Insulin-Like Growth Factor (IGF)-I Controls Prostate Fibromuscular Development: IGF-I Inhibition Prevents Both Fibromuscular and Glandular Development in Eugonadal Mice

Abstract

Although antiandrogen therapy has been shown effective in treating prostatic tumors, it is relatively ineffective in treating benign prostatic hyperplasia (BPH). In an attempt to understand better the role of androgens in the development of the normal prostate and BPH, we studied the relative effects of testosterone and IGF-I on the development of the two compartments of the prostate in castrated IGF-I((-/-)) male mice. Here we report that IGF-I stimulated the development of the fibromuscular compartment, but testosterone inhibited it (stromal epithelial ratio 2.17 vs. 0.83, respectively; P < 0.001). Testosterone also impaired IGF-I induced insulin receptor substrate-1 phosphorylation and cell division, and increased apoptosis in fibromuscular tissue. In sharp contrast IGF-I and testosterone both stimulated the development of the glandular compartment individually and together. The combined effects were either additive or synergistic on compartment size, cell division, insulin receptor substrate-1 phosphorylation, and probasin production. Together they also had a greater inhibitory effect on apoptosis in gland tissue. To determine whether IGF-I inhibition would inhibit both fibromuscular and glandular compartments, we tested the effect of IGF binding protein-1 on prostate development in two different models: castrated Ames dwarf mice and eugonadal normal male mice. IGF binding protein-1 blocked bovine GH-induced fibromuscular and glandular development in both. It also inhibited epithelial cell division and increased apoptosis in both prostate compartments in the eugonadal mice. The observed discordance between IGF-I and testosterone control of prostate compartment development might explain the relative failure of 5alpha-reductase inhibition in BPH and why testosterone inhibition might theoretically reduce gland volume but increase fibromuscular tissue. The work also provides a rationale for considering IGF-I inhibition as therapy for BPH to reduce the size of both prostate compartments.

Liver-derived IGF1 enhances the androgenic response in prostate

“…In a previous study, mice with global inactivation of the Igf1 gene displayed impaired development of the glandular prostate compartment (Ruan et al 1999). In a later study, it was shown that IGF1 can affect the development of both prostate compartments (Kleinberg et al 2007). In the present study, there were reductions in glandular size and luminal area, as well as a reduction in the FMS compartment surrounding the glandular structures in the VP and DLP lobes of LI-IGF1 K/K mice.…”

TRAF6 regulates proliferation of stromal cells in the transition and peripheral zones of benign prostatic hyperplasia via Akt/mTOR signaling

“…Studies also indicated that stroma play a pivotal role in prostatic epithelial pathogenesis . IGF‐1 stimulated the development of the fibromuscular compartment and local enforced IGF expression induced hyperplasia in prostate . The development of BPH preferentially occurs in the TZ of prostate .…”

“…17,18 IGF-1 stimulated the development of the fibromuscular compartment and local enforced IGF expression induced hyperplasia in prostate. [19][20][21] The development of BPH preferentially occurs in the TZ of prostate. 22 Interestingly, in the present study, we revealed that the expression of IGF-1 had no significant difference between TZ and PZ stroma of BPH, and our previous study showed that androgen treatment TRAF6 is an important adaptor molecule in various signaling pathway and possesses a broad spectrum of substrates.…”

Aberrant Transforming Growth Factor-β Activation Recruits Mesenchymal Stem Cells During Prostatic Hyperplasia

“…The stromal‐to‐epithelial ratio is relatively constant at 2:1 from birth to 40 years of age in normal glands increasing to 5:1 in BPH . Embryonic reawakening , , imbalance between androgen and estrogen , chronic inflammation , , stem cell defects , and epithelial‐stromal interactions , have been implicated in the pathogenesis of BPH. Investigation of the morphological analogies between the fetal prostatic stroma and the BPH stroma nodules showed a similar developmental profile: from immature mesenchyme toward fibroblastic stroma, culminating in predominantly smooth muscle .…”

“…Investigation of the morphological analogies between the fetal prostatic stroma and the BPH stroma nodules showed a similar developmental profile: from immature mesenchyme toward fibroblastic stroma, culminating in predominantly smooth muscle . Androgen/androgen receptor (AR) signaling plays an important role in BPH development by influencing the stromal cell paracrine factors that can regulate the adjacent epithelial growth and differentiation . Inversely, epithelial cells contribute to the increased stromal cell population via epithelial‐mesenchymal transition (EMT) , .…”