Natural and Traditional Cures for Prostatitis

The 21 Day Prostate Fix

21 Day Prostate Fix written by Radu Belasco is a healthier alternative to drugs and invasive medical procedures. Radu Belasco is an early prostate problem sufferer, with a family history of prostate pain, problems and cancer. Using a unique system of natural remedies, he fixed his prostate problems and wrote them in his smash hit eBook The 21 Day Prostate Fix. It is about miraculous herbs and fruits from all over the world. These unique foods have the power to cure your prostates inflammation in record time and shrink it to a healthier size. Also, you will learn how to concoct the miracle elixir that will not just cleanse your prostate, but also burn body fat. Aside from these, youll get topnotch information on nutrition, so you can keep your prostate healthy and your sex drive at its peak. Plus, youll learn other health conditions that might be contributing to your prostate issues, so you can also remedy them and get your body in its best shape ever.

The 21 Day Prostate Fix Overview

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Prostate cancer in the world

The mainly risk factors for PCa are (a) age (it is the strongest risk factor for PCa andthe probability of developing this disease is 1 in 12,833 for men aged birth to 39, 1 in 44 for men aged 40 to 59, and 1 in 7 for men aged 60 to 79 years), (b) family history (greater risk if father or brother had the disease and slightly higher for men whose mothers or sisters have had breast cancer ), (c) Race Ethnicity (greater risk among African American men compared with white, Asian, and American Indian men), (d) prostate changes (abnormal cells described as high-grade prostatic intraepithelial neoplasia), and (e) diet ( food with high animal fat and low in fruits and vegetables).Moreover, between 5 to 10 of the PCa cases are believed to be due primarily to high-risk inherited genetic factors or PCa susceptibility genes. Genetic testing has been a reality and it has been well documented that genetic factors might increase the risk of cancer onset 33, 34 .

The importance of the early diagnosis of the prostate cancer

The early diagnosis of PCa has been facilitated by the determination of the prostate specific antigen (PSA), rectal touch and ultrasonography, which has subsequently led to a high cure Concerning to the recurrent PCa, a key treatment decision is based on whether the disease is only localized in the prostate fossa. If the sites of cancer in the early phase of recurrent disease were known, patients would be treated properly, leading to fewer side effects, a better prognosis with curative approache, and reduced treatment cost. Nuclear medicine imaging has been considered a reliable technique to be used with this purpose and an important aspect of the nuclear imaging that should be understood is that this type of imaging demonstrates physiology rather than anatomy 4, 6, 10, 11 . Due to the limitations to use the 18F-FDG to detect PCa, other molecules to be labeled with a radionuclide, to be utilized as PET-radiopharmaceuticals, have been investigated with this purpose. Choline is a...

Concomitant prostate cancer screening in the patient preparing for an APR

Patients scheduled to undergo APR represent a patient population in which prostate cancer screening may be indicated. Most cases of rectal cancer are diagnosed after 50 years of age 17 , and are in the same age category of men at risk for prostate cancer diagnosis. However, the stage of rectal cancer should be taken into consideration when considering screening the same individual for prostate cancer Stage T1 and T2 rectal tumors treated with APR have a 90 5-year survival, while stage T3 and T4 tumors are generally treated with neoadjuvant chemotherapy and or radiation and generally have a 5-year survival of 50 and 25 , respectively 17 . Thus, prostate cancer screening in patients with advanced disease should be avoided. Terris and Wren previously described a prostate cancer-screening program for 19 consecutive men scheduled for APR for colorectal carcinoma with no history of prostate cancer 18 . Screening included serum PSA and DRE and those with suspicious findings underwent...

PostAPR prostate cancer screening and modalities for prostate biopsy

The clinical scenario of a patient with an elevated PSA and no access to the rectum precludes the urologist from performing a DRE or a TRUS biopsy of the prostate. Other approaches to the prostate to allow a biopsy include CT and MRI guided techniques, transurethral ultrasound guided perineal biopsy and TPUS-guided biopsy. 4.1. CT and MRI-guided prostate biopsy Transgluteal CT-guided prostate biopsy involves imaging the lower pelvis at 10-mm intervals and with a 10-mm slice thickness. The transgluteal approach allows sampling of both sides of the midline at the base, midgland and apical levels. When one entry site is used, the angle of the needle is projected to the contralateral side of the prostate entry sites are chosen 3-4cm off the midline to avoid paraspinal ligaments and potential post-APR fibrosis around the tip of the coccyx (Figure 1) 19 .

Screening of prostate cancer

Prostate cancer is one of the three major cancer sites in men commonly occures after 50 years of age, with incidence progressively increasing in later decades of life. Only males with positive family history of a disease (at least one blood relative father, grandfather, or brother) are at a higher risk even in age before 50 (American Cancer Society Guidelines for the Early Detection of Prostate Cancer, 2011 ESMO Guidelines Working Group, 2011). Screening protocol include digitorectal examination (DRE) and PSA (prostate-specific-antigen) measuring in serum, in patients aged > 50 years, in those who refer symptoms of prostatism and urinary tract disorders, or in those who require screening. The decision on whether or not to have a prostate biopsy (performed by transrectal ultrasound, TRUS) should take into account PSA parameters, such as free (f) PSA, fPSA PSA ratio, DRE findings, prostate size, patient age, comorbidities, patient values and history of previous biopsy (American Cancer...

Reasons for testosterone measurement in prostate cancer

Testosterone measurement in prostate cancer patients has more than 40 years history 2 . Confirmation of castrate testosterone level is necessary before identifying prostate cancer as castration resistant. Castrate states are at present defined as serum testosterone level below 20 ng dl ( 0.69 nmol l) or below 50 ng dl ( 1.73 nmol l) 3 , but it was not always this way and different testosterone measurement methods have important implications. Need for controlling quality of chemical castration treatment of prostate cancer steams from reports of up to 15 castration failures 4,5 . This means LHRH treated patients may not reach castration levels of testosterone due to different reasons 6 , not only non-compliance, application failures, but also other reasons, for example problems with depot formulation resorption due to granuloma formation on injection site 7 or may simply need more frequent dosages 8 . Further reason for testosterone measurements in prostate cancer patients lies in...

Prostate cancer incidence will increase in future

Prostate cancer is already most frequently diagnosed cancer among men in the developed world. As a cause of death among males, it is second in the USA and third in Europe. Large increase in prostate cancer incidence in recent years is not only due to availability of PSA (biochemical marker, which is useful for screening purposes) and due to better awareness of doctors and population at large, but in large part also due to changes in population pyramid and increased life expectancy. As breast cancer, which is most common in females over 60 years of age, also prostate cancer is cancer of older people. For example, in Slovenia (which may be in health related issues regarded somewhere in-between developed western and less advanced other parts of the world), incidence of prostate cancer increased 50 from 2000 to 2011 14 . At the same time, population at main risk (males above age 60) increased 28 . Therefore more than half of increase of prostate cancer incidence can not be attributed to,...

Need for hormonal treatment of prostate cancer may not decrease in future

Despite facts about prostate cancer incidence, presented in section 4 and despite undeniable proof that population based PSA prostate cancer screening reduces mortality due to prostate cancer 16 , it seems some professional bodies, like U.S. preventive services task force 17,18 recently advised against screening. Further, among young UK general practitioners, during non-formal conversation, in year 2012, one can easily hear claims like PSA - oh I thought it is NOT for screening, it is only for follow up purposes, only for patients, who have diagnosis of prostate cancer already (personal experience). With this recent trend by policy-makers, it seems hopes of urologists, who treat prostate cancer patients, that we will in the future find only very few patients, who will present with stage of disease, where nothing else but hormonal treatment would be possible or hormonal treatment will become necessary during the course of their disease, are dispelled. As it seems focus of attention is...

Castrate testosterone values in different prostate cancer studies

Serum testosterone value around 1.735 nmol l or 50 ng dl as castrate level for the purpose of hormonal treatment of prostate cancer was used already in 1970'ties 2 . Later, some LHRH formulations were designed to achieve serum testosterone below this value in 95 of treated patients. It was accepted as standard value in guidelines 50 . Guidelines have at present gone even a step further and stated testosterone levels above 50 ng dl to be in-sufficient and additional hormonal manipulation to be warranted in such patients 3 . It is further generally accepted patients with surgical castration to have lower levels of testosterone - around 15 ng dl and certainly below 30 ng dl 51 . As surgical castration provides lower testosterone levels, there were always claims one should aim as low as possible with testosterone levels and should try to reach below 20 ng dl - for example in a small study of 38 patients, treated with LHRH agonists, Oefelein found 5 did not reach values below 50 ng dl and...

Direct testosterone assays and prostate cancer The verdict

Inaccuracy of present day direct testosterone assays is already recognized in the field of female and male testosterone replacement, in pediatrics 59 and should be recognized also in the field of prostate cancer. Until indirect testosterone assays applying mass spectroscopy become widely available, publications should set realistic values of castrate levels and precisely state measurement methods used. They may be universally available in the USA, but in Europe, even western university hospitals are not quick in replacing direct immuno-as-says with gas chromatography methods - for example in Ghent they changed only recently, also for reasons like one can not publish any more anything about testosterone without this method. And even mass spectrometry methods show significant errors and inconsistencies. On the upside, direct chemiluminescent assays do measure something. They can unmask occasional testosterone outlier (skipped dose of drug, granuloma formation or an individual in need...

Natural history of prostate cancer

Although the natural history of prostate cancer (PCa) has not been fully elucidated, it is thought to arise from damaged prostate epithelium and progressively develop over many decades 27 . Prostate disease is heterogeneous and multifocal, further complicating the understanding of its progression. Based on autopsy studies, about one-third of men over the age of 50 years display histological evidence of PCa. However, a majority of these cases remain clinically insignificant, underscoring the variability in PCa and the protracted nature of this disease 3, 28 . The likelihood of disease progression of PCa is difficult to predict. Detection of cancer from a biopsy can result in a localised diagnosis however, upon a prostatectomy, it may be revealed that the disease had grown outside the margins of the gland or even had metastas-ised. Conversely, certain men diagnosed with PCa may live out their natural lives without suffering any morbidity or mortality from the disease.Therefore, it...

New therapeutics settings in the treatment of castration resistant prostate cancer

Being able to predict which patients will develop metastasis and death with rising PSA levels after treatment with androgen ablation is essential for deciding therpeutic interventions and gauging prognosis. The major biologic processes under therpeutic investigation in prostate cancer involve growth and survival, chemotherapy and hormone therapy resistance, ex-tragonadal androgen production, modulation of the androgen receptor, angiogenesis, the bone interface, immune surveillance and escape, epigenetic regulation and stem cell renewal. A better understanding of this mechanisms responsible for prostate cancer growth and metastatic spread has allowed for the development of a wide array of new therapies. The growth of prostate cancer is originally androgen dependent and metastatic tumors are generally treated with androgen ablation therapy, with or without antiandrogen supplementation 41, 42, 43 . However, resistance to hormonal therapy occurs within 12-18 months (remissions last on...

