Development of Immortalized and Tumorigenic Prostate Cell Lines of Defined Genetic Constitution

摘要

To develop an understanding of the molecular events that transform normal human prostate cells into prostate cancer, we have developed a system of cell transformation that permits the creation of immortalized and tumorigenic human prostate epithelial cell lines of defined genetic constitution. Expression of SV4O Large T antigen and hTERT, the catalytic subunit of telomerase, permitted immortalization. Transformation as assessed by the ability of these cells to form colonies in an anchorage independent fashion and to form tumors in immunodeficient host animals required the additional expression of an oncogenic version of the H-Ras protein. In addition, using hTERT alone, we have simultaneously created an immortalized human prostate stromal cell line. We have recently created human prostate epithelial cells expressing genes known to be altered in human prostate cancers (Myc, Akt) as well as the androgen receptor. These cell lines produce luminal prostate cancers when placed orthotopically in mice. These cell lines provide an important foundation for future studies that will allow us to investigate the precise molecular interactions that lead to the development of prostate cancer. Ultimately, the elucidation of these critical molecular determinants of prostate cancer will permit the identification and confirmation of important targets for future therapeutic intervention.