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Environment determines the risk of both prostate and breast cancer, and this risk can vary >10-fold. In contrast, no risk exists for human seminal vesicle cancer demonstrating tissue specificity. There is also species specificity, because there is no risk for prostate cancer in any other aging mammal except the dog. A study of evolution indicates that the prostate and breast appeared at the same time 65 million years ago with the development of mammals. All male mammals have a prostate; however, the seminal vesicles are variable and are determined by the diet so that species primarily eating meat do not have seminal vesicles. The exception is the human, who has seminal vesicles and consumes meat, although this is a recent dietary change. Human lineage departed from other higher primates 8 million years ago. The closest existing primate to humans is the bonobo (pigmy chimpanzee), which does not eat meat but exists primarily on a high fruit and fresh vegetable diet. Homo sapiens evolved only about 150,000 years ago, and only in the last 10% of that time (10 to 15 thousand years ago) did humans and dogs dramatically alter their diets. This is the time when humans domesticated the dog, bred animals, grew crops, and cooked, processed, and stored meats and vegetables. All current epidemiologic evidence and suggestions for preventing prostate and breast cancer in humans indicates that we should return to the original diets under which our ancestors evolved. The recent development of the Western-type diet is associated with breast and prostate cancer throughout the world. It is believed that the exposure to and metabolism of estrogens, and the dietary intake of phytoestrogens, combined with fat intake, obesity, and burned food processing may all be related to hormonal carcinogenesis and oxidative DNA damage. An explanatory model is proposed.

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BACKGROUND: Prostate cancer has displayed an increase in incidence unparalleled by any other tumor in the last two decades, with a steady, more gradual increase in mortality rate. Current curative strategies are focused on the detection and treatment of early-stage (T1-2 N0 M0), clinically significant tumors. METHODS: To this aim, refinement of surgical approaches, with appropriate adjuvant therapies, will ensure more complete cancer control, while minimizing associated morbidity. New delivery systems for radiotherapy, as well as other energy sources, are evolving, while a number of promising pharmacological agents, including angiogenesis inhibitors and drugs which alter signal transduction pathways, are currently under investigation. Early detection is also being facilitated by a more widespread implementation of screening programs. Advances in tumor markers, and imaging and biopsy techniques, will allow more accurate preoperative staging. These, coupled with improvements in prognostic markers, aid the physician and patient alike in deciding on the suitability of treatment options with better estimation of outcome. Perhaps the most exciting developments in prostate cancer will come from knowledge of the molecular mechanisms underlying carcinogenesis. The potential for the development of diagnostic and therapeutic tools is immense. The efficacy of treatment can be studied at a molecular level, and strategies for preventing or slowing the development of malignancy can be formulated. RESULTS AND CONCLUSIONS Application of this knowledge in the form of gene and cellular therapy and in the development of novel systemic agents is beginning to enter the realm of clinical practice, and it may be in this field that means for cure and prevention of prostate cancer will eventually be found.

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Of the hundreds of species of mammals, all of which have prostate glands, only humans and dogs are known to suffer from benign prostatic hyperplasia (BPH) and prostate carcinoma. In humans, prostate carcinoma is common, yet carcinomas of other sex accessory tissues are rare. In addition, different anatomic regions within the prostate gland have very different rates of BPH and carcinoma. In this article, we explore ideas and potential mechanisms relating to these paradoxical findings that may help explain the species, organ, and zone specificity of BPH and prostate cancer. We present an evolutionary argument that attempts to relate a high-fat diet, with its potential for generating oxidative DNA damage, to the species selectivity of prostate cancer. In addition, we outline an argument based on our preliminary studies indicating that chronic inflammation and the associated increase in cell turnover in the setting of increased oxidative stress may help to account for the organ selectivity of genitourinary carcinomas.