Prostate epithelium and stem cells

Human prostate is an exocrine gland that consists of basal, luminal and neuroendocrine cell types embedded in a fibro-muscular stroma. The basal cells are relatively undifferentiated, not dependent on androgens and hence express low levels of androgen receptors (ARs). Additionally, basal cells generate some secretory products such as CD44 5 , p63 6 , p27kip and c-Met 7 , cytokeratin 5 (CK 5) and CK 14 8 . In contrast to the basal layer of cells, luminal (or secretory) cells are terminally differentiated and specifically secrete the prostate like prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) into the glandular medulla in response to androgens. Because, survival of these luminal cells depend on andro-gens they express ARs on a high level whereas, their other specific secretory products are CD57 5 , CK 8 and CK 18 8 . The third type of cell in the cellular organization of the prostate epithelium is the neuroendocrine (NE) cell. The specific functions of NE cells...

Localization of stem cells within the prostate epithelium

In the 1980s, John Isaacs and colleagues performed classic androgen cycling experiments and suggested that prostate epithelium must contain a SC population. Than, when rodents are deprived of androgen by surgical or medical castration, the gland atrophies due to apop-tosis of terminally differentiated cells which are dependent on androgen for their survival 14 . However, when androgen is replaced the gland regenerates and resumes its normal functions. This involution and regeneration can be repeated for many sequential cycles. The regenerative capacity has been attributed to a population of long lived SCs within adult prostate epithelium that are thought not androgen-dependent for survival, but androgen-sensitive and androgen-responsive. Apoptosis occurs mostly in androgen-dependent lumi-nal cell epithelium, while the androgen-independent basal cells generally remain unaffected whereas, 90 of luminal epithelial cells are lost through programmed cell death 18 . Androgen treatment...

Prostate stem cell niche

In all epithelial organs, adult SCs are maintained in a tissue niche that regulates stem cell fate decisions. The niche provides structural support, as well as the biological cues that influence the SCs' decision to self-renew or divide into more differentiated progeny. Integrin and junctional proteins play a major role in regulating SC differentiation in the prostate 29 . For instance, integrin a6 shows a wider distribution amongst SC populations in the prostate tissue 28 . It was also shown that the high surface expression of a2pj integrin in human prostate epithelium correlates with colony forming ability and the potential to regenerate a fully differentiated prostate epithelium in vivo 25 . Additionally, proteins belonging to the connexin, cadherin and catenin families were reported as key molecules mediating cell-cell and cell-extracellular matrix interaction that dictate cell differentiation decisions 30 . Prostate homeostasis is maintained as a result of androgenic regulation...

Prostate cancer stem cells 41 Origin of PCSCs

Much stronger studies came from several independent laboratories that used different PC models to support the view that basal stem cells provide the cell-of-origin for PC. When CD49fhiTrop2hi cells were selected from the basal fraction, transfected with Akt Erg vectors and transplanted to induce initiation of prostatic intraepithelial neoplasia 57 these basal cells derived from primary benign human prostate tissue initiated PC in immunodeficient mice 24 . It was also reported that Lin'Sca-1+CD49fhi cells isolated from the basal fraction of murine prostate produced luminal-like disease characteristics of human PC after transplan tation 58 . Recently, Norman J. Maitland and colleagues reported that selected cells with basal phenotypes are tumor initiating and basal SCs are the source of a luminal progeny 23 . In addition, a small population of TRA-1-60+ CD151+ CD166+ tumor initiating cells (TICs) isolated from human prostate xenograft tumors exhibited stem-like cell characteristics and...

Natural Compounds Antioxidant and Antiandrogens in the Prevention of Prostate Cancer In vivo Evidences from Murine

Prostate cancer (PCa)is the most frequent malignant neoplasia in men. The number of cases has continuously increased over the past decades, partly due to the higher life expectancy. Additional factors are the high caloric diet and lack of physical exercise, typically seen in the Western countries. Notably, up to 40 of cancer incidents are preventable by consuming a healthy diet, regular physical activity, and maintenance of optimum body weight, and more than 20 by consuming vegetables and fruits. PCa represents an ideal candidate disease for chemoprevention. It is typically diagnosed in elderly men and even a modest delay in the neoplastic development could result in substantial reduction in the incidence of the clinically detectable disease.In this chapter we will review the history, the development, and the applications of some of the most common animal models of PCa,and we will discuss of the role of animal models in translational research. Prostate cancer (PCa) is the most common...

Inflammatory Microenvironment in Prostate Carcinogenesis

The association between prostate cancer and inflammation was first formally addressed in the nineteen century and since then many authors have confirmed the biological and clinical evidence of this association. However, the molecular mechanism involved is yet to be deciphered. Prostate cancer is a complex and progressive disease. Over time the cells become resistance to hormonal therapies that are designed to block the release and or the uptake of androgens. During this stage androgen receptor (AR) mutants are able to bind promiscuous steroids, and may convert AR antagonists to agonists. Other hormones and their receptors are involved in the abnormal growth of the gland. Particularly, oestrogens and oestrogen receptors defined a subclass of prostate cancer with a very aggressive clinical phenotype (such as the TMPRSS2-ERG fusion). In addition, other signaling cascades are switched on bypassing the androgen AR axis and favoring tumor progression. Among them, cyclooxygenase-2 (COX-2),...

MicroRNAs as emerging key players in the etiology and progression of prostate cancer Clinical implications

MiRNAs, as well as mRNAs, display tissue-specific expression profiles and, therefore, they may have different roles in cells from different origins. An example of this disparity is miR-125b which can have a tumor suppressor activity in ovarian and breast cancers but act as an oncomir in prostate cancer, thyroid cancer, neuroblastoma and glioblastoma 82 . The study of the global miRNA expression levels (miRNAome) has been rising in the past years and abundant miRNAome data are currently available for several cancers. The miRNA expression patterns in different types of tissues have been reported to be more predictive of tumor origin and differentiation status than mRNA profiles because, unlike mRNA expression, a modest number of miRNAs ( 200 in total) might be sufficient to classify human cancers 83 . In prostate cancer, the expression of several miRNAs and their target mRNAs are altered and involved in development, invasion and metastasis. Nevertheless, the data on miRNA expression in...

Chronic Prostatitis And Pelvic Pain

Evidence to support the herb's use in prostatitis is scarce. However, in April 2003 positive findings from a preliminary study using Permixon to treat symptoms of chronic prostatitis and chronic pelvic pain syndrome (CP CPPS) were presented at the annual meeting of the American Urological Association (Anon 2003). The RCT involving 61 patients with category IIIB CP CPPS found that 75 receiving active treatment experienced at least mild improvement in symptoms, compared with 20 of the control group. Furthermore, 55 of patients receiving Permixon reported moderate or marked improvement, compared with 16 of the control group. In contrast, results from a 2004 prospective, randomised, open-label study failed to find benefits for saw palmetto (325 mg daily) in men diagnosed with category III CP CPPS (Kaplan et al 2004). After 1 year, the mean total National Institutes of Health Chronic Prostatitis Symptom Index score decreased from 24.7 to 24.6 (P 0.41) and no benefits were seen for QOL or...

Antiproliferative Effects On Prostate Cells

The exact mechanism of action of the antiproliferative effects of nettle extract on prostate cells has not been fully elucidated (Hirano et al 1994, Hryb et al 1995, Lichius & Muth 1997, Lichius et al 1999). Results from several in vitro studies suggest that several mechanisms are responsible. Reduced prostate cell metabolism and growth may result from inhibition of membrane ATPase activity and decreased binding capacity of sex hormone binding Prostate cancer One study found that a methanolic extract of stinging nettle roots slows the progression of prostate cancer in both an in vivo model and an in vitro system (Konrad et al 2000). One study involving 20 males with prostatic adenoma found that treatment for 7 days with nettle produced a significant drop in zinc level, thought to be a result of altering zinc-testosterone metabolism and diminishing zinc secretion in adenomatous tissue (Romics & Bach 1991).

Benign Prostatic Hyperplasia

Open studies involving a total of over 1 5 000 men with BPH have found significant improvements in prostate size, night-time urination, frequency of urination, urine flow and residual urine (ESCOP 1996-97). One double-blind study over 9 weeks of nettle extract in 50 men with BPH showed a significant decrease in sex hormone binding globulin and non-significant improvements in micturition volume and maximum urinary flow (Vontobel et al 1985) however, the authors explain that the results were due to inappropriate length and dosage of therapy. In another doubleblind, placebo-controlled study, treatment of 67 men with nettle produced a 14 improvement in urine flow and a 53 decrease in residual urine (Dathe & Schmid 1987). An open study of 30 patients with BPH showed that nettle root extract over an average of 3.5 months significantly decreased residual urine volume and increased maximal urinary flow in 50 of cases (Romics 1987). Marked subjective relief was also reported. A randomised,...

Nonandrogen regulated transcription factors in prostate cancer rationale for targeting

Most targeted small molecule therapies under development interfere with the function of receptors on the cell surface or kinases located in the cytoplasm. Transcription factors have been underutilized as targets of cancer therapeutics, the exceptions being the steroid hormone receptors, such as the AR, and nuclear factor kappa B (NF- B) 8, 9 . However, it is imperative to identify novel targets for the design of molecular treatments for cancers, including AIPC. Advances in drug delivery systems and a better understanding of how transcription factors act should overcome issues with targeting this important group of proteins. Thus, we believe that effective therapeutics for AIPC can be developed by identifying and targeting key transcriptional regulators, other than the AR, that are required for prostate cancer proliferation and survival. To identify potential targets that are master transcriptional regulators, one looks for DNA binding proteins whose activity is required for cell fate...

YY1 studies in the clinical applications of prostate cancer

Many biological functions of YY1 implicate its oncogenic role in human cancers. Further corroborating these observations is the frequent overexpression of YY1 in cancer cells, including prostate tumors 123 . These oncogenic properties confer YY1 with great potential as a therapeutic target in prostate cancer treatment. YY1 antagonizes p53 function through multiple mechanisms, including facilitating Mdm2-mediated p53 ubiquitination and degradation, inhibiting p53-mediated transcription, blocking p53 acetylation, and attenuating p14ARF-mediated p53 stablization 47-49 . These suggest that p53 is a primary target of overexpressed YY1's role during prostate oncogenesis. Although p53 is most commonly deleted or mutated in prostate cancers, some tumors retain functional p53, especially at their early stages 124-126 . As a result, many tumors need to overcome p53 tumor suppression early in their cell transformation process, and it is reasonable to hypothesize that YY1 plays a role in...

