Differentiation (2002) 70:473–485 C Blackwell Verlag 2002 REVIEW Gerald R. Cunha ¡ Simon W . Hayward ¡ Y. Z. Wang Role of stroma in carcinogenesis of the prostate Accepted in revised form: 9 September 2002 Abstract Prostatic development is induced by andro- gens acting via mesenchymal – epithelial interactions. Androgens elicit their morphogenetic effects by acting through androgen receptors (ARs) in urogenital sinus mesenchyme (UGM), which induces prostatic epithelial development. In adulthood reciprocal homeostatic stromal – epithelial interactions maintain functional dif- ferentiation and growth-quiescence. Testosterone plus estradiol (T π E2) have been shown to induce prostatic carcinogenesis in animal models. Thus, tissue recom- binant studies were undertaken to explore the mechan- isms of prostatic carcinogenesis in BPH-1 cells in which ARs and estrogen receptors (ERs) are undetect- able. For this purpose, BPH-1 cells were combined with UGM, and the UGM π BPH-1 recombinants were grafted to adult male hosts. Solid branched epi- thelial cords and ductal structures formed in untreated UGM π BPH-1 recombinants. Growth was modest, and tumors did not develop. UGM π BPH-1 recombi- nants treated with T π E2 formed invasive carcinomas. BPH-1 cells lack ARs and ERs, whereas rat UGM expresses both of these receptors. These data show that immortalized nontumorigenic human prostatic Gerald R. Cunha ( ✉ ) Departments of Anatomy and Urology, University of California, San Francisco, CA 94143-0452, USA Fax: π1 415 502 2270 e-mail: grcunha/itsa.ucsf.edu Simon W. Hayward Department of Urologic Surgery, Vanderbilt University Medical Center, A1302, Medical Center North, 1161 21st Ave South, Nashville, TN 37232-2765, USA Y. Z. Wang BC Cancer Agency, Dept of Cancer Endocrinology, 601 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3 Canada U.S. Copyright Clearance Center Code Statement: 0301–4681/2002/709–473 $ 15.00/0 epithelial cells can undergo hormonal carcinogenesis in response to T π E2 stimulation via paracrine mech- anisms and demonstrate that the stromal environment plays an important role in mediating hormonal car- cinogenesis. During prostatic carcinogenesis the stroma undergoes progressive loss of smooth muscle with the appearance of carcinoma-associated fibroblasts (CAF). This altered stroma was tested for its ability to pro- mote carcinogenesis of nontumorigenic but immortal- ized human prostatic epithelial cells (BPH-1). CAF π BPH-1 tissue recombinants formed large carcinomas. In contrast, recombinants composed of normal pros- tatic stroma π BPH-1 cells exhibited minimal growth. This stroma-induced malignant transformation was as- sociated with additional genetic alterations and changes in gene expression. Thus, alteration in the stromal microenvironment was sufficient to promote malignant transformation of human prostatic epithelial cells. Key words mesenchymal ¡ epithelial interactions ¡ prostate ¡ prostatic carcinogenesis ¡ urogenital sinus mesenchyme ¡ human prostatic epithelial cells Introduction The prostate develops as a result of interactions be- tween epithelium and mesenchyme. This basic develop- mental mechanism is in fact employed for all organs and organ systems composed of an epithelial paren- chyma, e.g. male and female urogenital tracts, the gas- trointestinal system and the integument. For many or- gans, epithelial – mesenchymal interactions are not in- fluenced by the hormonal milieu. However, development of the prostate is dependent upon fetal testicular androgens, whose effects are mediated via androgen receptors expressed in fetal prostatic mesen-