Genetic susceptibility to prostate cancer

Prostate cancer is the most frequent malignant tumor among men over 50 years old. Its incidence varies according to countries and ethnic group. Known risk factors are race and positive family history of the disease. Familial aggregation (at least 2 cases in the family) is observed in about 20% of cases and an hereditary form of prostate cancer in 5%. This proportion increases with younger age at diagnosis. Six putative loci are already identified but undoubtedly, others will be found in forthcoming studies. The genetic heterogeneity observed in hereditary prostate cancer reflects variety of origins of the studied families. In some families, aggregation of prostate cancer and other cancers suggests the involvement of common predisposing genes. In other familial and in sporadic cases, the genetic component should be polygenic: prostate cancer wouldn't result to segregation of a major gene mutations transmitted according to a monogenic inheritance, but rather to sharing of alleles at many loci, each contributing to a small increase in cancer risk. Indeed, several genetic polymorphism were associated with an increased risk of developing prostate cancer and could explain the variations of prostate cancer incidence observed between populations.     

Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer

Disulfiram in conjunction with copper has been shown to be a potent anticancer agent. However, disulfiram’s therapeutic potential in prostate cancer is hindered by off-target effects due to its reactive and nucleophilic thiol-containing component, diethyldithiocarbamate (DTC). To minimize undesirable reactivity, we have strategically blocked the thiol moiety in DTC with a cleavable p-aminobenzyl (pAB) group linked to peptide substrates recognized by prostate specific antigen (PSA). Here we report the synthesis and evaluation in cancer cell models of two PSA-activatable prodrugs: HPD (Ac-HSSKLQL-pAB-DTC and RPD (RSSYYSL-pAB-DTC). In vitro exposure to PSA was found to trigger activation of HPD and RPD to release diethyldithiocarbamate, and both prodrugs were found to induce toxicity in prostate cancer cells, with HPD showing the most promising selectivity. With copper supplementation, the IC₅₀ of HPD was 1.4 µM in PSA-expressing LNCaP cells, and 11 µM in PC3 cells that do not express PSA. These studies demonstrate the utility of using peptide recognition handles to direct the activity of dithiocarbamate prodrugs for selective cytotoxicity of cancer cells.     

Transition to androgen-independence in prostate cancer

Prostate carcinoma is the most frequently diagnosed malignancy and the second leading cause of death as a result of cancer in men in the western countries. Withdrawal of androgens or the peripheral blockage of androgen action remain the critical therapeutic options for the treatment of advanced prostate cancer. However, after initial regression, most of the prostate cancers become androgen-independent and progress further, with eventual fatal outcome. Understanding the mechanisms of transition to androgen independence and tumor progression in prostate cancer is critical to finding new ways to treat aged patients that are ineligible for conventional chemotherapy. A large number of different molecular mechanisms might be responsible for the transition to androgen-independence. Many of these involve the androgen receptor (AR) and its signalling pathways, but they might also include genetic changes that affect several genes, which results in the activation of oncogenes or the inactivation of tumor suppressor genes. Here, we discuss the most recent and relevant findings on androgen resistance in prostate cancer in order provide a comprehensive interpretation of the clinical behaviour of tumors at molecular levels.     

Differential response to zinc-induced apoptosis in benign prostate hyperplasia and prostate cancer cells

Zinc concentrations in the prostate are uniquely high but are dramatically decreased with prostate cancer. Studies have suggested that increasing zinc in the prostate may be a potential therapeutic strategy. The goal of this study was to evaluate the antiproliferative effects of zinc in prostate cancer cells (PC-3) and noncancerous benign prostate hyperplasia (BPH) cells (BPH-1) and to define possible mechanisms. PC-3 and BPH-1 cells were treated with zinc (0–250 μM) for 24 and 48 h, and cell growth and viability were examined. Apoptosis was assessed by phosphatidylserine externalization, caspase activation and protein expression of B-cell CLL/lymphoma 2 (Bcl-2)-associated X protein (BAX):Bcl-2. BPH-1 cells were more sensitive to the antiproliferative effects of zinc compared to PC-3. The response to zinc in PC-3 and BPH-1 cells differed as evidenced by opposing effects on Bcl-2:BAX expression. Additionally, different effects on the nuclear expression and activity of the p65 subunit of nuclear factor kappa B were observed in response to zinc between the two cell types. The differential response to zinc in PC-3 and BPH-1 cells suggests that zinc may serve an important role in regulating cell growth and apoptosis in prostate cancer and hyperplasia cells.     