The prostate cancer microenvironment

Most of human prostate tumor cells have the ability to form spheres however, the frequency of cells forming spheres is very heterogeneous across all cell lines. In this regard, the adaptation of tumor cells to non-adherent culture conditions may be a determinant in forming spheres 112 . Also, the holoclone-forming cells, which are smaller than paraclone cells, more adherent, highly clonogenic, and whose progeny forms almost exclusively growing colonies, in prostate cancer specimens with the highest clonogenic potential has been associated with stem cell phenotypes 113 . Of great importance is the fact that large holoclones were also consistently present in prostate cancer cell spheres 109, 114 , suggesting that these spheres, which are sustained by tumor initiating cells with stem cell-like features, may have a strong self-renewal and pro-angiogenic capability 115 . These spheres were capable of forming new generations of spheres and retained proliferative capacity as well as...

Treating prostate cancer

Despite recent therapeutic approaches that have significantly increased survival, most prostate aggressive tumors become resistant to current treatment protocols 8, 121 . Prostate cancers that initially respond to standard chemotherapy often recur with selective outgrowth of tumor cell subpopulations that are resistant not only to the original chemotherapeutic agents, but also to other therapeutics 122 . Several events are thought to be involved in the dysregulation of pathways, which may activate a different pathway(s) for androgen independence probably through a paracrine androgen-independent pathway, which may explain the multifocality and heterogeneity of prostate cancer and for hormone therapy resistance. Indeed, in a xenograft model, most of androgen-responsive genes that were initially downregulated under conditions of androgen deprivation were later re-expressed in recurrence tumors, indicating failure of androgen-derivation therapy as well as irreversible commitment to tumor...

Treating prostate cancer with PARP1 inhibitors

Recently, the augmented immunodetection of PARP-1 was associated with prostate cancer progression and prediction of biochemical recurrence 138 . Preclinical data also indicated that PARP inhibitors might sensitize cancer cells and potentiate the effects of radiotherapy and chemotherapy. Interesting, inhibition or depletion of PARP-1 by antisense RNA 139 , chemical inhibitors 140-142 , or by the expression of dominant negative mutants (4-5), promotes genomic instability 143 , as revealed by increased DNA strand breakage, gene amplification, micronuclei formation, and sister chromatide exchanges (SCE) in cells exposed to genotoxic agents. Marked SCE frequency has been observed in PARP-1 deficient cell lines and treated with different inhibitors against PARP-1 activity 144 . Depletion of PARP-1 was indicated as the main contribution to genomic alterations that may promote aberrant expression of cell proliferative genes, which may initiate cancer formation or progression. These...

Integrins in Prostate Cancer Invasion and Metastasis

Prostate cancer is the most commonly diagnosed cancer in men and is the second leading cause of cancer deaths in men after non-melanoma skin cancer. According to the United States National Cancer Institute, it was estimated that almost 241 740 men would be diagnosed with prostate cancer in the United States alone in 2012 and more than 28 170 would die of prostate cancer. Despite considerable advances in prostate cancer research, this cancer is still associated with significant mortality and morbidity 1 . The risk factors involved in the development of prostate cancer include advancing age, race and family history. If detected in the early stage of disease, prostate cancer is considered curable by surgical excision methods, radiotherapy and androgen deprivation therapy 2 . However, in a percentage of men disease recurs, is frequently refractory to treatment and this is associated with poor prognosis. It is thought there is a population of prostate tumour cells that have the capacity to...

The relationship between the expression of PARP1 and p53 in prostate cancer

Other studies have demonstrated that PARP-1 is dispensable for the repair of DNA doublestrand breaks induced by alkylating agents, UV, and gamma-radiation. In this respect, it was proposed the existence of an alternative radiation-induced pathway involving p53 that may function independently of PARP-1 involvement. Although this alternative mechanism may explain the cytotoxic response detected in PARP-1 null cells after radiation treatment 61, 98 , this does not necessarily support the significant delay in the transient accumulation of p53 in PARP-1-depleted intestinal epithelial stem cells after exposure to irradiation. Similarly, the survival analysis was markedly reduced in crypts of PARP-1 knockout mice, even at radiation doses that have sublethal effects on wild type animals 65 . These observations extended the crucial role of PARP-1 to stem cells survival after DNA damage in vivo. Indeed, considering the prolonged regenerative capacity of prostate progenitor stem cells may...

Roles of integrins in prostate cancer progression

Integrins are expressed in normal prostate basal cells and are required for the interaction of the cells with surrounding stroma which influences their growth, survival and differentiation potential. These integrins include a2p1, a3p1, a5p1 and a6p4 29-33 . Altered expression of integrins affects cell adhesion to adjacent cells and to the ECM and such affects have been observed in solid tumours and prostate cancer cell lines. Table 2 highlights the most well characterised integrins involved in prostate cancer progression, migration and invasion, and these integrins are discussed below. Bonkhoff et al. (1993) investigated the expression of integrin a2p1 in normal, hyperplastic and neoplastic human prostate tissue as well as lymph node metastases samples. Results showed downregulated a2p1 in 70 of the hyperplastic samples compared to normal prostate tissues. However, a2p1 was upregulated in the lymph node metastases compared to primary lesions. In another study, the role of integrin a2...

The nuts and volts of prostate cancer survival mastering the tumoral vasculature angiogenesis vasculogenic mimicry or

The use of anti-vascular endothelial growth factor antibodies have been used for the abrogation of angiogenesis and growth of human prostate carcinoma microtumors and even metastasis in orthotopic prostate cancer xenografts. Although up to date there are no reports suggesting that vessel co-option is also an alternative route for growth and dissemination of prostate tumors, the contribution of this vascular route to prostate tumorigenesis needs further exploration specifically, the involvement of this survival tool for growth of microtumors 110, 111 . The literature on vasculogenic mimicry in prostate cancer is scarce, although therapeutic implications of it have been described in aggressive prostate cancer in vitro 116 . The prognostic value of vasculogenic mimicry remains debatable as there is at least one study showing that there is no significant correlation between vasculogenic mimicry channels and histolog-ical grading of prostate cancer 117 . Interestingly, Liu et al. 114...

Evidence of YYls oncogenic regulation in prostate cancer

Many lines of evidence support an oncogenic role of YY1. Most functions of YY1 discussed above contribute to this role in prostate cancer. Importantly, the overexpression of YY1 in prostate cancer augments the oncogenic effects caused by its regulated pathways. We allocate the role of YY1 in prostate oncogenesis into two categories based on the different regulatory mechanisms. The Rex1 protein is a marker of both mouse and human embryonic stem cells and exhibits reduced expression in prostate cancer cells compared to normal prostate epithelial cells 106 . YY1 positively regulates Rex1 expression in normal human prostate epithelial cells, but this regulation is not observed in prostate cancer cells, suggesting that YY1 transcrip-tional activity may be altered during transformation 106 . Prostate stem cell antigen (PSCA) is differentially regulated during prostate oncogenesis and its expression is correlated with the development of malignant human prostate cancer. YY1 cooperates with...

Prostate Cancer Inflammation and Antioxidants

Prostate cancer (PCa) is a long latency type of tumour that usually develops in men older than 50 years of age. Prostate epithelial neoplasia (PIN), the initial malignant lesion, progresses to invasive carcinoma over the course of years. Because of the particular features of prostate carcinogenesis, this type of tumour may represent a paradigm for cancer prevention. The lack of a comprehensive aetiology for prostate cancer and the need for an effective and inexpensive biological treatment modality, devoid of side effects, has resulted in a multitude of therapeutic trials. Present evidence suggests that chemo preventive agents may be used in cancer treatment (Tallberg et al. 2008 Crohns et al. 2009). Because they are considered pharmacologically safe and derived from natural sources, most chemo preventive agents can be used in combination with chemotherapeutic agents to enhance the effect at lower doses and thus minimize chemotherapy-induced toxicity. There are various therapies that...

Cancer of the prostate

If the cancer is located close to the urethra, there may be a frequency of micturition, urgency, difficulty in voiding, blood in urine or blood in the ejaculate. Cancer of the prostate is often diagnosed by rectal examination, where it feels nodular and hard. Prostate cancer usually spreads to the bones and produces bony pain, or causes fractures in the bone after trivial injury.

The oxidative stress imbalance in the prostate tumor Gearing the journey to cancer

The development of cancer is a complex process. Cancer cells associate, both in primary as well as in secondary colonization sites with resident stromal fibroblasts, smooth muscle cells, macrophages, endothelium, neurons and migrating cells at metastatic niches and phenotypically and genotypically activate them, triggering different signaling mechanisms. During this process, the cancer cells and cells in the cancer microenvironment co-evolve in part due to oxidative stress, and acquire the ability to mimic other cell types (which can be termed osteomimicry, vasculomimicry, neuromimicry and stem cell mimicry), and undergo transition from epithelium to mesenchyme with definitive behavioral modifications. Prostate cancer cells co-evolve in their genotypic and phenotypic characters with stroma and acquire osteomimetic properties allowing these cells to proliferate and survive in the skeleton as bone metastasis 45 . ROS, RNS and other factors implicated in oxidative and nitrosative stress...

Salinomycin reduced viability of prostate cancer cells at a lower dose than nonmalignant prostate epithelial cells

Our recent study has revealed that salinomycin induces apoptosis in human prostate cancer cells by accumulated reactive oxygen species and mitochondrial membrane depolarization 20 . Using androgen-independent PC-3 and DU-145, the androgen-dependent LNCaP prostate cancer cells and non-malignant RWPE-1 prostate epithelial cells, we examined the effects of salinomycin on the viability of prostate cancer cells. When the cells were treated with increasing concentrations of salinomycin for different time periods, the viability of prostate cancer cells were reduced in a dose- and time-dependent manner (Fig. 2A, 2B and 2C). By comparison, RWPE-1 cells were relatively less sensitive to salinomycin, since at 0.15 M concentration, the drug did not significantly inhibit viable cell number (Fig. 2D), unlike the all three cancer cells, which showed significant drop in viability in MTT assay. To some extent, differential sensitivity to the drug was also seen for LNCaP vs PC3 and DU-145 cells, since...

Salinomycin in human prostate cancer cells

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death among men in the United States. Considerable progress has been made in the early detection and treatment of prostate cancer over the last two decades. Nevertheless, mortality from prostate cancer remains a significant health care problem 17 . Androgen deprivation therapy is increasingly becoming a central component in the management of prostate cancer. Although initially effective, patients acquire resistance and eventually develop metastatic castration-resistant prostate cancer (CRPC) 18-20 . For treatment in patients with CRPC, chemotherapy with docetaxel represents the standard first-line treatment. However, in order to prolong overall survival time after treatment with docetaxel, development of novel therapeutic strategies is essential.

