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...

Classical Cadherins Type II 51 Cadherin

Type II cadherins, cadherins 5, 6, 7, 8, 9, 10, 11, and 12, have structural features similar to Type I cadherins, but differ in amino acid sequence. Type II mesenchymal cadherins are normally expressed on stromal cells and osteoblasts. A mesenchymal cadherin, cadherin 11, and its truncated variant are expressed on highly invasive breast cancer cell lines (Pishvaian et al., 1999), but not on non-invasive cell lines. Previous studies have shown that cadherin 11 is expressed in embryonic...

Inhibition of MMP activity

Inhibition deactivation of MMPs can be accomplished by several factors including a-2-mac-roglobulin, tissue inhibitors of metalloproteinases (TIMPs), small molecules with TIMP-like domains, and the membrane-bound inhibitor RECK (reversion-inducing cysteine-rich protein with kazal motifs) (Sasahara et al., 2002). In tissue fluids, a2-macroglobulin forms a complex with MMPs that can bind to a scavenger receptor. Endocytosis removes the trimer-ic complex, a2-macroglobulin-MMP-scavenger receptor,...

The Notch pathway

Notch gene mutations were first discovered in Drosophila via malformations of the wing 69 . This ligand-activated signaling pathway is a highly conserved mechanism for maintaining stem cell function and regulating apoptosis, proliferation and cell fate specification 69 . Mammals express four Notch receptor family members, termed Notch 1-4 and five ligands two Jagged family ligands (jagged-1 and jagged-2) and three delta-like li-gands (Dll1, Dll3 and Dll4) 69 . The Notch receptors are highly...

Some characteristics of testosterone

Testosterone is principal male androgen, sex hormone and anabolic steroid. It is found not only in humans, but also in many other vertebrates. In males, testosterone is secreted by Leydig cells in testicles, in females by theca cells in ovaries. Small amount is produced also in zona reticularis of adrenal cortex in both genders and in placenta. Chemically (figure 1), it is white powder, soluble in methanol, name is17beta-Hydroxyandrost-4-en-3-on or 4-An-drosten-17beta-ol-3-on, Chemical...

Exponential growth

In 1934 Mottram 4, 5 reported work on the rat tar wart. Tar warts are tar-carcinogen induced neoplasms of the skin starting 75-100 days after the continuous painting of the rat's neck with tar. Histologically, some warts appear benign while others are clearly malignant. Using the tar wart tumor growth model, Mottram was the first to describe tumor expansion as exponential. Exponentially growing tumors graphically produce straight lines by plotting linear time on the x-axis versus the log (at...

Acute and late adverse events of LDR brachytherapy

Almost all patients after LDR brachytherapy develop some kind of acute urinary symptoms, for example, urinary frequency, urgency, and occasional urge incontinence. These symptoms often peak at about 3 months after brachytherapy, subsequently gradually decline over the ensuing 3 to 6 months, and resolve with in 1 year (71). Most patients benefit with the use of an a-blocker. However, Brown et al 71 reported that 22 of patients experienced persistent urinary symptoms even after 12 months. Acute...

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...

Daily rhythm of testosterone

Circadian and ultradian mean testosterone level fluctuations peak is around 8 AM and through level around 8 PM. Over this, there is a 90 min oscillation in testosterone values as reflection of pulsatile secretory pattern. Sleeping increases testosterone values 31 . Some even claim sleep, not circadian rhythm to be more important for regulation of testosterone 31 . Pattern of physical activity (physical work or training in the morning versus evening) does not influence testosterone...

Units for testosterone measurement

Guidelines 3 state testosterone values in ng dl only and some countries still use old values (for example US, Germany, Belgium), but in many countries laboratory results only in SI units - International System of Units - (nmol l) - are available (for example Slovenia). Some articles, to further confusion, use other combinations, like ng ml or mg dl. To allow easier reference to practicing physicians, in Table 3, some typical serum testosterone values are presented in different units. Conversion...

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...

