A human prostatic epithelial model of hormonal carcinogenesis

The effects of stromal and hormonal environment on the immortalized but non tumorigenic human prostatic epithelial cell line BPH-I were investigated in an in vivo model. BPH-I cells were recombined with rat urogenital sinus me senchyme (UGM), and the tissue recombinants were grafted to the renal capsu le of adult male athymic mouse hosts. BPH-1 + UGM recombinants formed solid branching epithelial cords with a well-defined basement membrane. The cord s canalized to form ductal structures. The mesenchymal cells formed thick s heets, of well-differentiated smooth muscle surrounding the epithelium, rei nforcing the idea that the epithelium dictates the patterning of prostatic stromal cells. When hosts carrying BPH-1 + UGM tissue recombinants were exp osed to testosterone propionate and 17-beta -estradiol (T + E2), the tissue recombinants responded by forming invasive carcinomas, demonstrating mixed , predominantly squamous as well as adenocarcinomatous (small acinar and mu cinous) differentiation. When either untreated or T + E2-treated hosts were castrated, epithelial apoptosis was observed in the grafts. When tumors we re removed and regrafted to fresh hosts they grew rapidly. Tumors were seri ally regrafted through six generations. Histologically these tumors consist ed largely of focally keratinizing squamous cell carcinoma with high-grade malignant cytological features. BPH-I eel Is grown in the absence of UGM su rvived at the graft site but did not form tumors or organized structures. T his behavior was not influenced by the presence or absence of T + E2 stimul ation. These data show that an immortalized, nontumorigenic human prostatic epithelial cell line can undergo hormonal carcinogenesis in response to T + E2 stimulation. In addition, the data demonstrate that the stromal enviro nment plays an important role in mediating hormonal carcinogenesis.