Conversion from a paracrine to an autocrine mechanism of androgen-stimulated growth during malignant transformation of prostatic epithelial cells

Normal adult prostate epithelium of both human and rat origin was transplan ted with Matrigel into intact or androgen-ablated (i.e., castrated) nude mi ce, Within these transplants, an influx of mouse mesenchymal cells was one of the earliest events to occur resulting in the development of a collar of smooth muscle cells and fibroblasts surrounding the transplanted epitheliu m, A subset of these surrounding stromal cells express androgen receptor (A R). The surrounded transplanted epithelium initially expresses high molecul ar weight cytokeratins characteristic of prostatic basal cells and AR. In b oth intact and androgen-ablated hosts, this epithelium subsequently develop s a patent lumen producing a rudimentary glandular acini, Only in the nonab lated hosts, however, do these rudimentary acini undergo a further prolifer ative growth phase, as determined by Ki67 immunocytochemical stainings and the development of a low molecular weight cytokeratin positive laver of lum inal (i.e., secretory epithelial cells, Because AR is expressed in both the donor epithelium and host (i.e., mouse) stromal cells, this androgen-stimu lated growth response could involve either autocrine pathways initiated wit hin donor normal adult epithelial cells themselves or paracrine pathways in itiated within the AR-expressing subset of mouse stromal cells. To resolve this issue, mice carrying the testicular feminized mutation in the X-linked AR gene mere cross-bred to AR-wt nude mite to produce BR-null nude male mi ce. None of the cells in these AR-null nude male mice express functional AR protein, Therefore, these animals can he used to prevent any possibility o f host stromal cell paracrine involvement in initiating an androgen-stimula ted growth response when normal adult or malignant prostatic epithelial cel ls are transplanted into these null hosts. In these AR-null nude male mice, the androgen-stimulated growth of normal adult prostatic epithelial cells did not occur (i,e,, androgen-induced growth response of normal prostatic e pithelial cells requires stromal cell paracrine involvement), In contrast, using. four different prostatic cancer models (i.e., human PC-82, human LNC aP) human LAPC-4, and rat R3327G), the androgen-stimulated growth of prosta tic cancer cells occurred identically in both AR-null and AR-wt nude male m ice (i.e,, a direct autocrine mechanism is responsible for androgen-stimula ted growth of malignant prostatic epithelial cells). In summary, a fundamen tal change in the mechanism for androgen-stimulated growth occurs during th e transformation from normal to malignant prostatic epithelial cells.