Targeted therapies might require SGR calculations to evaluate the full spectrum of tumor response

Figures 6, 7 display tumor responses evaluable in the clinic. RESIST 1.1 criteria follow for comparison. 1. Disease stabilization (complete inhibition of pre-therapy SGR) The marker or tumor's inherent growth rate is inhibited causing it or its surrogate marker value to remain unchanged during therapy. The tumor or marker continues its calculated pre-therapy growth rate without change during therapy. The growth noted in the surrogate marker or tumor after therapy is predictable and equal to the...

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...

Phosphatidylinositol 3kinases

The PI3Ks are enzymes that are grouped into three classes (I-III). Most members of this family are bound to regulatory subunits which determine its specificty and function 83-85 . Class I PI3Ks are subdivided into IA and IB and are members to the canonical PI3K AKT pathway. They are heterodimeric serine and threonine kinases comprising a catalytic subunit, p110, and a regulatory subunit encoded by the PIK3CA and PIK3R1 genes, respectively 83 . The four isoforms of p110 (a-5) and their...

Cancer

Http dx.doi.org 10.5772 45948 Edited by Gerhard Hamilton Glenn Tisman, Elba Vazquez, Geraldine Gueron, Javier Cotignola, Miguel lvarez-M gica, Ugo Rovigatti, Vildan Bozok Retinta , B rgin Tezcanli Kaymaz, Buket Kosova, Soon Cheol Ahn, Hak-Jong Choi, Kwang-Youn Kim, Sun-Nyoung Yu, Sang-Hun Kim, Sung-Sik Chun, Yeong-Min Park, Yong-Lark Choi, Sun-Yi Lee, Prada, Peng Lee, Mandeep Singh, Yirong Li, Garrett Daniels, Sujata Persad, Jacqueline R Ha, YuHao D Huang, Amit Persad, Meyers, Jutta Engel,...

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...

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...

Summary and conclusion

In this chapter, a review of general literature, as well as data previously published or unpublished by the author, was presented with the specific aim of fostering an ongoing debate on prostate cancer aetiology. This debate was particularly spurred in the past six years by the controversy arising after isolation of a new retrovirus, highly homologous to endogenous xenotropic and polytropic murine retroviruses, called XMRV 55 1 . The first part of the chapter has focused on XMRV, its isolation...

Salinomycin induced PC3 cell apoptosis

To examine if the salinomycin effect is due to apoptosis, we examined PC-3 cells for the nuclear morphology, annexin V staining and induction of various apoptosis-related molecular events before and after salinomycin treatment 20 . Laser scanning confocal microscopy of DAPI-stained PC-3 cells showed that in the absence of the drug, the nuclei were round and homogeneous, whereas salinomycin treatment caused a reduction of cell volume, nuclear condensation (a hallmark feature of apoptotic cells),...

Notch pathway inhibitors

Regardless of the data implicating the Notch pathway in tumor suppression as well as onco-genesis, chemotherapeutic targeting of the Notch pathway employing y-secretase inhibitors (GSI) to block release of the NICD has generated much interest 92 . GSIs, which were designed primarily for Alzheimer's disease, developed by Merck, Novartis, Pfizer and Roche are currently in clinical trials for a number of malignancies including T-ALL, lymphoma, breast, colorectal, brain, pancreatic, and non-small...

References

Comparative gompertzian analysis of alterations of tumor growth patterns. Cancer Res 1994, Aug 15 54(16) 4385-92. 2 Demicheli R, Foroni R, Ingrosso A, Pratesi G, Soranzo C, Tortoreto M. An exponen-tial-gompertzian description of lovo cell tumor growth from in vivo and in vitro data. Cancer Res 1989, Dec 1 49(23) 6543-6. 3 Norton L. A gompertzian model of human breast cancer growth. Cancer Res 1988, Dec 15 48(24 Pt 1) 7067-71. 4 Mottram JC. On the correlation between malignancy...

