Inflammation

Virtually 100 of prostate specimens contain histological and immunological evidence of chronic inflammation.10 Inflammation is a physiological response to a variety of stimuli such as infection, tissue injury, growth factors, or chemokines.2'11 The distribution, location and histology of leukocytes determine the type of inflammation.12 Persistent immune activation resulting in chronic inflammation often has pathological consequences. Acute chronic inflammation is characterized by distinct...

Radiation Therapy With or Without Androgen Ablation Therapy

As discussed in the previous section, several retrospective and prospective dose escalation trials have suggested that the use of higher radiation doses, particularly in intermediate risk groups (clinical stage T2B or Gleason score 7, PSA 10-20 ng ml) of prostate cancer patients, may lead to improvements in biochemical control and DFS. However, the optimum radiation dose has yet to be determined, and in especially high-risk patients, RT dose escalation alone may not be adequate. In addition,...

DNMT Inhibitors

DNMT inhibitors act mainly by inhibiting methylation however, other mechanisms are involved. After phosphorylation, these compounds incorporate into DNA or RNA.41 After incorporating into DNA, they covalently bind DNMT resulting in its inhibition42-44 without causing DNA demethylation per se.44 Additionally, their incorporation into DNA causes structural instability resulting in DNA damage.45 Currently, five DNMT inhibitors have been used in preclinical clinical trials, namely 5-azacytidine...

Risk Factors

Over 80 of prostate tumors in the US are diagnosed among men over age 65,8 and the incidence of prostate cancer increases exponentially Garbados Trinidad and Tobago 8 a ha mas Cuba Venezuela Costa Rica Argentina Colombia Switzerland Sweden Denmark Belgium Portugal Finland Estonia Netherlands Croatia Czech Republic Austria UK, England,and Wales France Germany Lithuania Spain Slovakia Italy Poland Belarus Russia Israel Japan Philippines Korea, South Source http www-depdb.iarc.fr who menu.htm *...

Hormone Therapy and Brachytherapy

No randomized trial has been completed analyzing the role of hormone suppression in patients treated with brachytherapy, i.e. the placement of radioactive seeds within the prostate. A retrospective matched-pair analysis failed to identify an improvement in survival for low risk patients treated with hormone therapy and brachytherapy vs. brachytherapy alone. Stratification by Gleason score and pretreatment PSA also failed to reveal a subpopulation that benefited from hormonal therapy.40 In a...

Vitamin E Absorption and Transport

Major dietary sources of vitamin E include vegetable oils, margarine, nuts, seeds, whole grains, soybeans, eggs, and avocados. The recommended dietary allowance of vitamin E is 15 mg day (15 mg 22.5 IU),12 however, common doses range from 100 to 800IU day with no significant adverse side effects, and have not been associated with mutagenic or teratogenic properties.13 Vitamin E is absorbed in the intestine and circulates through the lymphatic system. It is absorbed together with lipids, packed...

Incidence

There is considerable variation in reported incidence rates of prostate cancer worldwide.5'6 Age-adjusted prostate cancer incidence rates among African-Americans are the highest in the world (185.4 per 100,000 person-years), and rates among Caucasian-Americans are second (107.8 per 100,000 person-years) (Fig. 1). Reported rates in the Caribbean and in Brazil, where there are large populations of African descent (92-96 per 100,000 person-years), are comparable to the high rates among...

Summary

In summary, there is considerable evidence that NED represents an integral and potentially important part of prostate carcinogenesis. The propensity of prostate carcinoma cells to undergo NED under a variety of conditions including androgen withdrawal suggest that it is an innate property of prostate epithelial cells to survive and to overcome adverse conditions. Although the cellular signals involved in this trans-differentiation process vary with different inducing conditions, the...

Future Therapies for HRPC

Despite the valuable palliative role of current chemotherapeutic regimens for HRPC patients, improvement in the survival rates of these patients will require novel approaches. Efforts to develop new, more selective, and potentially less toxic, molecularly targeted agents have benefited from recent experimental advances identifying genetic and cellular aberrations implicated in prostate cancer cell survival and progression against which these agents can be directed. Signal transduction pathways...

Risk of DHT Formation

Men castrated at a young age and patients with male hypogonadism seldom experience prostate cancer. Ethnic differences in the incidence of clinical prostate cancer are evident, although differences in the incidence of latent cancer among the races are small. Therefore, the activity of 5a-reductase in the formation of DHT may be an etiological and or progressive factor in clinical cancer.42 The levels of total and free testosterone in African-Americans were 19 and 21 higher than those in whites...