Stromal cells in prostate carcinogenesis

The role of stromal cells on the initiation and promotion of carcinogenesis has been studied over many years. This concept was pioneered from previous studies showing 1-3 that tumor stroma, termed as CAF (cancer associated fibroblast), TAS (tumor associated stroma), or RS (reactive stroma), is often different from the normal stroma 1 . Normal prostate stromal cells play a protective role and maintain growth quiescence within the prostatic tissue. Some investigators have demonstrated in animal studies that when normal prostate stromal cells are associated with malignant epithelial cells, there is a decrease in the proliferation rate 4,5 and an apparent loss of former malignant properties of epithelial cells 6 . Some studies have also shown restriction of growth of epithelial cells and induction into a more differentiated phenotype 7 . Recombination studies using Dunning rat adenocarcinoma revealed that normal stromal environment may override the effects of oncogenic mutations in tumor...

Involvement of PARP1 in prostate cancer progression

Localized prostate tumors are treated by either radical prostatectomy or radiotherapy and usually survive many years 67 . For aggressive prostate cancer, hormonal therapy is the standard treatment however a significant amount (approximately 30 ) of these tumors become hormone-independent (hormone-refractory) 11 . Prostate cancer cells that survive chemotherapy or radiation treatment may be capable to repair most radiation-induced DNA breaks. This is supported by evidence showing both in androgen dependent and independent prostate cancer cell lines in which the EGFR-ERK signaling pathway up-regulates a series of DNA repair proteins, including ERCC1, XPC, and XRCC1, in response to DNA damage 68 . These proteins efficiently repaired the damaged DNA, and enhanced the survival of cells following exposure to genotoxics 68, 69 . The activation of PARP-1 in the presence of DNA breaks consistently promotes the recruitment of XRCC1 and the physical interaction of XRCC1 with PARP-1 has been...

PSADT and Survival of prostate cancer patients

The importance of PSA-DT in predicting survival is illustrated by Freedland et al. 41 Figure 5. This chart presents data for a group of patients experiencing biochemical recurrence of PSA after prostatectomy. Under these circumstances, PSA-DT clearly defined prostate cancer survival into four groups 1) PSA-DT > 15 months, 2) PSA-DT 9-14 months 3) PSA-DT 3-8.9 months, 4) PSA-DT < 3 months. For this study, PSA-DT is clearly a surrogate for prostate cancer-specific survival. Fifteen-year Actuarial Kaplan-Meier Prostate Cancer-specific Survival Curves by PSADT 5096 patient with prostate adenocarcinoma who had undergone radical prostatectomy al the Johns Hopkins Hospital from April 1982 tc October 2000 with follow-up data available During a mean (SO of 4 4) years and median fallow-jp pi 5 years, 973 (19 ) developed a biochemical recurrence, defined as a single postoperative PSA of at leasl 0.2 ng mL, This study included patients with at least 2 PSA values separated by at least 3 months...

Evidence for the association between Mfvmfrvs and prostate cancer 41 The Interferon IFN pathway

Evidence presented so far indicate that 1. in prostate carcinoma, an interferon-sensitive pathway appears to be affected. Attempts to identify an infectious agent (also on the basis of these observations), had led to identification of XMRV, a candidate virus, which has been eventually falsified by several groups (see part 1). However, as it has been emphasized in this chapter, evidence for viral involvement in PCa are rather strong and independent from the particular isolate XMRV. Indeed, as previously underlined, XMRV isolation is based upon usage of viro-chip technology and logical inference analysis predicts that this step is most error-prone 1 . In order to list and underline numerous elements indicating MFV as a strong candidate, the general IFN pathway is here considered and RNase-L as next point. The first one has been targeted in the carboxy-terminal of PKR, where is present the kinase activity, and doesn't show impairment of antiviral response or TNF-a responses, thus...

Role of MMP in prostate cancer

Growth factors and receptor kinases can also influence transcriptional regulation of MMPs. MMPs have been shown to play a significant role in prostate cancer metastasis (Wood et al., 1997 Sehgal et al, 1998 Pajouh et al, 1991 Powell et al, 1993). Moreover, recent evidence suggests an increase in MMP-2 and TIMP-2 ratio is associated with high-grade and high-stage prostate tumors (Still et al., 2000). MMP expression could be induced by two possible mechanisms. First, prostate stromal cells could secrete growth factors such as epidermal growth factor (EGF) and induce expression of downstream effectors such as metalloprotei-nases. Growth factors and their receptors have been shown to be key components of tumor development and progression (Sundareshan et al., 1999). Epidermal growth factor receptor (EGFR) expression in bladder cancer cells, for example, is associated with high tumor stage and grade (Nutt et al., 1998). EGF has been shown to induce the AP-1 transcriptional regulatory...

Prostate stem cells

Prostate stem cells (PSCs) need to carry following characteristics they must be castration-resistant, able to renew themselves and regenerate new tissue 13 . In contrast to the epithelial tissue of other adult organs, the prostate and mammary glands exert hormonal-dependence. Therefore, to account for changes in hormone levels the PSCs should be responsive to, but not dependent on, androgen for survival. This property is referred to as castration-resistance. PSCs should have tissue-regenerative capacity to replenish the gland after routine cell death. But, when compared to the hematopoietic stem cells that must generate a vast array of mature lineages, PSCs only must regenerate a relatively simple double-layered epithelium. Eventually, and most importantly, PSCs must be able to self-renew meeting the needs of the organ over the course of a man's lifetime.

Prostate Cancer

Abstract Prostate cancer is a major cause of death from cancer among men in the Western world. It's most striking clinical peculiarity is its tendency to metastasise to bone, resulting in osteoblastic (sclerotic) deposits. This phenomenon may be related to anatomical factors, or to specific biological factors. These include alterations in the expression of adhesion molecules by prostate cancer cells (such as reduced E-Cadherin expression or function, loss of integrins such as a4, a5, and av). The production of growth factors and cytokines such as TGFP or IGF may mediate crosstalk between bone cells and prostate cancer cells. An understanding of these various factors may result in novel approaches to the treatment of metastatic prostate cancer. Other factors which impact on earlier stages of metastasis, such as expression of the collagenase uPA, might also be amenable to therapeutic intervention, but the applicability of such interventions in patients with already established...

Prostate Problems

Prostate problems include inflammation, enlargement, or cancer of the prostate gland which surrounds the urethra, the tube through which urine flows. An inflammation of the gland is called pros-titis resulting in pain during urination and ejaculation, frequent urination and possibly low back pain. The causes include infection, too much or too little ejaculation, jarring exercises such as horseback and bicycle riding, and food irritants like caffeine, alcohol, tobacco, and red pepper. Drinking plenty of water is important in keeping a flow of urine and in preventing dehydration, which can be in effect even though not thirsty, and is a condition that is very stressful for the prostate. Enlargement of the prostate, called benign prostatic hyperplasia (BPH), usually occurs in men over 50 and causes difficulty in urination because enlargement squeezes the urethra it surrounds and interferes with urine flow. BPH is due to an excess of testosterone in the gland. Symptoms are night and...

Incidence and mortality

In Table 1 absolute numbers and age-standardized rates of incidence and mortality are presented for selected regions and countries 1 . In 2008 it was estimated that nearly every seventh case of male malignoma was prostate cancer (899 thousand new cases, 13.6 of the total). Therefore, in men prostate cancer was the second most diagnosed cancer after lung cancer. Approximately three quarters of these cases were diagnosed in more developed countries. The highest incidence rates were measured in Australia, New Zealand, Northern and Western Europe and Northern America. Moderate incidence rates were found in South Despite its high proportion of cancer diagnoses, prostate cancer is the cause of cancer specific death in only every 16th case (258 thousand deaths, 6.1 of the total). This places prostate cancer on the sixth position of cancer-specific causes of death, topped by lung, liver, stomach, colorectal and oesophageal cancer. These deaths occur almost equally in both, more developed and...

Discovery and falsification of XMRV 21 Linkage Rnasel Hpc1

Ing the antiviral response triggered by Interferon (IFN). Robert Silverman's work was pioneering and seminal in this effort together with Ian Kerr, he clarified the Interferon (IFN) response to viral infection, initially by characterizing the 5'-triphosporylated, 2',5'-linked oli-goadenylates or 2-5A, a second messenger in the IFN response and its synthesizing enzyme (oligo-2',5'-A synthethase, or OAS) and finally discovering that 2-5A is the activator of an endogenous RNase activity, called RNase L 5 3 . This is ubiquitously distributed but inactive inside cells, but it becomes strongly activated by binding 2-5A. By using radiolabelled 2-5A as probe, Silverman was able to identify and clone the gene RNASEL and to map later its location on chromosome 1q25 5 . After approximately ten years, these studies intersected a totally different discovery path. Linkage studies on families with increased hereditary risk of prostate cancer, identified in 2002 the prostate carcinoma susceptibility...

Treatment sideeffects and their psychological impact

Relatively little research has been conducted to examine the relationship between ED and psychological morbidity among men with prostate cancer. Nevertheless, ED has been reported to have a profound effect on a patient's quality of life post-treatment. Nelson et al. 10 examined the relationship between depressive symptoms and erectile function. A group of men, who did not receive any treatment for their prostate cancer, completed self-report questionnaires measuring anxiety and depression symptoms and erectile function approximately 4-years post-diagnosis. Erectile dysfunction was found to be a significant predictor of depression independent of other influential factors of depression, such as anxiety and marital status. This finding suggests that men can experience lasting psychological effects from their disease. Another study by Nelson et al. 11 examined men's responses to ED affecting their sexual function and their adjustment to diminished erections after having undergone a...

Personal beliefs and treatment selection

Extensive research has found that personal beliefs can predict a range of outcomes, including quality of life, help-seeking behaviour and treatment adherence 16-18 . These beliefs have also been shown to affect treatment choice, mainly by way of selecting between conventional treatment and complementary and alternative medicines (CAM) for conditions, such as chronic pain, hypertension, and both localised and advanced prostate cancer 19-22 . These studies reported that patients who used CAM were more likely to hold negative beliefs about their illness (i. e. , that their illness was chronic and that they had little personal control over its management) and about conventional treatments (i. e. , believed the treatments would result in significant undesirable side-effects). In contrast, patients who were less likely to favour CAM held positive beliefs about their illness and its treatment (i. e. , believed the condition was not severe and would easily be controlled with conventional...

