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 transplanted with Matrigel into intact or androgen-ablated (i.e., castrated) nude mice. 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 epithelium. A subset of these surrounding stromal cells express androgen receptor ( AR). The surrounded transplanted epithelium initially expresses high molecular weight cytokeratins characteristic of prostatic basal cells and AR. In both intact and androgen-ablated hosts, this epithelium subsequently develops a patent lumen producing a rudimentary glandular acini. Only in the nonablated hosts, however, do these rudimentary acini undergo a further proliferative growth phase, as determined by Ki67 immunocytochemical stainings and the development of a low molecular weight cytokeratin positive layer of luminal (i.e., secretory) epithelial cells. Because AR is expressed in both the donor epithelium and host (i.e., mouse) stromal cells, this androgen-stimulated growth response could involve either autocrine pathways initiated within donor normal adult epithelial cells themselves or paracrine pathways initiated 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 were cross-bred to AR-wt nude mice to produce AR-null nude male mice. None of the cells in these AR-null nude male mice express functional AR protein. Therefore, these animals can be used to prevent any possibility of host stromal cell paracrine involvement in initiating an androgen-stimulated growth response when normal adult or malignant prostatic epithelial cells 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 epithelial cells requires stromal cell paracrine involvement). In contrast, using four different prostatic cancer models (i.e., human PC-82, human LNCaP, human LAPC-4, and rat R3327G), the androgen-stimulated growth of prostatic cancer cells occurred identically in both AR-null and AR-wt nude male mice (i.e., a direct autocrine mechanism is responsible for androgen-stimulated growth of malignant prostatic epithelial cells). In summary, a fundamental change in the mechanism for androgen-stimulated growth occurs during the transformation from normal to malignant prostatic epithelial cells.[1]References
- Conversion from a paracrine to an autocrine mechanism of androgen-stimulated growth during malignant transformation of prostatic epithelial cells. Gao, J., Arnold, J.T., Isaacs, J.T. Cancer Res. (2001) [Pubmed]
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