Carbohydrate structure and differential binding of prostate specific antigen to Maackia amurensis lectin between prostate cancer and benign prostate hypertrophy

Serum prostate-specific antigen (PSA) assay is widely used for detection of prostate cancer. Because PSA is also synthesized from normal prostate, false positive diagnosis cannot be avoided by the conventional serum PSA test. To apply the cancer-associated carbohydrate alteration to the improvement of PSA assay, we first elucidated the structures of PSA purified from human seminal fluid. The predominant core structure of N-glycans of seminal fluid PSA was a complex type biantennary oligosaccharide and was consistent with the structure reported previously. However, we found the sialic acid alpha2-3 galactose linkage as an additional terminal carbohydrate structure on seminal fluid PSA. We then analyzed the carbohydrate moiety of serum PSA from the patients with prostate cancer and benign prostate hypertrophy using lectin affinity chromatography. Lectin binding was assessed by lectin affinity column chromatography followed by determining the amount of total and free PSA. Concanavalin A, Lens culinaris, Aleuria aurantia, Sambucus nigra, and Maackia amurensis lectins were tested for their binding to the carbohydrates on PSA. Among the lectins examined, the M. amurensis agglutinin-bound fraction of free serum PSA is increased in prostate cancer patients compared to benign prostate hypertrophy patients. The binding of PSA to M. amurensis agglutinin, which recognizes alpha2,3-linked sialic acid, was also confirmed by surface plasmon resonance analysis. These results suggest that the differential binding of free serum PSA to M. amurensis agglutinin lectin between prostate cancer and benign prostate hypertrophy could be a potential measure for diagnosis of prostate cancer.     

Markers of prostate region-specific epithelial identity define anatomical locations in the mouse prostate that are molecularly similar to human prostate cancers

Although the basic functions of the prostate gland are conserved among mammals, its morphology varies greatly among species. Comparative studies between mouse and human are important because mice are widely used to study prostate cancer, a disease that occurs in a region-restricted manner within the human prostate. An informatics-based approach was used to identify prostate-specific human genes as candidate markers of region-specific identity that might distinguish prostatic ducts prone to prostate cancer from ducts that rarely give rise to cancer. Subsequent analysis of normal and cancerous human prostates demonstrated that the genes microseminoprotein-beta (MSMB) and transglutaminase 4 (TGM4) were expressed in distinct groups of ducts in the normal human prostate, and only MSMB was detected in areas of prostate cancer. The mouse orthologs of MSMB and TGM4 were then used for expression studies in mice along with the mouse ventrally expressed gene spermine binding protein (SBP). All three genes were informative markers of region-specific epithelial identity with distinct expression patterns that collectively accounted for all ducts in the mouse prostate. Together with the human data, this suggested that MSMB expression defines an anatomical domain in the mouse prostate that is molecularly most similar to human prostate cancers. Computer-assisted serial section reconstruction was used to visualize the complete expression domains for MSMB, SBP, and TGM4 in the mouse prostate. This showed that MSMB is expressed in prostatic ducts that comprise 21% of the mouse dorso-lateral prostate. Finally, the expression of MSMB, SBP, and TGM4 was evaluated in a mouse prostate cancer model created by the prostate epithelium-specific deletion of the tumor suppressor PTEN. MSMB and TGM4 were rapidly and dramatically down-regulated in response to PTEN deletion suggesting that this model of prostate cancer includes a more rapid de-differentiation of the prostatic epithelium than is observed in organ-confined human prostate cancers.     

Combining biomarkers to detect disease with application to prostate cancer

In early detection of disease, combinations of biomarkers promise improved discrimination over diagnostic tests based on single markers. An example of this is in prostate cancer screening, where additional markers have been sought to improve the specificity of the conventional Prostate-Specific Antigen (PSA) test. A marker of particular interest is the percent free PSA. Studies evaluating the benefits of percent free PSA reflect the need for a methodological approach that is statistically valid and useful in the clinical setting. This article presents methods that address this need. We focus on and-or combinations of biomarker results that we call logic rules and present novel definitions for the ROC curve and the area under the curve (AUC) that are applicable to this class of combination tests. Our estimates of the ROC and AUC are amenable to statistical inference including comparisons of tests and regression analysis. The methods are applied to data on free and total PSA levels among prostate cancer cases and matched controls enrolled in the Physicians' Health Study.     