A systematic review of the literature

An initial scope for existing literature reviews in prostate cancer research yielded two reviews 25, 26 . The more recent review 26 was conducted five years ago and restricted its search period to a 14 year time span, used a small number of literature databases and only searched for original, peer-reviewed studies to explore broadly the personal (not just beliefs specifically) and external factors pertaining to the decision-making process of patients. It concluded that there is a general lack of understanding about the role of patients' beliefs in treatment selection and that this was an area worthy of enquiry. Our aim was, therefore, to provide an updated review on factors influencing treatment selection for LPCa, as well as specifically examine the literature pertaining to patients' personal beliefs about LPCa and or its treatments. A systematic search of the literature was conducted in electronic databases to retrieve relevant published papers from 1980 - 2010, which included...

Synthesis of findings

Beliefs underpinning treatment selection for localised prostate cancer 5.1.1. Radical prostatectomy Patients' beliefs and other influences in selecting to undergo a radical prostatectomy were clearly reported in nine of the studies 27-35 . Many of the patients perceived their cancer as a localised problem and that the most tangible and definitive method of curing or preventing the disease from spreading was to remove the tumour 27-29, 31, 35 . These findings were also replicated in three of the quantitative studies, which reported that beliefs about the effectiveness of surgery and complete tumour removal were statistically associated with selecting surgery 33-35 . Surgery would also allow for surgeons to be more informed about the nature and extent of the cancer and would provide the patients with more information about their disease 27, 28 . Surgery was considered to have the best evidence base in terms of its efficacy in combating cancer compared to other curative treatment...

Recommendations for further research

A further limitation concerned the majority of the patient samples being predominantly white and from North America. Therefore, the experiences of other groups, such as men of Afro-Caribbean origin in whom the risk of prostate cancer is greater, were not represented. Further research is required across a range of ethnic and cultural groups.

Abdominoperineal resection

In patients with rectal cancer, the most common initial presenting symptom or complaint is bleeding, followed by changes in bowel habits, diarrhea, and lower abdominal pain. A DRE may detect rectal masses located within the distal 1 3 of the rectum. A potential source of confusion from a standard DRE may arise from carcinoma of the prostate encroaching on the nearby rectum, causing similar obstructive symptoms 11 . Flexible sigmoidoscopy or colonoscopy allow for a more thorough visual characterization, location, and size of the mass, and provides an opportunity for biopsy and histological examination. Endoluminal ultrasonography has recently been shown to be a diagnostic tool for characterizing the depth of invasion of the rectal mass. Pre-operative evaluation using colonoscopy and CT and or MRI is indicated to rule-out synchronous lesions and or metastatic disease 13 . is deemed resectable, the surgeon on the perineal side can begin dissection simultaneously. In the abdominal...

Conventional External Beam Radiation Therapy EBRT

In the 1970s, the treatment field size and portal configuration for radiation therapy were based on estimations of the anatomic boundaries of the prostate defined by plain-film radiography and by the digital rectal examination. At that time, a variety of treatment techniques were used. In general, four fields were used to treat the pelvis and prostate to an initial dose of 45 Gy, with a boost to 70 Gy to the prostate only 1, 2 . Early conventional external beam radiation therapy used total doses in the range of 60 to 70 Gy, because it was believed that this dose was close to the maximum dose allowed by the surrounding normal tissues, especially rectum. Today, it is obvious that this dose is not sufficient to get an adequate local control rate.

Three Dimensional Conformal Radiation Therapy 3DCRT

Common principles that offer significant advantages over conventional external beam radiation therapy techniques. CT-based images referenced to a reproducible patient position are used to localize the prostate and normal organs and to generate high resolution 3D reconstructions of the patient. Treatment field directions are selected using beam's-eye-view techniques and the fields are shaped to conform to the patient's CT-defined target volume, thereby minimizing the volume of normal tissue irradiated. Compared with treating a patient by conventional external beam radiation therapy technique, 3D-CRT is associated with a nearly 30 reduction in the dose received by 50 of the rectum. Based on this kind of analysis, it greater than or equal to 10 should be possible without an increase in acute or chronic toxicity 3 .

Intensity Modulated Radiation Therapy IMRT

IMRT is a relatively recent refinement of three-dimensional conformal techniques that uses treatment fields with highly irregular radiation intensity patterns to deliver exquisitely conformal radiation distributions. These intensity patterns are created using special inverse and optimization computer planning systems. Rather than define each shape and weight as is done in conventional treatment planning, planners of IMRT treatment specify the desired dose to the target and normal tissues using mathematical descriptions referred to as constraints or objectives 4 . Sophisticated optimization methods are then used to determine the intensity pattern for each treatment field that results in a dose distribution as close to the user-defined constraints as possible. IMRT delivery is significantly more complex than conformal delivery as well. Delivery of an IMRT intensity pattern requires a computer-controlled beam-shaping apparatus on the linear accelerator known as a multi-leaf collimator...

Clinical results of EBRT

The results of several large single-institution comparison between radical prostatectomy (RP) and EBRT were reported. D'Amico et al. reported a retrospective cohort study of 2635 patients with either RP or RT of median dose to 70.4 Gy (95 CI, 69.3-70.4 Gy) 7 . Eight-year bRFS rates for low-risk (T1c, T2a, PSA < or 10 ng ml, and Gleason score (GS) < or 6) patients were 88 and 78 for RP and RT, respectively. Eight-year bRFS rates for intermediate-risk (T2b or GS 7 or PSA > 10 and < or 20 ng ml) patients with < 34 positive prostate biopsies were 79 and 65 for PR and RT, respectively. Eight-year bRFS rates were 36 versus 35 for intermediate-risk patients with at least 34 positive prostate biopsies and 33 versus 40 for high-risk (T2c or PSA > 20ng ml or GS > or 8) patients treated with RP versus those treated with RT, respectively. In conclusion, in their retrospective cohort study, intermediate-risk and low-risk patients with a Investigators from Memorial Sloan Kettering...

Acute and late adverse events

EBRT delivered with conventional techniques is fairly well tolerated, although grade 2 or higher acute rectal morbidity (discomfort, tenesmus, diarrhea) or urinary symptoms (frequency, nocturia, urgency, dysuria) requiring medication occur in approximately 60 of patients. Symptoms usually appear during the third week of treatment and resolve within days to weeks after treatment is completed. The incidence of late complications that develop > or 6 months after completion of treatment is significantly lower, whereas serious complications that require corrective surgical intervention are rare. An analysis of 1,020 patients treated in two large Radiation Therapy Oncology Group (RTOG) trials 7506 and 7706 demonstrated an incidence of chronic urinary sequelae, such as cystitis, hematuria, urethral stricture, or bladder contracture, requiring hospitalization in 7.7 of cases, but the incidence of urinary toxicities requiring major surgical interventions such as laparotomy, cystectomy, or...

Introduction to permanent implants

Interstitial prostate brachytherapy was first performed by Barringer in 1915 29-31 . Its first widespread adoption occurred in the 1970s, when the retropubic method was popularized 32 . A laparotomy was done for lymph node dissection and exposure of the prostate. Io-dine-125 sources were implanted under direct visualization. The procedure was technically difficult to perform, in part because of limited working space in the pelvis. As a result, retropubic implantation lost popularity in the 1980s 33 . Instead, ultrasound-guided permanent prostatic implantation emerged in the early 1980s and has spread all over the world. The ultrasound-guided transperineal technique was initially described by Holm and coworkers in 1983 34 . Transrectal ultrasound (TRUS) allowed visualization of the needle location within the prostate, facilitating real-time read-justments of needle position as necessary. Implants could be computer preplanned using transverse ultrasound images. Transperineal implants...

Introduction to HDR brachytherapy

HDR brachytherapy has been used as the brachytherapy component in combination with EBRT for the treatment of prostate cancer 84-90 . In general, for this approach patients undergo transperineal placement of afterloading catheters in the prostate under ultrasonographic guidance. After CT-based treatment planning, several high-dose fractions are administered during an interval of 24 to 36 hours using 192Ir. This treatment is followed by supplemental EBRT directed to the prostate and periprostatic tissues to a dose of 40 to 50.4 Gy using conventional fractionation. Recently, dose-escalation studies have been implemented to increase gradually the dose per fraction delivered with the HDR boost 91 . Improved outcomes with higher HDR boost doses were observed compared with outcomes achieved using lower dose level. Single higher dose fraction also becomes used for dealing with the issue of needle displacement between each fraction 92 . More recently, several institutes have used HDR...

Brachytherapy implant characteristics

Brachytherapy procedure is done under spinal anesthesia with the patient in the lithotomy position (Fig. 1). A Foley catheter is placed, and the bladder is partially filled with 100 cm3 of sterile water. The needles are positioned (Fig. 2) by transperineal placement under real time TRUS guidance using a template. Axial cross-sections is captured in 5mm steps and transferred to the Treatment Planning Software. Prostate gland, normal structures (urethra and rectum) and needle positions are identified and mapped based on the ultrasound image. Dose optimization is done on the reconstructed applicator geometry using dose point and manual optimization algorithms to determine dwell positions and times (Fig. 3). The prostate without safety margins is then defined as the planning target volume (PTV) to be treated (Fig. 4) with the prescribed dose (PD). prostate) will be enough to provide a significant radiation dose reduction from HDR brachytherapy 11, 12 .

Problems with direct testosterone immunoassays

Large differences were reported from measurements of the same serum sample with chemi-luminescent assays from different manufacturers 39,40 . Direct RIA techniques were not better 41 . In the low range (values of interest for castration control in patients with prostate cancer), which was close to range of female testosterone levels, direct assays gave results more than 20 different from the gold standard 41 . Abbot Architect assay was also reported to give consistently up to 20 higher results compared to standard in this range of values 39 .

PSADT as a surrogate for drug activity

Kelloff et al. 31 , reviewed the use of PSA-DT as a surrogate for tumor response to drugs in patients with prostate cancer. They concluded that protocols that demonstrate significant changes in PSA-DT might be used to support accelerated approval of newer therapies. There is data to suggest PSA-DT in castrate resistant patients is predictive of outcome after chemotherapy 32 . An important caveat is expressed by Newling's review 33 of the subject which concluded that though dynamic changes in the PSA such as PSA-DT are commonly used in clinical trials of new drug therapies, PSA-DT might be affected by other factors including assay variations and false elevations of serum PSA caused by irritation of bladder catheters, prostatitis and cystitis. A substantial incidence of transient elevations of PSA (55 ) was reported following combined external beam radiation and brachytherapy for prostate cancer 34 . These complicating issues should always be considered before PSA-DT is used to modify...

