Lopaczynski W, Hruszkewycz A M, Lieberman R
Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.
Urology. 2001 Apr;57(4 Suppl 1):194-9. doi: 10.1016/s0090-4295(00)00973-0.
The preprostatectomy setting serves as a valuable clinical model for early developmental clinical trials for evaluating promising agents for chemoprevention. In the preprostatectomy model, study agents are administered between the diagnostic biopsy for prostate cancer and definitive therapy. The prostatic tissue that is available after prostatectomy allows for biomarker evaluation of all the components of the prostate, including the glandular epithelium, blood vessels, and the stroma. This provides an opportunity to study the reciprocal interactions between the stroma and the epithelium. Morphologic studies suggest that prostatic stromal cells play a critical role in affecting the growth and maturation of prostatic epithelium. Experimental studies in tissue culture show that carcinoma-associated stromal cells can promote prostatic carcinogenesis, and normal stromal cells may be able to inhibit prostatic carcinogenesis by inducing differentiation and decreasing the proliferation of the epithelium. Although the complex molecular mechanisms through which stroma modulates the epithelial cell phenotype remain to be elucidated, there are several well-characterized signaling pathways, such as for growth factors and steroid hormones, that are likely to contribute to the modulation of transformed epithelial cells. There is evidence of an association between increased serum levels of IGF-I and an increased risk of prostate cancer. The IGF system appears to play an important role in the development of prostate cancer by modulation of paracrine pathways, and also by modulation of the concentrations of different stromal and epithelial IGFBP, which are differentially expressed in the epithelium and stroma. Nerve growth factor is capable of stimulating a proliferative response via a high affinity Trk receptor present in normal and malignant prostate epithelia, and alternatively can mediate apoptosis via the low affinity p75NTR receptor that is progressively lost from the malignant prostate. As the role of each stromal element involved in carcinogenesis becomes further defined, these elements offer promising targets for new chemopreventive strategies.
前列腺切除术前阶段是评估有前景的化学预防药物的早期临床开发临床试验的宝贵临床模型。在前列腺切除术前模型中，研究药物在前列腺癌诊断性活检和确定性治疗之间给药。前列腺切除术后获得的前列腺组织可用于对前列腺所有成分进行生物标志物评估，包括腺上皮、血管和基质。这为研究基质与上皮之间的相互作用提供了机会。形态学研究表明，前列腺基质细胞在影响前列腺上皮的生长和成熟方面起关键作用。组织培养的实验研究表明，癌相关基质细胞可促进前列腺癌发生，而正常基质细胞可能通过诱导分化和减少上皮细胞增殖来抑制前列腺癌发生。尽管基质调节上皮细胞表型的复杂分子机制仍有待阐明，但有几种特征明确的信号通路，如生长因子和类固醇激素相关的信号通路，可能有助于调节转化的上皮细胞。有证据表明血清IGF-I水平升高与前列腺癌风险增加之间存在关联。IGF系统似乎通过调节旁分泌途径以及调节上皮和基质中差异表达的不同基质和上皮IGFBP的浓度，在前列腺癌的发生发展中发挥重要作用。神经生长因子能够通过正常和恶性前列腺上皮中存在的高亲和力Trk受体刺激增殖反应，或者通过低亲和力p75NTR受体介导凋亡，而该受体在恶性前列腺中逐渐丧失。随着参与致癌作用的每个基质成分的作用得到进一步明确，这些成分成为新的化学预防策略的有前景的靶点。