Relationship of urinary isoprostanes to prostate cancer occurence

To estimate the oxidative stress in patients with prostate cancer and in a control group, we used the biomarker of lipid peroxidation?Cisoprostanes (8-isoPGF₂) and the level of selected antioxidants (glucose and uric acid [UA]). The level of urinary isoprostanes was determined in patients and controls using an immunoassay kit according to the manufacturer??s instruction. The levels of UA and glucose were also determined in serum by the use of UA Assay Kit and Glucose Assay Kit. We observed a statistically increased the level of isoprostanes in urine of patients with prostate cancer in compared with a control group. The concentration of tested antioxidants in blood from patients with prostate cancer was also higher than in healthy subjects. Moreover, our experiments indicate that the correlation between the increased amount of UA and the lipid peroxidation exists in prostate cancer patients (in all tested groups). Prostate cancer risk by urinary isoprostanes level was analyzed, and a positive association was found (relative risk for highest vs. lowest quartile of urinary isoprostanes?=?1.6; 95?% confidence interval 1.2?C2.4; p for trend?=?0.03). We suggest that reactive oxygen species induce peroxidation of unsaturated fatty acid in patients with prostate cancer, and the level of isoprostanes may be used as a non-invasive marker for determination of oxidative stress. We also propose that UA may enhance the oxidative stress in patients with prostate cancer.     

Dynamic process of prostate cancer metastasis to bone

Prostate cancer metastasis to the bone occurs at high frequency in patients with advanced disease, causing significant morbidity and mortality. Over a century ago, the "seed and soil" theory was proposed to explain organ-specific patterns of metastases. Today, this theory continues to be relevant as we continue to discover factors involved in the attraction and subsequent growth of prostate cancer cells to the bone. These include the accumulation of genetic changes within cancer cells, the preferential binding of cancer cells to bone marrow endothelial cells, and the release of cancer cell chemoattractants from bone elements. A key mediator throughout this metastatic process is the integrin family of proteins. Alterations in integrin expression and function promote dissociation of cancer cells from the primary tumor mass and migration into the blood stream. Once in circulation, integrins facilitate cancer cell survival through interactions between other cancer cells, platelets, and endothelial cells of the target bone. Furthermore, dynamic changes in integrins and in integrin-associated signal transduction aid in the extravasation of cancer cells into the bone and in expansion to a clinically relevant metastasis. Thus, we will review the critical roles of integrins in the process of prostate cancer bone metastasis, from the escape of cancer cells from the primary tumor, to their survival in the harsh "third microenvironment" of the circulation, and ultimately to their attachment and growth at distant bone sites.     

Applying radiobiological plan ranking methodology to VMAT prostate SBRT

The impact of a rectal spacer and an increased near maximum target dose in VMAT prostate SBRT is studied.For a group of 11 patients (35 Gy-in-five-fractions VMAT prostate SBRT) a set of 4 plans were generated, namely two VMAT plans, with D2% ⩽ 37.5 Gy (Hom) and with D2% ⩽ 40.2 Gy (Het), were created for each of two CT scans taken before (NoSpc) and after (Spc) transperineal spacer insertion. Consequently the methodology for parameter invariant TCP (tumor control probability) plan ranking was applied for comparison of the plans in terms of tumor control. NTCPs (normal tissue complication probabilities) were calculated for rectum and bladder using Lyman’s model.For all 11 patients the TCP plan ranking has shown that the Het plans would perform considerably better in TCP terms than the Hom ones. The plans without rectal spacer were ranked worse compared to those with rectal spacer except for one set of Hom plans. The calculated NTCPs for rectum produced by the Het plans were quite similar to the NTCPs of the Hom ones. The rectal NTCPs of the Hom Spc plans were always lower than the NTCPs of the Hom NoSpc plans. The NTCP values for bladder were extremely low in all cases.The use of rectal spacer leads in general to lower risk of rectal complications, as expected, and even to better tumor control. Plans with increased near maximum target dose (D2% ⩽ 40.2 Gy) are expected to perform much better in terms of tumor control than those with D2% ⩽ 37.5 Gy.     