Defining PSA response

Investigators participating in new prostate cancer drug trials commonly define PSA response according to the Bubley guidelines 35 for phase II clinical trials in androgen-inde-pendent prostate cancer. The guidelines qualify the following categories of PSA PSA normalization, PSA < 0.2 ng ml PSA decrease, PSA decline > 50 , confirmed by a second PSA value 4 or more weeks later PSA progression, PSA > 25 increase over the baseline (and an increase in the absolute value PSA level by at least 5 ng mL). Though useful for evaluating clinical trials, these PSA changes lack sensitivity when evaluating subtle drug effects vs. prostate tumor growth 36,37, 38 . Therasse 39, 40 , in his thesis reports on MRI and PSA as tools in a RECIST evaluation used to define tumor response in prostate cancer patients with measurable soft tissue lesions. When comparing MRI soft tissue responses to serum PSA changes, the correlation of PSA and MRI showed agreement in 14 of the 20 (70 ) patients.

PSA in the era of biologic and targeted therapy

Kelly 48 reported on 110 assessable patients treated on seven sequential protocols at Memorial Sloan-Kettering Cancer Center for hormone-refractory prostate cancer a statistically significant survival advantage in 110 patients with > 50 PSA decline (> 25 months survival) versus those without a 50 PSA decline (8.6 months survival). These results suggest that post therapy PSA declines can be used as a surrogate end point to evaluate new agents in hormone-refractory prostate cancer and criteria for response need prospective validation for phase III trials. Smith et al. 49 showed that a PSA decline > 50 for at least 8 weeks resulted in a longer mean survival time of 91 weeks versus 38 weeks for patients showing a smaller PSA reduction. An improved PSA response was associated with prolonged survival in the TAX 327 study (Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer), with a median survival of 33 months when the PSA was normalized (< 4 ng...

Assessment of molecularly targeted cytostatic or antiangiogenic agents

Bellmunt 53 and others expressed concern that PSA response criteria are not established to properly evaluate molecularly targeted cytostatic or anti-angiogenic agents 54 therefore, certain drug-specific limitations may exist when using PSA or PSA-DT as an indicator of progression or response. One clear example was noted in a study of sorafenib (Nexavar) in castrate resistant prostate cancer, in which two patients with PSA progression were found to have dramatic resolution of bony disease 55 . Therapy-associated PSA surge has been described after effective chemotherapy. PSA surge occurs with Samarium153 radiotherapy, androgen deprivation and chemotherapy and is generally transient. The surge may be due to rapid lysis of prostate cancer cells thus spilling intracellular contents into the intravascular space 56 . Similarly, 10 of 16 patients who discontinued sorafenib and did not receive other therapy demonstrated post-discontinuation PSA declines of 7-52 57 . The review by Bell-munt 58,...

Predicting approximate tumor size or marker value for any arbitrary date in the future

Assuming untreated clinical cancers and their markers expand at a relatively constant exponential rate, it is possible to predict values for tumor diameter, volume and marker for any arbitrary future date. Figure 16 displays a PSA projection made for a patient with newly diagnosed prostate cancer who asked if a preplanned three-month holiday before initiation of therapy could jeopardize his chance for a curative procedure. The prediction, assuming constant exponential expansion of serum PSA, is that the PSA value upon returning from sabbatical would increase from 9.4 to 16.28 ng ml. This alarmed the patient and he cancelled the trip to initiate therapy.

Targeting key biological pathways

A leading premise for the treatment for advanced prostate cancer is to target the androgen receptor (AR) axis or to identify cases where a single pathway mutation is thought to drive carci-nogenesis. It is proposed that triaging the current pipeline of agents can be directed by building on prior successes. In light of recent advances in our knowledge of AR pathway signaling, further exploration of this pathway is warranted. Moreover, since molecular interrogation of distinct clones driving individual prostate cancers is now possible, treatment of these tumours with agents targeting these mutations would also be desirable. In the past the prostate cancer treatment paradigm has been to expose the patient to an established sequence of agents in a 'one size fits all' approach - which may have missed identifying a drug with major activity in a few patients. A strategy that is being increasingly more recognized is the need to characterize a patient's cancer and select the most appropriate...

An advanced understanding of cancer biology comes of age 41 Specific targeting of DNA repair mechanisms

DNA repair is prevented and apoptosis occurs. Following pre-clinical and more recently proof of concept clinical trials in patients with BRCA mutated breast and ovarian carcinoma, the PARP inhibitor olaparib has demonstrated significant activity 46 . Whilst it is hoped that the application of these agents may broaden to include sporadic tumours in which mutations in DNA pathways may also be found, there has also been considerable interest in other tumours types where these mutations may be found. The inherited BRCA-2 mutation is associated with a 20 lifetime risk of developing prostate cancer that often occurs before 65 years of age. The subsequent tumors are often of high Gleason score, more advanced stage at diagnosis and patients have a shorter survival than patients with sporadic prostate cancers 47 . One of three prostate cancer patients with germ-line BRCA variant had a prolonged response to olaparib in a phase 1 trial 48 . In addition to BRCA mutated cancers, pre-clinical...

Oncogene addiction pathways

The development of drugs targeting tumours driven by so-called 'oncogene addictions' has lead to some success. Examples include imatinib targeting the bcr-abl translocation in CML and mutated c-kit in GIST, trastuzumab and laptinib in HER-2 positive breast cancers BRAF inhibitors in melanomas with BRAF mutations. Molecular studies in prostate cancer have to date identified mutations of this type in less than 20 of all sporadically occurring prostate cancers. Analysis of a cohort of 206 prostate cancer cases found the common BRAF mutation V600E in 10.2 (or 21 206 cases) 51 , whilst PI3 kinase mutations were found in only 3 of a separate cohort 52 . Drugs inhibiting BRAF as well as PI3 kinase mutations may lead to meaningful responses in patients with tumors been driven by these mutations. It is hoped that further oncogene addiction pathways will be uncovered and be able to be drugged.

Ligand and transcription factor driven survival pathways

Whilst it is often hoped that mutations in a single molecular pathway will be uncovered as the crucial oncogenic event in tumour development and its abrogation lead to meaningful anticancer activity, to date this has been rarely found to be the case for sporadic tumours. Another approach is to consider the factors that cause and or are associated with the development as well as the survival of cancer. The role of androgens and androgen receptor is clear for prostate cancer. Other biological approaches associated with cancer development and survival include the metabolism and inflammatory systems. In both cases, there is epi-demiological, preclinical and pathological data implicating these systems in the development of prostate cancer. In comparison to the oncogene addiction phenomenon, these cancers are driven by altered expression of ligands and control mechanisms (such as transcription factors). Knowledge of these pathways has provided valuable clues for the treatment of cancer.

Conclusion future directions

Will work given the inherent multiple redundant survival pathways. This is probably more apparent for castration resistant disease. Therefore, one can argue that waiting for metastatic disease or castrate resistant disease to assess a new drug is a defeatist approach, and that an assessment earlier in the disease spectrum to prevent the emergence of resistance is a more proactive and promising approach to improve outcomes in prostate cancer. The conduct of a study in patients with a biochemical relapse after definitive localized therapy provides a major opportunity for drug development. This approach allows the analysis of a drug in isolation and as well as an assessment and effective triage of the numerous new agents that are now available for testing. Also the primary pathology can be interrogated to look for activation of the pathway and provides an opportunity to biologically direct the evaluation of drugs relevant to a given a pathway in an individual's cancer. Ultimately, key...

Mechanisms involved in the development and progression of the disease

To understand prostatic growth in diseased states, it is important to understand the hormonal influences at play in normal prostate development and function. Testosterone is the primary circulating androgen in men. Within the prostate, testosterone is converted to a more potent androgen dihydrotestosterone (DHT) by the action of intracellular 5a-reductase enzymes 6 . Circulating DHT levels are low (1 10) when compared with testosterone, whereas in the prostate, this ratio is reversed, making DHT the primary prostatic androgen 7 . Dihydrotestosterone is essential for the development of the prostate gland. Inside the prostate, both testosterone and DHT bind to the androgen receptor (AR), stimulating the AR signalling axis that promotes cell-cycle regulation, cell survival and lipogenesis 8 . Although both the androgens are capable of binding AR, DHT has a stronger affinity than testosterone Depending on the developmental stage of the individual, DHT signalling could promote the...

Antiandrogen therapies

Drugs that reduce circulating levels of androgens or that competitively inhibit the action of androgens remain central to the treatment of prostate cancer. The surgical or medical castration with orchiectomy or gonadotropin-releasing hormone (GnRH) agonists, respectively, suppresses testicular testosterone generation. However, the duration of response to castration is short 12-33 months) and, in almost all patients, is followed by the emergence of a castration-resistant phenotype 34 . The combination with antiandrogens to achieve the maximum androgen blockade (MAB) did not prove to prolong survival and 30 of the patients have a drop in PSA after discontinuing antiandrogens 3, 43 . For patients whose disease progresses after a MAB, antiandrogen can be discontinued 49 , or can be switched to an alternative antiandrogen as showed in several reports 3, 43 . High-dose 150 mg daily) bicalutamide as second-line hormonal therapy resulted in > 50 PSA reduction in 20 -45 of patients 12, 34 ....

Vaccinesbased immunotherapy

GVAX (CGI940 CG8711 is a cellular vaccine composed of two allogeneic prostate cancer cell lines (LNCaP and PC-3 that is genetically modified to secrete GM-CSF 69 . This vaccine showed clinical benefit with limited toxicity in phase I and II trials 70, 71 . However, the two phase III trials (VITAL-1 and VITAL-2 evaluated GVAX against docetaxel plus pre-dnisone in nai've CRPC and both were closed prematurely 70 . The VITAL-1 study was closed when the unplanned futility analysis revealed a < 30 chance of meeting its predefined primary endpoint of OS improvement and the VITAL-2 terminated when an interim analysis revealed more deaths in the GVAX arm than in the control 71 .

Bonetargeted treatments

Metastatic prostate cancer has an affinity to spread to the bone. Bone metastases occur in up to 90 of patients with HRPC. These metastases can lead to significant morbidity, including severe pain, fractures, and spinal cord compression tumors in the bone may cause pain, compression, or pathologic fratures, known as skeletal related events (SRE's). Because of the frequent involvement of vertebrae by metastatic prostate cancer, the incidene of cord compression is of particular concern. Zoledronic acid has been shown to prevent or delay skeletal complications in men with bone metastases, as well as to palliate bone pain 74, 75 . At an average followup of 24 months, there was a significant reduction in the frequency of skeletal related events (SREs) in men receiving zoledronic acid compared to placebo 38 versus 49 percent), and the median time to develop an SRE was significantly longer with zoledronic acid 488 versus 321 days) 76 . Biphosphonates may also have a role in...

