Sugimura Y, Foster B A, Hom Y K, Lipschutz J H, Rubin J S, Finch P W, Aaronson S A, Hayashi N, Kawamura J, Cunha G R
Department of Urology, Aichi Cancer Center, Nagoya, Japan.
Int J Dev Biol. 1996 Oct;40(5):941-51.
Prostatic growth occurs through ductal elongation and branching into the mesenchyme. Ductal branching morphogenesis in the prostate is elicited by androgens via mesenchymal-epithelial interactions mediated by paracrine influences from mesenchyme. The role of keratinocyte growth factor (KGF) was investigated in the developing prostate as KGF has been suggested to be a paracrine acting factor. KGF transcripts were detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in neonatal rat ventral prostates (VPs) in vivo, in VPs cultured in vitro, and in isolated VP mesenchyme. KGF receptor was detected in VP's by RT-PCR and was localized specifically to the epithelium by in situ hybridization. KGF was investigated as a potential paracrine mediator during androgen-induced prostatic development by examining neonatal rat VPs cultured for 6 days under serum-free conditions using a basal medium supplemented only with insulin and transferrin. When testosterone (10(-9) to 10(-8) M) was added to the basal medium, VPs grew and underwent ductal branching morphogenesis similar to that in situ. Neutralization of endogenous KGF with a monoclonal antibody to KGF (anti-KGF) or a soluble KGF receptor peptide inhibited androgen-stimulated VP growth (DNA content) and reduced the number of ductal end buds after 6 days of culture. When KGF (50 or 100 ng/ml) was added to the basal medium in the absence of testosterone, VP growth and ductal branching morphogenesis were stimulated. The number of ductal end buds was about 70% of that obtained with an optimal dose of testosterone (10(-8)M), and DNA content of VP's cultured with 100 ng/ml KGF was equivalent to that of glands cultured with testosterone. The stimulatory effect of KGF was partially blocked by cyproterone acetate, a steroidal anti-androgen. These data imply that KGF plays an important role as a mesenchymal paracrine mediator of androgen-induced epithelial growth and ductal branching morphogenesis in the rat VP.
前列腺的生长通过导管伸长并分支进入间充质来实现。前列腺中的导管分支形态发生是由雄激素通过间充质-上皮相互作用引发的，这种相互作用由间充质的旁分泌影响介导。由于角质形成细胞生长因子（KGF）被认为是一种旁分泌作用因子，因此对其在发育中的前列腺中的作用进行了研究。通过逆转录聚合酶链反应（RT-PCR）在新生大鼠腹侧前列腺（VP）的体内、体外培养的VP以及分离的VP间充质中检测到了KGF转录本。通过RT-PCR在VP中检测到KGF受体，并通过原位杂交将其特异性定位到上皮细胞。通过使用仅添加胰岛素和转铁蛋白的基础培养基，在无血清条件下培养新生大鼠VP 6天，研究KGF作为雄激素诱导前列腺发育过程中潜在旁分泌介质的作用。当向基础培养基中添加睾酮（10^(-9)至10^(-8) M）时，VP生长并经历了与原位相似的导管分支形态发生。用抗KGF单克隆抗体或可溶性KGF受体肽中和内源性KGF可抑制雄激素刺激的VP生长（DNA含量），并减少培养6天后导管末端芽的数量。当在无睾酮的情况下向基础培养基中添加KGF（50或100 ng/ml）时，VP生长和导管分支形态发生受到刺激。导管末端芽的数量约为最佳剂量睾酮（10^(-8)M）时的70%，用100 ng/ml KGF培养的VP的DNA含量与用睾酮培养的腺体相当。KGF的刺激作用被甾体抗雄激素醋酸环丙孕酮部分阻断。这些数据表明，KGF作为间充质旁分泌介质在雄激素诱导的大鼠VP上皮生长和导管分支形态发生中起重要作用。