Different hormonal treatments influence testosterone differently

Different drugs for hormonal treatment of prostate cancer have different effects on serum testosterone. Non-steroidal antiandrogens increase overall serum testosterone levels. Steroi- dal antiandrogen (cyproterone) reduces testosterone levels, but not to castrate values. Often old patients take two 100 mg tablets daily and testosterone values are than commonly around 7 nmol l. With proper dosing (3 times 100 mg daily), values nearing castration levels have been reported (mean 2.5 nmol l, 19 ),...

YY1 as a regulator of posttranslational modifications

YY1 was first identified as a transcription factor and has been shown to regulate the expression of many genes. However, our understanding of YY1 function has evolved with an increasing appreciation for its DNA-binding independent activities, many of which contribute to YYl-mediated gene expression. Proteins undergo different types of post-translational modifications, including acetylation, methylation, ubiquitination and sumoylation that contribute to the complexity of protein stability,...

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...

Clinical application of DT and SGR Discordant results

Mehrara retrieved data from two previously published clinical studies 70 . The first by Guess et al. 38 Table 1 who studied the effect of modified citrus pectin (MCP) on PSA-DT of 12 prostate cancer patients. Mehrara extracted data and analyzed for both PSA-DT and PSA-SGR before and after therapy. The difference between PSA-DT before and after treatment was not found to be statistically significant by the paired t-test (p 0.27). Nevertheless, when transforming PSA-DT to PSA-SGR the difference...

External beam radiotherapy and radioisotope drugs

Focal external beam radiation therapy (RT) is a palliative treatment possibility that should be considered for men with CRPC and bone pain that is limited to one or a few sites. Several clinical trials as well as a systematic review of the literature suggest that single treatments with frac-tionation schedules provide palliation with cost effectiveness and patient convenience 80 . Hemibody RT could also be considered in selected patients with symptomatic disease limited to one side of the...

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...

The CYP17 enzyme One active site two activities

The eukaryotic class II cytochrome P450 enzyme CYP17 is an endoplasmic reticulum membrane bound multifunctional protein with 17a-hydroxylase and C17,20-lyase activities, both engaged on a single active site (Fig. 2) 23-28 . Figure 2. CYP17 and androgen physiology. i. P450 cholesterol side-chain cleavage (P450scc) ii. 3p-Hydroxysteroid dehydrogenase, A45-isomerase iii. CYP17 (OHase) iv. CYP17 (lyase) v. 170-Hydroxysteroid dehydrogenase vi. 5a-Reduc-tase vii. Aromatase (CYP19). Figure 2. CYP17...

Tumor marker Doubling Time DT

Miyamoto 19 studied the growth of hepatic metastases in colorectal cancer patients. He established that a tumor marker could accurately reflect tumor volume and its changes. Using the CEA tumor marker he reported an almost equal and parallel correlation between CEA doubling time and hepatic tumor volume doubling time. PSA-DT Figure 4 is the time it takes for the serum PSA to double. Evidence indicates PSA-DT closely mirrors prostate tumor volume doubling time. Kato et al. in 2008 20 undertook...

Role of physiotherapy

Physiotherapeutic procedures have an important role in the healthcare of people of all ages and with different types of clinical status. These procedures are relevant in the treatment, in the prevention of diseases or complications and in the management or treatment of undesirable pathological conditions to thus minimize the impact these may have in the quality of life of the patient 7 . Physiotherapy is a profession defined by great diversity in areas of clinical practice with the purpose of...

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...

Unique treatment paradigms may be suggested by analysis of tumor growth rate

Figure 17 illustrates results for a patient with pancreatic cancer post Whipple procedure who was found on 6 4 10 to have an enlarged peri-aortic mass 1.8 cm (3.1 cc). Repeat CT on 8 27 10 noted increased size to 2.9 cm (12.8 cc). Therapy with gemcitabine was initiated on 8 27 10. Post therapy reevaluation of the mass on 12 24 10 revealed growth to 3.1 cm (15.6 cc). The patient was discouraged and frightened and thought he had wasted precious C a n ce r P a 1 Tumor Kinetics Analysts Projected...