Mechanism of Antitumor Action in Prostate Cancer by Vitamin D

A key feature of cancer cells is their increased rate of growth relative to normal cells, and this can be attributed to increased cell proliferation, decreased cell death, or a combination of the two. 1,25-VD has been demonstrated to regulate cellular differentiation and proliferation in a number of normal and malignant cells, including prostate cancer cells, however the response to 1,25-VD in cancer cells appears to be cell type-specific. The majority of the 1,25-VD-mediated signals function...

Microarray Studies of Gene Expression in Prostate Carcinoma

Microarray analysis has been used in several published studies designed to profile gene expression alterations in prostate carcinoma (Table 1). Importantly, although all of these experiments used microarrays, there are important differences that preclude a simple comparison of the reported results. These include the use of different patient samples, microarrays with different genes represented and variations in experimental and analytical approaches. Magee et al. used oligonucleotide arrays to...

Estrogen Effect on Initiation Growth and Progression of Prostate Cancer

While androgens play essential roles in the development and growth of prostate and pathogenesis of prostate cancer, extensive in vivo and in vitro studies suggested that estrogens are required for carcinogenesis of prostate cancer. It was demonstrated that treatment with both estrogen and testosterone will induce 100 dorsolaterol prostate carcinoma in rats.77 In human, direct estrogen effects and the balance of androgens and estrogens may contribute to these estrogen activities. Men synthesize...

Estrogen Imprinting Effect on the Development of Prostate

Although estrogen levels are low or undetectable in adult male mice, administration of exogenous estrogens during development48 dramatically affects prostate growth and function.49-54 The effects of estrogens vary according to timing and duration of exposure, in addition to the type and dose of estrogen administered. Furthermore, the individual lobes of the prostate exhibit varied degrees of response to estrogens and androgens. The neonatal period after birth is very fundamental for the rodent...

ARKO Human Prostate Cancer CWR22R Cells

The advantage of using gene targeting in human somatic cells is that it provides a tool to study the roles of the signaling of interest in human cells instead of ARKO animal model. For this purpose, we attempted to disrupt AR signaling in human androgen-refractory prostate cancer cells in order ARKO-TRAMP 2 2 small tumor at 28th week ARKO-TRAMP 2 2 small tumor at 28th week Fig. 2. Model for development of inducible ARKO-TRAMP mice. to investigate the biological importance of AR signaling in...

Conclusion

The safety and efficacy of gene therapy for prostate cancer has been demonstrated through various preclinical and clinical trials. In recent years, interest in this field has expanded and will continue to do so. It is conceivable that, in the near future, a safe gene therapy modality will be developed to replace hormone ablation therapy which causes unpleasant side effects, decreases the quality of life of the patient, and only temporarily controls the disease. Due to its convenient...

Inducible ARKO and Arko Tramp Mice

The normal prostate development depends on the androgen-AR signaling. In the total ARKO model, agenesis of prostate revealed that AR plays a critical role in the embryonic development of prostate. The prostate-specific ARKO model using probasin-cre lox strategy had nearly normal prostate growth after adolescence. These two models suggested the time-specific role of AR in the development of prostate. What is the role of AR between embryonic and adolescence The time-specific role of AR in the...

Vaccines

Tumor vaccines cause induction of a cell-mediated response to antigens and are often composed of tumor-associated proteins mixed with a nonspecific antigen.2,27 Demonstrating that antigen specific T-cells are up-regulated by a particular vaccine strategy is important for immunologic therapies.27 Antigen presentation is critical for any immunization technique and its enhancement can modulate tumor immunity. Anti-tumor vaccines that activate cytotoxic lymphocytes (CTLs) and human tumor...

Tissue Specific Promoters

Recently, much effort has been made to develop tissue-specific delivery systems that eliminate the threat of harm to the patient. Several studies have demonstrated the importance of tissue-specific vectors, revealing systemic toxicity with the administration of high doses of nonspecific vectors.14'15 Essentially, viral vectors can transfer their therapeutic genes to any cell in the body, provided that it expresses the correct receptors for the virus. Through the use of prostate-specific...

Functional Mechanisms of Vitamin E in Prostate Cancer

Currently, a new clinical trial, SELECT,20,21 has been initiated in the US, and an earlier epidemiological study also indicated that daily supplements of Vitamin E could reduce the incidence and mortality of prostate cancer.2 However, the functional mechanisms remain largely unclear. We summarize the functional mechanisms of vitamin E as follows. Vitamin E and Its Analogs Induce Proapoptotic Properties in Prostate Cancer Cells a-Vitamin E (a-tocopherol) has been shown by researchers to have...

Monoclonal Antibody Therapy

Antigenic modulation in the treatment of many diverse cancers has been used for a number of years. In fact, the Food and Drug Administration has approved several monoclonal antibodies for treatment of various cancers and non-malignant diseases.47 Ideally, by treating tumor cells with an antibody, one would hope for complete destruction of the tumor without recurrences. However, tumors seem to regenerate once the antibody treatment has ceased.2 Passive administration of antibodies or active...

