, TGF-P1, TGF-P type I1 receptor, hepatocyte growth factor (HGF), and c-MET/ HGF receptor, increased after castration in greater or lesser degree, and after a brief pause or a decrease some of them increased again attaining a second peak 3-5 days after androgen replacement. The second increase was evident in TGF-a, EGF receptor, KGF, and c-MET mRNAs. These results indicate the possibility that multiple growth factor-receptor systems participate in the androgen-dependent regrowth of castrated rat prostates. 0 1996 Wiley-Liss, Inc.

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

“…Among the specific target genes that are downregulated by androgen in normal prostate tissue is the EGFR. Regulation of EGFR expression by androgens is shown to be at the transcriptional level, both in normal prostate tissue and prostate cancer (PCa) cell lines (Brass et al, 1995;Ravenna et al, 1995;Nishi et al, 1996;Itoh et al, 1998;Schwartz et al, 1998;Hammarsten et al, 2007;Pignon et al, 2009). This regulation seems to be negatively regulated in normal cells and upregulated in PCa, especially in androgen-independent PCa.…”

“…The EGFR protein binds the epidermal growth factor (EGF) and plays an important role in regulating cellular growth and function (Traish and Wotiz, 1987;St-Arnaud et al, 1988;Nishi et al, 1996;Itoh et al, 1998;Migliaccio et al, 2006;Bonaccorsi et al, 2004Bonaccorsi et al, , 2007Léotoing et al, 2007). Binding EGF to EGFR modulates cellular function by activating EGFR through autophosphorylation, which results in a downstream cascade that leads to increased cellular proliferation (Migliaccio et al, 2006).…”

“…Furthermore, medical castration by administration of luteinising hormone-releasing hormone agonist or anti-androgen treatment also increased EGFR protein expression in the prostate (St-Arnaud et al, 1988). Nishi et al (1996) investigated the changes in the steady-state levels of mRNAs coding for EGFR by northern blot analysis during castrationinduced involution, and subsequent re-growth induced by androgen in the prostate. EGFR increased after castration, suggesting that EGFR expression is downregulated by androgens (Nishi et al, 1996).…”

Vascular density is highest in the proximal region of the mouse prostate

“…The parallel changes in the epithelium and prostatic vasculature suggests that the vascular cells may be responding to changes in expression of angiogenic factors secreted by the epithelium. A number of studies have shown that expression of a variety of angiogenic factors, including VEGF, VEGF-B, placental growth factor, and FGF-2 are regulated by androgens in whole prostate or cultured prostate epithelial cells (14)(15)(16)(17)(18)(19)(20)(21). As recent studies have indicated that expression of VEGF is necessary not only for initial vascularization but also for maintenance of some normal adult capillary beds (22), decreased production of VEGF or other angiogenic factors by the prostatic epithelium or stroma may be responsible for the vascular regression observed after castration.…”

Androgens and growth factors in prostate cancer: a transgenic perspective

“…This was the ®rst polypeptide growth factor to be implicated as an andromedin, that is, a factor synthesized in the stromal compartment that indirectly mediates androgen action on prostate epithelial cells to in¯uence their differentiation and function. 26,27,30,31 Studies by Nishi et al 32 have demonstrated that levels of steady state mRNA for FGF-2, KGF and FGFR1 increased 2 ± 4-fold in the dorsolateral rat prostate following castration. Hence subtle changes following castration (ie elaboration of the FGFR1 gene not normally expressed in differentiated epithelium 33 ) may facilitate disease progression to a form that is independent of androgens and stroma.…”