By Mary Josephine Pilat, PhD; Jeffrey M. Kamradt, MD; and Kenneth J. Pienta, MD
Prostate tumors, although initially androgen dependent, inevitably progress to an androgen-independent phenotype after treatment by androgen deprivation. The events that characterize the progression from the androgen-dependent to the androgen-independent state remain unclear. One of the central questions in the study of androgen-independent prostate cancer concerns the point at which androgen-independent cells arise. Two main theories have been proposed.
The first theory suggests that androgen independence arises as a consequence of androgen deprivation therapy. Specifically, this theory proposes that prostate cancer begins as a collection of androgen-dependent cells, and only as a result of androgen deprivation do androgen-independent cells arise.
The second theory suggests that androgen-independent cells are present at diagnosis. In this scenario, androgen deprivation creates an environment in which only the androgen-resistant cells are able to continue to grow exponentially and therefore become the dominant cell type (Figure 1). This hypothetical selective growth advantage results in a situation in which the tumor is eventually composed of only androgen-independent cells, and clinical androgen independence arises.
This second theory is supported by experimental evidence from several animal models. In a series of studies using the Dunning 3327-H adenocarcinoma model, Isaacs and Coffey57 demonstrated that selective growth of androgen-resistant cells already present at the initiation of androgen depletion is the mechanism for the development of androgen resistance. Castrated animals were inoculated with trocar pieces of H-tumor taken randomly from a hormonally responsive sample. The researchers hypothesized that if the tumor were initially composed of a heterogeneous population of cells in terms of androgen sensitivity, then random samples of this tumor would demonstrate widely varied growth rates in castrated animals. On the other hand, if the tumor were composed of only androgen-sensitive cells that through adaptation became androgen resistant, the growth rates would be similar. They found a tremendous variation in the growth rates of the implanted samples, indicating that the original tumor was initially heterogeneous in terms of only androgen sensitivity. The researchers concluded that the development of androgen resistance is a result of selective growth of the initial androgen-resistant clone and not an adaptation of androgen-sensitive cells.
Further supporting this theory of the early presence of androgen resistance was the development of the transgenic mouse prostate adenocarcinoma model (TRAMP).58 TRAMP mice spontaneously develop high-grade prostate intraepithelial neoplasia and/or well-differentiated prostate cancer by 10 to 12 weeks. By 30 to 36 weeks, all animals display primary tumors and metastatic disease.59 Sixty-five percent of mice castrated at 12 weeks of age demonstrate initial reduction of the primary tumor followed by rapid regrowth of an androgen-independent tumor. This rapid regrowth again supports the concept that the tumor is initially heterogeneous in terms of androgen sensitivity.
The mechanism by which a prostate tumor cell first becomes androgen insensitive remains undefined. This phenotype has been associated with multiple changes at the molecular level- limitations of the androgen-receptor protein, androgen-receptor gene amplification, increased expression of bcl-2, and altered p53 status (Figure 2). Several studies suggest that androgen-independent tumors contain an altered form of the androgen receptor-evolving from a gene rearrangement, point mutation, or deletion-which leads to the existence of a receptor that is active even in the absence of androgens or the presence of anti-androgens.60 There has also been evidence suggesting an amplification of the androgen-receptor gene, resulting in increased transcriptional activity of the androgen receptor.61 Furthermore, secondary signaling mechanisms are altered in hormone-refractory prostate cancer.62-66
None of these alterations has been universally demonstrated in androgen-independent tumors. Most likely it is the accumulation, as well as yet-to-be-described synergism, of multiple genetic alterations that leads to the androgen-resistant phenotype.
Advances in Oncology, Vol 14, #2, June 1998: pp 18-19