LNCaP prostate cancer cells are insensitive to zinc-induced senescence

Prostate cancer is an age-related disease that is linked to the inability of prostate cells to accumulate zinc following transformation. It is shown in the present study that the basal percentage of normal prostate cells expressing senescence-associated beta-galactosidase (SA-beta-gal) is higher than that of the cancer cells. In the presence of high zinc in the cell culture medium, the percentage of normal prostate cells expressing the SA-beta-gal increased but not that of the cancer cells. Increased intracellular zinc occurs in the prostate cancer cells treated with supraphysiologic concentration of zinc but it does not induce senescence or decrease the telomerase activities in these cells. Senescence, however, occurred when the prostate cancer cells DNA is damaged by irradiation. These findings suggest that prostate cancer cells are insensitive to the senescence-inducing effects of zinc but the cancer cells retain the capacity to undergo senescence through other pathways.     

Biomarkers of prostate cancer sensitivity to the Sendai virus

Metastatic prostate cancer is often associated with either primary or intractable castration-resistant prostate cancer (CRPC), thus justifying the search for entirely new ways of treatment. Oncolytic viruses are able to selectively induce the death of tumor cells without affecting normal cells. A murine Sendai virus has potential to be used as an oncolytic agent. However, tumors vary in their sensitivity to different viruses, prompting us to attempt to identify corresponding biomarkers that reflect the interaction of cancer cells and the virus. Here, we show that the sensitivity of primary prostatic adenocarcinoma cell lines to Sendai virus strain (SeVM) vary substantially. Using quantitative PCR, we evaluated expression levels of genes that encode RIG-1-like and Toll-like receptors (TLRs) in cell lines and showed that the levels of mRNAs that encode TLR3 and TLR7 correlate with a degree of sensitivity of the cells to Sendai virus. The lines with lower levels of TLR3 and TLR7 expression are more sensitive to the virus.     

New approaches to the treatment of advanced prostate cancer

Several presentations by attendees of the 11th International Prostate Cancer Update addressed recent advances in prostate cancer treatment. A study that examined whether a relationship exists between neuroendocrine (NE) cell differentiation and hormone-refractory prostate cancer (HRPC) concluded that the appearance of NE cells in prostatic carcinoma is an important phenomenon in the development of HRPC. Exisuland, a selective apoptotic antineoplastic drug, was compared to placebo in a recent study and was found to significantly inhibit the increase of prostate-specific antigen in patients who had undergone radical prostatectomy. A new dosing regimen for flutamide (500 mg daily) was found to have no significant differences from the currently recommended dose (250 mg every 8 hours); the new, single daily dose could meet with greater compliance and would reduce drug cost by 30%. The antiproliferative effect of vitamin D on prostatic carcinoma cells was discussed, along with the possible role of vitamin D supplementation during prostate cancer treatment. Finally, a presentation on hospice care acknowledged that referral for such care is unfortunately at times delayed by physicians, patients, and patients' families, leaving insufficient time for all the benefits of that stage of care to be realized.     

Lycopene: modes of action to promote prostate health

Epidemiological evidence strongly suggests that lycopene consumption contributes to prostate cancer risk reduction. Preclinical studies show that lycopene acts via different mechanisms, which have the potential to cooperate in reducing the proliferation of normal and cancerous prostate epithelial cells, in reducing DNA damage, and in improving oxidative stress defense. The mechanisms include inhibition of prostatic IGF-I signaling, IL-6 expression, and androgen signaling. Moreover, lycopene improves gap-junctional communication and induces phase II drug metabolizing enzymes as well as oxidative defense genes. These findings provide plausible explanations for the epidemiological findings how lycopene can contribute to reduced prostate cancer risk. The novel finding that lycopene reduces local androgen signaling in the prostate suggests also efficacy in prevention of benign prostate hyperplasia. Intervention trials in humans are required to finally prove clinical efficacy of the lycopene molecule in prostate health.