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New frontiers are emerging in our understanding of the biology of prostate cancer. Four topics are addressed in this article. The first topic addressed is the search for candidate genes for cancer susceptibility that are related to familial forms of prostate cancer. Second, the demonstration of a correlation between prostate cancer, shortened telomere lengths, and the appearance of telomerase activity as well as related findings regarding cellular senescence and immortalilty are presented. Third, epigenetic aspects of tumorigenesis, in particular, the recognition that cancer-related genes only function within the context of certain cell types, are discussed. This tissue specificity is dictated, in part, by the cell matrix structures that serve to hard wire the interaction of the DNA with the external environment. Fourth, concepts recently developed in the fields of complexity and chaos theory are discussed that may offer a better understanding of the fundamental changes in tumor cell morphology and heterogeneity, which are hallmarks of the cancer state. Specifically, the authors discuss the concept that dynamic attractors may dictate the three-dimensional organization of the DNA within the nucleus through interactions with the nuclear matrix. The nuclear matrix is a dynamic scaffolding structure, which temporally and spatially organizes the genome and plays a major role in determining tissue specificity. The authors believe that the new principles and concepts presented in this article will provide additional insight into prostate cancer as well as potential foci for future therapeutic interventions. Cancer 1995 ; 75 : 2027-35.

Telomeres, the repetitive non-coding DNA sequences found at the ends of all eukaryotic chromosomes, shorten with each cell division. It has been proposed that telomere shortening may be the counting element of a mitotic clock that keeps track of cell divisions; with shortening to a critical length acting as a senescence signal underlying cellular aging. The enzyme telomerase functions to maintain telomere length, thus allowing unlimited cell division, and has been associated with cellular immortalization and cancer. Stem cells have large, perhaps unlimited, replicative capacities. Since these cells are potentially immortal, we reasoned that they might posses active telomerase. We therefore assayed for telomerase activity in the stem cell enriched pools of the androgen-depleted sex accessory tissues in the castrated male rat. Following castration, the ventral prostate and seminal vesicles of the rat involute, losing approximately 90% of their cells by 21 days. These residual glands persist, and are enriched for stem cells, being capable of fully regenerating these glands if testosterone is re-introduced into the animal. We assayed telomerase activity in extracts from normal, involuted, and regenerating ventral prostate and seminal vesicles. Normal glands were found to be telomerase negative, whereas telomerase activity appeared as these glands involuted following castration. Conversely, telomerase activity disappeared during testosterone-induced regeneration of these residual glands. These results provide strong evidence for the ability of androgen to negatively-regulate telomerase activity in stem cell populations of the rat ventral prostate and seminal vesicles. and represent the first in vivo model system for the modulation of telomerase activity.