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PURPOSE: We present a new hypothesis suggesting that the different malignant potential of benign prostatic hyperplasia (BPH) and high grade prostatic intraepithelial neoplasia may be explained by distinct alterations in stem cell-like properties. MATERIALS AND METHODS: We used our results and the recent literature to develop this hypothesis in the context of an updated prostate stem cell model. RESULTS: While high grade prostatic intraepithelial neoplasia is a likely precursor lesion to many prostatic adenocarcinomas, BPH rarely if ever progresses directly to carcinoma. Prostate epithelium contains basal and secretory compartments. Secretory cells appear to differentiate from basal cells. Thus, prostatic stem cells most likely reside in the basal compartment. In BPH there is a slight increase in epithelial proliferation, yet most replicating epithelial cells within BPH maintain their normal restriction to the basal compartment. In high grade prostatic intraepithelial neoplasia there is a marked increase in cell proliferation. In contrast to BPH, the majority of proliferating cells in high grade prostatic intraepithelial neoplasia reside in the secretory compartment. The biological significance of this topographic infidelity of proliferation in high grade prostatic intraepithelial neoplasia remains unclear but may relate mechanistically to down regulation of the cyclin dependent kinase inhibitor, p27kip1. Normal basal cells express GSTP1, an enzyme that inactivates reactive electrophiles and organic hydroperoxides, and that may protect cells from deoxyribonucleic acid damaging agents. In contrast, normal secretory cells and high grade prostatic intraepithelial neoplasia cells do not express this enzyme. CONCLUSIONS: We propose that topographic infidelity of proliferation produces a population of secretory cells replicating in the absence of key genome protective mechanisms, thus setting the stage for an accumulation of genomic alterations and instability in high grade prostatic intraepithelial neoplasia. This action occurs along with activation of telomerase, resulting in an immortal clone capable of developing into invasive carcinoma. The model predicts that genome protection remains intact in BPH, minimizing its malignant potential.

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The stem cells of rapidly renewing tissues give rise to transiently proliferating cells, which in turn give rise to postmitotic terminally differentiated cells. Although the existence of a transiently proliferating compartment has been proposed for the prostate, little molecular anatomical evidence for its presence has been obtained to date. We used down-regulation of the cyclin-dependent kinase inhibitor p27Kip1 to identify cells capable of entering the proliferative phase of the cell cycle and, therefore, competent to fulfill the role of the transiently proliferating compartment. We examined the expression of p27Kip1 in relation to its role in the development of prostatic carcinoma. Formalin-fixed paraffin-embedded specimens from matched samples of normal-appearing prostate tissue, benign prostatic hyperplasia, high-grade prostatic intraepithelial neoplasia, primary adenocarcinomas, and pelvic lymph node metastases were evaluated by comparative immunohistochemistry against p27Kip1. In normal-appearing prostate epithelium, moderate to strong nuclear staining of p27Kip1 was present in greater than 85% of the terminally differentiated secretory cells. The normal basal cell compartment, believed to contain prostatic stem cells, showed distinctive p27Kip1 expression; acini in epithelial benign prostatic hyperplasia tissue contained more p27Kip1-negative basal cells than acini from non-benign prostatic hyperplasia tissue. A third layer of cells was identified that was sandwiched between the basal cells and the luminal cells, and this layer was consistently p27Kip1 negative. This intermediate layer was accentuated in the periurethral region, as well as in prostate tissue that had been subjected to prior combined androgen blockade. We hypothesize that, on appropriate additional mitogenic stimulation, cells in this layer, and other p27Kip1-negative basal cells, are competent for rapid entry into the cell cycle. Consistent with the fact that cancer cells are capable of cell division, all cases of high-grade prostatic intraepithelial neoplasia and invasive carcinoma also showed down-regulation of p27Kip1 as compared with the surrounding normal-appearing secretory cells. In pelvic lymph node metastases, p27Kip1 expression was also reduced. In summary, our results suggest that lack of nuclear p27Kip1 protein may delineate a potential transiently proliferating subcompartment within the basal cell compartment of the human prostate. In addition, these studies support the hypothesis that reduced expression of p27Kip1 removes a block to the cell cycle in human prostate epithelial cells and that dysregulation of p27Kip1 protein levels may be a critical early event in the development of prostatic neoplasia.

