Evidence for clonal outgrowth of androgen-independent prostate cancer cells from androgen-dependent tumors through a two-step process

Prostate cancers require androgen for growth but progress to an androgen-in dependent stage under the selective pressure of androgen ablation therapy, Here we describe a novel human prostate cancer xenograft (LAPC-9) propagate d by serial passage in mate severe combined immunodeficient mice that expre sses prostate-specific antigen and wild-type androgen receptor. In response to castration, LAPC-9 cells undergo growth arrest and persist in a dormant , androgen-responsive state for at least 6 months. After prolonged periods of androgen deprivation, spontaneous androgen-independent outgrowths develo p. Thus, prostate cancers progress to androgen independence through two dis tinct stages, initially escaping dependence on androgen for survival and, s ubsequently, for growth. Through the use of serial dilution and fluctuation analysis, we provide evidence that the latter stage of androgen independen ce results from clonal expansion of androgen-independent cells that are pre sent at a frequency of about 1 per 10(5)-10(6) androgen-dependent cells, We conclude that prostate cancers contain heterogeneous mixtures of cells tha t vary in their dependence on androgen for growth and survival and that tre atment with antiandrogen therapy provides selective pressure and alters the relative frequency of these cells, thereby leading to outgrowths of androg en-independent cancers.