Antiangiogenic strategies

Tumor angiogenesis is likely to be an important biologic component of prostate cancer growth and progression. An elevated levels of the potent angiogenic molecule vascular endothelial growth factor (VEGF) have been shown to correlate with advanced clinical stage and survival. Microvessel density in clinically localized prostate cancer is an independent prognostic for progression and survival 87, 88 . Antiangiogenic agents using monoclonal antibodies to VEGF, such as bevacizumab (Avastin ) have been studied in prostate cancer. Although single-agent studies have failed to demonstrate significant results, a phase II trial conducted by the CALGB added bevacizumab to docetaxel and estramustine in men with HRPC 79 of patients had a greater than 50 decline in PSA level, median time to progression of 9.7 months, and overall median survival of 21 months 89 . On the basis of these promising results, a randomized, double-blind, placebo-controlled, phase III trial has been designed...

Clinical phase II studies of IAS

Following apparently successful pilot studies, a number of phase II IAS trials were conducted (Table 1) 16 . Since the end points of most phase II studies were safety and feasibility of IAS, survival data were not reported in general. Out of the 19 studies reviewed by Abra-hamsson only five involved more than 100 patients (102, 103, 146, 250 and 566 patients, respectively) and the other smaller studies employed a mean number of 52 patients 16 . Although patients with advanced, metastatic prostate cancer were included in several studies, most patients treated in phase II IAS trials had localized disease or biochemical progression following prostatectomy radiation therapy. The number of IAS cycles given ranged from 1 to 12, with an average of 2-3 per patient, and the length of time off therapy generally decreased or remained stable with each succeeding cycle. Most of the studies reported off-treatment periods of approximately 50 of the duration of the IAS cycles, dependent on the tumor...

IAS trials currently under investigation

Table 2. lists the trials comprising IAS treatment of prostate cancer patients registered in the United States National Institute of Health (NIH) clinical studies site. With exception of a few further trials comparing IAS to CAS in metastatic cancer patients, several drugs are investigated for their potential to prolong the off-treatment phase of IAS. Exisulind (Aptosyn or su-lindac sulfone) may be useful as a treatment for men with advanced prostate cancer, achieving disease stabilization. This drug increases the rate of programmed cell death in cancer cells without damaging normal tissue by interfering with cyclic GMP phosphodies-terase in abnormally growing precancerous and cancerous cells 45 . Zactima (vandetanib) is an oral inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2), epidermal growth factor receptor (EGFR) and Ret tyrosine kinases involved in tumor growth, progression and angiogenesis 46 . Although, as single agent, no significant antitumor activity has...

Characterization of prostatic stem cells

Recent studies have revealed that a very small subpopulation of multipotent and undiffer-entiated PSCs, comprising about 0.1-3.0 of the total prostatic epithelial cell population, principally reside within specialized areas or niches localized in the basal cell layer of acinar and ductal regions of the human prostate gland 5 . Anne T. Collins and colleagues isolated and characterized human adult SCs based on the identity of cell surface integrin antigens 25 . They showed that, in vivo, putative SCs express higher levels of the a2-integrin subunit than other cells within the basal layer. Later, it was shown that a subpopulation of a2p1hi basal cells express the CD133 antigen and that this expression correlates with a high proliferative potential and ability to regenerate a fully differentiated prostatic epithelium with expression of prostatic secretory products in vivo 22 . CD133+ cells possess three important attributes of epithelial stem cells they are rare, comprise a high in vitro...

Regulatory mechanisms of CSCs

Nent E-cadherin can also lead to metastasis 45, 46 . Differentiation and self-renewal of adult SCs is usually controlled by the SHH pathway and disruption of it results in their aberrant differentiation and proliferation 47 . The NOTCH signaling pathway also regulates the differentiation, proliferation and self-renewal of adult SCs. Dysregulation of this pathway affects specific tissues and often leads to basal cell carcinoma, breast-, kidney- and prostate cancer 48-50 . In mouse models a significant inhibition of tumor growth could be achieved when the NOTCH signaling cascade was blocked 51 . The PTEN, a tumor suppressor protein with function in cell cycle regulation, is acting on the PI3K AKT mTOR signaling pathway. Inactivating mutations of PTEN can cause uncontrolled growth and cell division and are often found in tumors such as brain, bladder, prostate and kidney cancers 52-54 .

Methods for assaying PCSCs

Cunha and Ben Lung have developed tissue recombination of a rodent model for the growth of normal epithelial cells in 1978 68 . In this system, tissue fragments of fetal urogenital sinus mesenchyme were used to support the growth of normal prostate epithelial tissue fragments when implanted in collagen under the renal capsule of immunodeficient mice. This system was later modified to evaluate the growth activities of different prostate cell subpopulations using mechanical and enzymatic digestion to dissociate both, the urogenital sinus mesenchyme and adult murine prostate tissue into single cell suspensions 69 . Dissociated prostate epithelia regenerate ductal structures that histologically resemble normal murine prostate. Matrigel transplantation method was described that provides a reconstitution assay of prostatic cells. It was shown that the prostate contains stem cells capable of reconstituting the whole prostate and this method can be used to analyze prostate stem...

Alterations in signaling pathways of PCSCs

Alterations in the signaling pathways are probably one of the reasons why cancer stem cells gain a tumorigenic potential. Thus, disclosing the signaling pathways' expressional regulations might provide potential therapeutic targets. The WNT, JAK STAT, NF-kB, NOTCH, and PI3K AKT mTOR signaling pathways were found to be the regulators of CSC biology in prostate tissue and therefore are candidate targets. The idea of inhibiting signaling that induces proliferation and survival could mean an effective therapy for PC 77 . The PI3K AKT mTOR signaling pathway member PTEN was first identified as a candidate tumor suppressor gene that was frequently mutated in brain, breast, and prostate tumors 82 . Introduction of PTEN into cancer cells that lack PTEN function down-regulated cell migration and survival, and induced cell cycle arrest and apoptosis 82 . PTEN is the most mutated gene in metastatic PC that is advanced and has an aggressive tumor phenotype and has been associated with cancer...

Endocrine effects on PCSCs

AR is a member of the steroid hormone receptor family and its over-expression is involved prostate tumorigenesis. Consequently, androgen deprivation therapy (ADT) has been used to treat locally advanced and metastatic PC 86 . Despite initial regression of the tumor the majority of patients inevitably develop castrate-resistant prostate cancer (CRPC), which establishes metastases relatively rapidly and is subsequently incurable by current treatment strategies. Mouse model studies revealed that androgen ablation can select for more aggressive and metastatic disease, which means that current hormonal therapies do not affect the AR'-CSCs 87 . ADT may promote disease progression by causing an increase in the castrate-resistant SC pool and or activating quiescent SCs to repopulate the tumor with andro-gen-independent SCs. Vander et al. reported that unlike normal adult human prostate SCs, CD133+ PCSCs are AR+ and suggested that AR+ prostate TICs are derived from a malignantly transformed...

Potential role of PCSCs in metastasis

CSCs contain a subpopulation of cells that are exclusively capable of disseminating and subsequently providing the substrate for tumor metastasis e.g. CD44+ PC cells are more tumori-genic and metastatic than the corresponding CD44- cells 93 . Stromal cell derived factor and its C-X-C chemokine receptor type 4 (CXCR4) form a critical regulatory axis for SC migration, engraftment and homing, and also function in the metastasis of breast and prostate cancer 94 . Using a mouse human comparative translational genomics approach an 11-gene signature that consistently displays a stem cell-like expression pattern in metastatic lesions of prostate carcinomas could be recovered from multiple distant target organs 95 . Tumor microenvironment facilitates cancer metastasis by several mechanisms. When human PC cells were injected into the dorsal prostate of a nude mouse more metastasis was generated, than when cells were injected subcutaneous 99 . Later, it was shown that dorsal prostate-implanted...

MicroRNAmediated regulation of PCSCs

For the identification of novel PC therapeutic targets it is important to evaluate functional genes that are related with CSCs self-renewal and survival abilities. The experiences with PC therapy showed that PC recurs frequently meaning that chemotherapy, radiotherapy, androgen-ablation therapy, and radical prostatectomy are not sufficient enough to eliminate TICs or metastatic cells. PCSCs are androgen independent and therapy resistant cells. Thus, generating novel therapies that specifically target PCSCs may be more effective than those that target differentiated PC cells. New approaches depend on CSC exterminating rather than total tumor decay. The limitation for these studies is to be able to specifically target CSCs in normal tissue that also contains its specific SCs since, they have similar expression-al and antigenic profiles 101 . Consequently, new markers are needed to distinguish CSCs from tissue specific SCs. microRNAs (miRNA) can be considered as such novel therapeutic...

Progressive loss of AR expression

Numerous studies have focused on AR expression in the epithelial cells during prostate carcinogenesis and the progression of prostate cancer from primary to metastatic cancer and from hormone sensitive to castration resistant prostate cancer (CRPC). It has been established that epithelial AR is continuously expressed throughout prostate cancer disease progression. Increased AR expression has been associated with aggressive disease and decreased progression free survival (PFS) in patients 19 . The expression and function of stromal AR may be distinct from epithelial AR. As a result of the structural, genetic and genomic 11,15 modifications of the stromal cells, there are behavioral modifications expressed in tumor associated stroma. AR expression in stroma is progressively decreased during the transition from benign tissue to cancer and during progression of prostate cancer from low grade to high grade, primary to metastatic, hormone sensitive to CRPC, as well as aggressive prostate...

Stromal AR inhibits cancer epithelial cells

We have observed and previously demonstrated by co-culture experiments using well characterized stromal cell lines, both in vitro and in vivo that, in the presence of androgen, stromal cells expressing AR decrease the growth and invasive ability of prostate cancer epithelial cells. It was hypothesized that this distinct effect of AR in stromal cells is due to the involvement of paracrine factors mechanisms regulated by both the epithelial and stromal cells. The analysis was established 21 by using a well characterized prostate stromal cell line morphologically similar to the tumor stroma. We constructed an immortalized stromal cell line from prostate with BPH, termed as PShTert, stably expressing the human telomerase catalytic subunit - hTert. Morphologically and ultra structurally, the cells expressed typical characteristics of myofibroblasts. IHC showed diffuse, strongly positive stain for Vimentin with a strong SMA staining in 25 of cells, and negative staining for Desmin. Together...