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OBJECTIVES: Rates of prostate cancer in Kingston, Jamaica are extremely high (occurring in more than 300 men out of 100,000 in 1989 to 1993). This article addresses the familial aggregation of prostate cancer in Jamaica. Early evidence for familial prostate cancer was found in the Utah Mormon population. Increased risk of prostate cancer in men with a family history of prostate cancer has been consistently observed in subsequent studies. There have been few studies, however, involving black men, who are known to have an overall higher risk of developing prostate cancer. METHODS: Two hundred sixty-three patients with prostate cancer documented by histology were studied. Two hundred sixty-three age-matched control patients were used for comparison. Extensive pedigrees were obtained for both patients with cancer and controls. Data on other malignancies including lung, breast, colon, stomach, and uterine were also collected. RESULTS: The patients with cancer and the controls were comparable with respect to age and family size. Thirty patients with cancer had a first degree relative (ie, brother, father, or son) with prostate cancer compared to 15 controls. The odds ratio is 2.1 (95% confidence interval 1.1 to 4.4). Nine patients with cancer had a second degree relative (ie, grandfather, grandson, or uncle) affected compared to 3 controls. The odds ratio is 3.1 (95% confidence interval 0.8 to 17.8). There was no statistically significant difference in the rates of any of the other cancers studied. CONCLUSIONS: Familial aggregation of prostate cancer is clearly evident in black Jamaican men. A man with one first degree relative with prostate cancer is twice as likely as the general population to develop prostate cancer. In addition, there may be a statistical difference in the risk of developing prostate cancer if an individual has one second degree relative affected.

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PURPOSE: Before this study, the highest reported incidence of prostate cancer in the world was thought to be among United States black men. The age adjusted rates in 1992 for United States black and white men were 249 and 182/100,000 respectively. The epidemiology of prostate cancer in Jamaica, a country of 2.5 million people of primarily African descent, was studied and compared with that of white and black Americans. MATERIALS AND METHODS: The study included 1,121 cases of prostate cancer diagnosed from 1989 to 1994. Sources of information included the Jamaican Cancer Registry, government pathology laboratory, hospital and clinic records, and physician office records. Incidence rates were computed using data from the 1991 Jamaican census. Age adjustments were made using the 1970 United States standard population. RESULTS: The average age adjusted incidence of prostate cancer in Kingston, Jamaica was 304/100,000 men. Median patient age at diagnosis was 72 years. More than 80% of the cases were pathologically confirmed. Of the patients 30% presented with acute urinary retention, 16% presented with bone metastases, 15% had gross hematuria at the time of diagnosis and an abnormal rectal examination suspicious for cancer was noted in 42%. Prostate specific antigen was measured in only 7% of cases in 1989 but in 48% of cases by 1994. CONCLUSIONS: These data demonstrate that Jamaican men in Kingston have a high incidence of prostate cancer, much higher than even black Americans during a similar period. Furthermore, the cancers are more significant clinically with greater morbidity in Jamaica than in the United States.

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OBJECTIVES: A nuclear matrix protein (PC-1) was previously identified and reported to be present only in human prostate cancer but absent in tissue from the same prostate containing either benign prostatic hyperplasia (BPH) or normal prostate tissue. The PC-1 protein was identified by high resolution two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and exhibited a molecular mass of 56 kDa and an isoelectric point of 6.58. This work investigates the immunohistochemical characterization of PRO:4-216, a monoclonal antibody to PC-1. METHODS: Areas of the 2D-PAGE gels containing the human prostate cancer nuclear matrix proteins near PC-1 were isolated, eluted, and injected into mice to develop monoclonal antibodies. Antibodies were screened by immunofluorescence for nuclear reactivity to a human prostate cancer cell line (LnCaP) and by 1D and 2D Western blots for reactivity with prostate cancer nuclear matrix proteins. Monoclonal antibodies from the selected clones were affinity purified. The monoclonal antibody PRO:4-216 was used to analyze frozen tissue from 20 cancerous, 22 BPH, and 22 normal regions from fresh human prostate specimens. Tissue sections were analyzed for their immunohistochemical (IHC) (horseradish peroxidase) staining. RESULTS: Using a reference value for positive staining at an IHC score of greater than 50, 85% (17 of 20) of the cancerous, 5% (1 of 22) of the BPH, and 9% (2 of 22) of the normal prostate tissues stained positive. The one BPH and two normal tissues that stained positive were taken from prostates in which the adjacent cancerous tissue also demonstrated high IHC scores (greater than 225). CONCLUSIONS: These data demonstrate nuclear reactivity on fresh frozen human prostate cancer tissue for the monoclonal antibody PRO:4-216. PRO:4-216 may aid in distinguishing normal prostate and BPH from cancerous tissue.

