UC San Diego

The progression from local prostate tumor to lethal prostate cancer is not well understood. Although current treatments cure a majority of patients, a significant minority (̃12 %) of people are diagnosed with late-stage, hormone-independent disease. As yet, the origin of the hormone-independent prostate cancer cells is unknown. In the present study, the transition to the lethal form of this disease is hypothesized to occur when a genetically- compromised tumor cell undergoes (1) an immortalization or (2) a pluripotentiation step. In this work, cells from early-stage, human prostate tumors were grown in optimized culture conditions in the absence of testosterone. We then utilized the prostate tumor cells to assess the mechanisms involved in the transition from local tumor to aggressive cancer. Two separate groups of genes were used to model this transition. In one study, prostate tumor cells were retrovirally transduced to express Bmi-1 and telomerase (TERT), a combination that allows epithelial cells to bypass senescence and become an immortal cell line. In the second approach, prostate tumor cells were transduced using a four-gene, induced pluripotent stem (iPS) cell strategy that reprograms adult cells to a pluripotent embryonic stem (ES)-cell state. Cellular response to different microenvironments was assayed in vivo by subcutaneous injection, implantation under the kidney capsule with embryonic urogenital mesenchyme (a technique termed "tissue recombination"), and orthotopic engraftment into the anterior prostate of SCID/Beige mice. The results of this work demonstrate that prostate cells can be selectively cultured from local tumors. These cells express prostate stem cell characteristics and initially grow from clusters within a putative prostate tumor stem- cell niche. Bmi-1 and TERT extended cell lifespan and increased proliferation, but did not promote a malignant phenotype. Thus, immortalization of prostate tumor cells may be necessary but not sufficient to progress the disease. In contrast, the induction of pluripotency in prostate cells triggered a highly invasive phenotype. This finding suggests that the acquisition of pluripotency is a mechanism that promotes the transition from local tumor to a more aggressive cancer.