The androgen receptor and CaP progression

The development and progression of prostate cancer (CaP) is largely dependent on the dysregulation of the androgen androgen receptor (AR) signaling pathway though, the mechanism of CaP progression remains elusive. Initial treatments for CaP included prostatectomy or radiation to destroy cancerous cells 1 . However, these treatments were not curative and more often than not there were recurrences and metastases of the cancer. Mainstay treatments that target the androgen AR pathway through anti-androgen and androgen ablation therapies have been promising yet again, these therapies seem to fail as the tumor progresses. This suggests that the androgen AR dependence of CaP cells vary over time such that alterations in androgen availability, AR sensitivity and receptor promiscuity fuel a more aggressive CaP. The prostate requires androgenic steroids for development and function. Testosterone is the main circulating androgen and is secreted from the testes as well as the adrenal glands...

AR in CaP progression

Somatic mutations are largely single base substitutions 49 at the LBD, 37 at the NTD, and 7 at the DBD 3 . For those CaP that harbor gain of function mutations the result is primarily an increase in ligand promiscuity. The AR is activated by testosterone and DHT however, mutations in the LBD make the AR less stringent of its partners. For example, in LNCaP cells, a Threonine (Thr T) to Alanine (Ala A) mutation (T877A) caused the expansion of ligand binding activity 1, 8 . This mutation permitted AR activation by androgens, estrogens, progesterones as well as the non-steroidal antagonist, flutamide. A study by Gaddipati et al., (1994) found that 25 of patient metastatic tumors had a T877A mutation. Patients that were treated with flutamide often experienced a worsening of symptoms over time. Once flutamide was withdrawn, patients tended to do better. Interestingly, some patients also experienced a rise in serum PSA levels upon flutamide treatment. Taplin et al., (1999) studied patients...

Phosphatase and tensin homolog deleted on chromosome Ten Pten

The tumor suppressor, PTEN, is a dual phosphatase that has activity for both lipid and protein substrates. It is a gene that is lost in both heritable and spontaneous cancers where germline mutations cause autosomal dominant hamartoma tumor syndromes and where spontaneous missense mutations occur frequently in the central nervous system (20 ), endometrial (39 ), colorectal (9 ), skin (17 ), prostate (14 ), and breast (6 ) cancers 95 . Its role within the PI3K pathway serves to negatively regulate PI3K signalling. PTEN functions to remove phosphates in position 3' from phosphoinositides 93, 106, 107 , therefore, returning PIP3 to PIP2 and terminating the PI3K signal. Monoallelic loss (loss of heterozygosity) and or mutation of PTEN thus, leads to a hyperactive PI3K pathway to drastically impact tumor growth and disease severity. PTEN mutants that retain protein tyrosine phosphatase activity but lose the ability PTEN is tightly regulated at the transcriptional level as well as by post...

The incidence of genetic PTEN alteration

The deletions involving the chromosome 10q, which hosts the PTEN locus, 10q23, in CaP is a frequently observed phenomenon. Modifications to PTEN in various stages of CaP have been characterized to include both homozygous and hemizygous deletions, as well as inactivating mutations. Although the incidence and the modes of these alterations have been inconsistent across studies, the severity of PTEN loss seems to correlate with disease progression 119 . Whereas locally confined CaP presents homozygous deletions of PTEN ranging from 0 to 15 , the incidence within metastases can increase up to 30 . Likewise, heterozygosity loss occurs in 13 of the locally confined cases and up to 39 in metastatic phenotypes 120 . Further support has comefrom interphase fluorescence in situ hybridization (FISH) analysis of histologic sections, which reported genomic deletion of PTEN in 23 of high-grade intraepithelial neoplasia (HGPIN) and 68 of prostate tumors 121 . Recently, Han et al., (2009)...

Current therapy implications and future directions

The reciprocal interactions and interplay between the AR and PI3K AKT axis suggests that the underlying mechanism potentiating CaP progression is complex and impacts the very balance of these prosurvival pathways. Current literature shows that there is indeed crosstalk between the AR and PI3K AKT pathway occuring at various levels. The integration of these oncogenic pathways potentiates CaP tumorigenesis and this is further complicated by the levels of androgens and stage of CaP progression. In effect, the transition from AD-CaP to AI-CaP in prostate carcinogenesis provides major clinical challenges. Androgen ablation and or anti-androgen therapies are only temporarily effective. Such therapies yield a hormone refractory tumor that is essentially untreatable with the most effective standard chemotherapeutic regimens which only increase patient survival for 2 months 191 . In this case, the pharmacological challenge then, will be to consider the contributions from both PI3K AKT and AR...

Cancers associated with alterations to CBF

The expression of RUNX factors in prostate epithelial cell lines and normal prostate tissue was identified by real-time RT-PCR 56 . RUNX1, RUNX2, and RUNX3 were variously expressed in normal prostate tissue, an immortalized, non-transformed cell line, prostate cancer cell lines and primary prostate cancers 56 . To confirm that mRNA expression led to active DNA binding activity, CBF presence was confirmed using electrophoretic mobility shift assay (EMSA) 56 . While RUNX1 and RUNX2 were always expressed in prostate cancer cell lines, RUNX3 expression was not observed in most prostate cancer cell lines 56 . This correlates well with other studies that have identified RUNX2 expression in prostate cancer cell lines and showed that decreasing RUNX2 expression inhibits cell growth 57 . RUNX2 may play a role in tumor spread since RUNX2 triggers expression of bone-specific genes in prostate cancers, which may be involved in bone metastasis 58, 59 . Moreover, in a PTEN-deleted mouse model of...

Summary and future directions

Although the AR is an important target of therapeutics in the struggle against prostate cancer, it remains imperative to develop effective strategies to target other important transcirp-tion pathways, especially in AIPC. To alter gene transcription, some scientists, for example, are developing histone acetyl transferase inhibitors 97 . However, any such therapeutic would be expected to lack specificity for particular oncogenic pathways. DNA binding transcription factors represent druggable targets that should produce a more specific outcome, and are under appreciated as targets of small molecule inhibitors. Master transcriptional regulatory factors such as CBF and CSL clearly play important roles in cancer cell biology. Numerous studies show that inhibiting their function results in cancer cell death or loss of malignancy. These may be particularly useful targets in prostate cancers as the pathways intersect and CBF enhances AR function. In the case of CBF, it may make sense to target...

Roles of integrins in cancer progression

Integrin avp3 has been associated with tumour progression in a range of cancers including lung cancer, gastric cancer, breast cancer and prostate cancer 15-18 . Integrin avp3 remains the most well-studied integrin involved in tumour progression. Interestingly, integrin avp3 is usually only expressed in activated leukocytes, macrophages, platelets and osteoclasts and not normally expressed in epithelial cells. It has been found to mediate adhesion of breast cancer cells to bone matrix and also facilitate migration of breast cancer cells in bone sialoprotein 19, 27 . In colon cancer, blocking integrin avp3 resulted in a decrease in tumour metastasis and improved survival in mice 21 . This integrin was also found to bind to periostin, which is upregulated in epithelial ovarian cancer cells, and promotes cell adhesion and migration 22 . Changes in integrin a2p1 have also been associated with tumour progression with loss of integrin a2p1 resulting in the induction of breast cancer cell...

Integrins as therapeutic targets

As previously discussed, integrins have been shown to mediate tumour progression, tumour cell metastasis and EMT in both in vitro and in vivo models. Thus, these preclinical studies have suggested that integrins could be a novel therapeutic target to prevent cancer progression, including prostate cancer. Currently, studies have been focused on targeting integrin avp3 in breast cancer, ovarian cancer and prostate cancer. Integrin avp3 is likely to be a good cancer angiogenesis target because it is highly expressed on tumour-associated new blood vessels and the surface of most epithelial tumours cells. There are currently antibody-type inhibitors (LM609, MEDI-522, CNTO95, c7E3, 17E6) or peptide-type inhibitors (Cilengitide, ATN-161) under investigation. However, here only inhibitors that have been tested specifically on prostate cancer models will be reviewed. MEDI-522 is a humanized monoclonal antibody specific for integrin avp3 and a phase I dose escalation trial was conducted in 25...

Role of Cadherinin physiologicalandpathological processes

Association of E-cadherin with neighboring cells acts to inhibit cell mobility and to maintain normal epithelial cell phenotype. Tumorigenesis is an example of a pathological process that involves E-cadherin regulation. The loss or down-regulation of E-cadherin expression has been described in several tumors including stomach (Shino 1995 Tamura, 2000), colon (Van Aken, 1993 Dorudi, 1993), pancreas (Pignatelli, 1994), liver (Joo, 2002), prostate (Morton et al., 1993 Umbas et al., 1994 Ross et al., 1994 Bussemakers et al, 1994 Pan et al., 1998 Noe et al., 1999 Cheng et al., 1996), breast (Lim and Lee, 2002 Hiraguri et al, 1998 Moll et al., 1993 Palacios et al., 1995 Gamallo et al., 1993 Oka et al., 1993 Rasbridge et al., 1993 De Leeuw et al., 1997), uterus (Sakuragi et al., 1994), ovary (Veatch et al., 1994), thyroid (Brabant et al., 1993), and head and neck (Mattijssen et al., 1993). Recent reports suggest that poorly differentiated tumors exhibit reduced E-cadherin expression as a...

Targeting the metabolism system

Incidence and disease specific mortality in prostate cancer exhibit marked global variation with the highest levels seen in Western Europe, North America and the lowest in Asia 53 . It is assumed that whilst this is accounted for by a significant genetic component, that diet and lifestyle factors may also contribute. Epidemiological studies also support an association between dietary fat intake, poor prognosis and risk of relapse 54 . In order to identify new pathways that are important in prostate cancer pathogenesis, evaluating a role for the metabolism system and its key components is crucial. Phase III studies recruiting in NSCLC (ADVIGO 1016). Phase II in breast, prostate, colorectal & Ewings sarcoma Preclinical studies show inhibition of prostate cancer cell proliferation Inhibition of tumour growth in prostate cancer xenograft models prostate cancer cases resistant prostate cancer An important downstream intracellular signaling pathway that has been implicated in prostate...

Extinguishing the AR axis

The androgen dependence of prostate cancer on testosterone was first observed as early as 1941 when the effect of castration on androgen levels in prostate cancer was studied 17 . This lead to the introduction of androgen deprivation therapy and the generation of the castrate state where serum levels of testosterone are reduced to < 50ng dl or 1.7nmol l. This treatment is initially effective in 80-90 of patients and results in PSA or radiological responses and clinical improvement in the patient's symptoms. Eventually, the patient's cancer progresses despite serum testosterone levels continuing to be low. The current term used to describe this state is 'castrate resistant prostate cancer' which has replaced the misleading term 'hormone-refractory prostate cancer'. CRPC more accurately describes the ongoing dependence of the cancer on AR signaling despite low measureable testosterone levels. Orteronel (or TAK 700, Takeda Pharmaceuticals) is another 17,20 lyase inhibitor which has...