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This review will describe the current state of knowledge of telomerase as it relates to human malignancies, focusing primarily on published measurements of this enzymes activity in benign and malignant neoplasms and their normal tissue counterparts. Key questions concerning the potential clinical utility of assaying for telomerase activity will be addressed and the implications of recent findings discussed.

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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.

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OBJECTIVES: To determine the ability to predict prostate cancer progression using shape, size, and chromatin texture nuclear grading features preselected by logistic regression analyses based on expert-selected prostate cancer cell nuclei captured using a computer-assisted image analysis system. METHODS: One hundred fifteen patients with clinically localized prostate cancer were identified at the Johns Hopkins medical institutions. The mean follow-up period was 10.4 +/- 1.7 years in 70 patients without disease progression, whereas the mean time to progression for the entire group was 3.8 +/- 2.5 years. Using 5-microns Feulgen-stained tissue sections, approximately 150 cancer cell nuclei were selected and captured for each case using a CAS-200 Image Analysis System. Thirty-eight different nuclear morphometric descriptors (NMDs) were calculated for each cell nucleus. The variance of the NMDs for each tumor was examined by univariate and multivariate logistic regression analyses and by Cox survival analyses to assess their ability to predict prostate cancer progression. RESULTS: Postoperative Gleason scoring was significantly correlated with disease progression (P < 0.00001; sensitivity, 73%; specificity, 84%; receiver operating characteristic curve area under the curve (ROC-AUC), 83%). Using backward stepwise logistic regression at a stringency of P < 0.05, the variances of 11 of the NMDs were found to be multivariately significant for progression prediction (P < 0.00001; sensitivity, 78%; specificity, 83%; ROC-AUC, 86%). A single value, termed the quantitative nuclear grade (QNG), was created from the variances of these, 11 multivariately significant NMDs using the logistic regression function. The QNG and the postoperative Gleason score were combined to create a model for the prediction of progression having a sensitivity of 89%, specificity of 84%, and ROC-AUC of 92%. These two parameters (QNG and Gleason score) clearly separated the patient sample into three statistically distinct risk groups and predicted the time to progression on the basis of Kaplan-Meier survival probability analysis. CONCLUSIONS: The QNG, combined with the postoperative Gleason score, may assist in the more accurate stratification of patients undergoing radical prostatectomy into low-, moderate-, and high-risk groups for cancer recurrence and may permit the early initiation of adjuvant therapy.

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Normal prostate epithelial cells exhibit uniformity of structure, function, and DNA content. This uniformity is dramatically perturbed in cancer with the development of variance associated with tumor cell heterogeneity. The development of this kind of diversity is paralleled in models of chaotic oscillators that produce multiple pseudosteady states. We have tested prostatic cancer cells in culture for the presence of chaos by comparing the micromotion of two related rat prostate cancer cell lines that exhibited large differences in motility and metastatic potential. In these extremes of cancer cell types, our data suggest that the three criteria which characterize a chaotic oscillation are fulfilled by their cellular micromotions: (a) absence of defined regularity in the time series as evidenced using Fourier analysis and visual inspection; (b) determinism as evidenced by attractor reconstruction; and (c) sensitive dependence on initial conditions as evidenced by a positive Lyapunov exponent. Cellular motion was studied by using an electronic cell impedance sensor which records, in real time, the fluctuations in the resistive and capacitive properties of cells cultured on recording electrodes. Our data and a preliminary screen of other cell types support a model of established cell lines in culture as chaotic oscillators.

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