Proteomic Approaches for Assessing Gene Expression in Prostate Carcinoma

Isotope Coded Affinity Tag

While important information has been gained through the profiling of transcripts, it is important to keep in mind that the end-point for gene expression is the protein, as proteins represent the actual scaffolds, molecular engines and communication mechanisms utilized by cells. In addition, the development of most biomedical interventions center on protein endpoints. Large-scale efforts are underway to analyze the proteome the total protein complement of the genome.32 However, the proteome...

Gene Therapy Strategy

The ultimate goals of research in this area are to develop treatment modalities that increase survival, enhance quality of life, and cure men afflicted with prostate cancer. In order to do so, four factors must be considered when developing strategies. These include the selection of the disease to be targeted, the genetic material to transfer, the method of delivery, and the route of administration. The safety and efficacy of the trial underlie each of these factors. The discussion begins with...

Histological Changes in Prostates of aERKO and Perko Mice

To understand the roles of estrogen, ERa and ERp in the development of prostate glands, the gene knockout strategy has been used. The adult male aERKO mouse prostate shows normal development and histology, specifically in the ventral prostate (VP)42'43 and anterior prostate (AP).44 With aging, the weights of aERKO seminal vehicle (SV) and AP increased,45 although they remain histologically indistinguishable from that of WT littermates.42,44 The initial description of targeted disruption of the...

Distribution of ERa and ERP in Prostate Tissues Cancer Specimens and Cancer Cell Lines

Estrogen has been used for the treatment of prostate cancer since the early 1940s.3 It is generally believed this action is indirectly mediated at the hypothalamic level to suppress the circulating androgens.4 However, in the early 1960s, a direct action of estrogen via their own receptors in the prostate was proposed by Mangan et al.5 Recently, the evidences that ER expressed in normal prostate, benign prostatic hyperplasia (BPH), prostate cancer specimens, and different prostate cancer cell...

Intracellular Signaling Molecules

Pten Immunostaining

A number of transgenic mouse lines have been produced in which a single gene encoding an intracellular signaling molecule is overexpressed or disrupted in the prostate epithelium. The design to increase expression concerns genes that are known to be overexpressed in human prostate cancer. Similarly, the targets of inactivation are those genes each of whose function is diminished or abolished in human prostate cancer. While the first approach is straightforward transgenic development, the latter...

Androgen Independent PSA Secretion

Secretion Androgene

Androgens are well documented as key factors regulating PSA gene expression.65 Since PCa cells initially depend on androgens for proliferation, androgen ablation therapy is the mainstay of treatment for advanced PCa, and leads to a drop in circulating PSA. Unfortunately, cancer cells eventually escape from the steroid requirement and progress to androgen independence, which is indicated by the rebound of PSA levels in circulation.66 The ability to treat these patients is limited. Interestingly,...

ARKO Mice with AR97Q and AR24Q Transgene Expression

Despite the substantial public health impact of prostate cancer, little is known about its etiology. The generally accepted risk factors for the development of prostate cancer are advanced age, familial predisposition and perhaps ethnicity. The exon 1 of the AR contains several polymorphic repeats the most variable is a polymorphic CAG repeat, which encodes a polyglutamine (poly-Q) chain. The range of CAG repeat lengths is from 14 to 35 repeats in man and may vary somewhat with ethnicity and...

Editor Chawnshang Chang

Chawnshang Chang was born and raised in Taiwan. In 1997 he became the George Hoyt Whipple Distinguished Professor at the University of Rochester in Rochester, New York. He received his B.S. from the National Taiwan University and Ph.D. from the University of Chicago in 1985. In 1990, at the University of Wisconsin-Madison he began his independent research career and was promoted to full professor in 1996. Dr. Chang has published more than 250 peer-reviewed articles related to AR and TR2 TR4...

Prostate Development and Carcinogenesis in Prostate Specific ARKO Mice

The cre-lox ARKO mouse model provides a much-needed in vivo animal model system to study androgen functions in the selective androgen target tissues in male mice. In this regard, it is of paramount importance to derive a cre recombinant transgenic animal system with robust expression of a biologically active Cre protein in a prostate epithelial cell-specific manner. We selected a rat probasin PB promoter to drive expression of the Cre gene.13 The AR gene was gradually deleted during the...

List Of Contributors And Affiliations

Bo-Ying Bao, Departments of Pathology amp Laboratory Medicine and Urology, University of Rochester Medical Center, Rochester, New York Elie A. Benaim, Department of Urology, UT Southwestern Medical Center, Dallas, TX Ralph A. Brasacchio, Department of Radiation Oncology and JP Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York Chawnshang Chang, George H. Whipple Lab for Cancer Research, Departments of Urology, Pathology, Radiation Oncology, and the Cancer Center,...