Measuring tumor growth

It is imperative to depend on sensitive and precise marker assays. Guess 38 tried to address this problem by use of splines or line segments to average all PSA-DT values in an attempt to better detect therapy-induced changes of PSA-DT. Unfortunately, this computerized technique is cumbrous for most to apply. The accurate and reproducible measurement of tumor diameters from imaging studies is critical. Keep in mind that occasionally plain radiographs of larger lesions are preferred because CT...

Literature review Individual TrxG genes 31 ASH2L

ASH2L is the human homologue of Drosophila ASH2 (absent small homeotic 2) and represents a core member of the COMPASS and COMPASS-like complexes. Through interactions with WDR5 (WD-repeat protein 5) and RBBP5 (retinoblastoma binding protein 5), ASH2L activates SET1 domain-containing proteins (SET1A, SET1B and mixed lineage leukemia (MLL)1-4) which subsequently catalyze H3K4 trimethylation 54 . The presence of ASH2L is essential for optimal H3K4 trimethylation as knockdown of ASH2L led to a...

Prostate Cancer Inflammation and Antioxidants

Marika Crohns, Tuomas Westermarck and Faik Atroshi Additional information is available at the end of the chapter http dx.doi.org 10.5772 53296 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...

SGR acceleration SGR after Rx SGR before Rx t211 A positive number

The dynamic of PSA change was used as an early predictor of overall survival after a short exposure to docetaxel therapy (4 doses). Knowledge that a drug may extend survival after just a short exposure would minimize toxicity from ineffective drugs. Hannenin's work 81 found that a rapid rate of PSA decline expressed as PSA half-life < 70 days was associated with a longer overall-survival Figure 13. This result was independent of other known markers of survival and allowed for a greater...

Considerations in evaluating tumor growth effects of targeted therapies

Newer targeted therapies are often cytostatic or cytolentic (slowing proliferation) 60 , resulting in disease stabilization, improved quality of life and extended survival. Examples of such drugs include sorefinib (Nexavar) 61 , axitinib (Inlyta) for renal cell carcinoma 62 , and mTOR inhibitors (everolimus (Afinitor) 63 and temsirolimus (Torisel)). Dasitinib (Sprycel) and sorefinib (Nexavar) are active in prostate cancer. Dasatinib is active in chronic granulocytic leukemia and GIST, inhibits...

Regulation of YY1 expression and activity

In addition to transcriptional regulation, YYl-mediated gene transcription and protein modifications, YY1 expression and function are also modulated at multiple levels. 4.1. YY1 is regulated by gene regulatory proteins As a transcription factor, YY1 regulates the expression of itself through binding to consensus sequences in the first intron of the YY1 gene 82 . These YY1 binding sites are necessary for YY1 gene transcription. Interestingly, overexpressed exogenous YY1 inhibits the...

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. As a transcription factor, YY1 generally activates the expression of oncogenic or proliferative genes and inhibits...

Clinical phase III studies of IAS

Nowadays a number of phase III trials have been completed comparing IAS with CAS 16 . Of the ten reported trials, two included patients with relapse after radical prostatectomy or radiation therapy, all others studied locally advanced and metastatic disease 22,34 . The number of patients in these trials varied from 68 to 1386, but only four involved > 500 patients the average age of patients was around 70 years. Full details of trial design are not available for all studies, several reports...

Epithelialmesenchymal transition

Epithelial cell structure is maintained by cell-cell interactions involving tight junctions and desmosomes and these cells are non-motile. In contrast, mesenchymal cells do not have cell-cell contacts but have distinct cell-ECM interactions and cytoskeletal structures and are motile. Epithelial-mesenchymal transition (EMT) is a series of events where the cell-cell and cell-ECM interactions are altered resulting in detachment of epithelial cells from the sur rounding tissue followed by...

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

Angiogenesis as a hallmark of cancer The hallmarks of cancer define distinctive and complementary capabilities that allow tumors to grow and disseminate. One of those capacities is the induction of angiogenesis. This process specifically refers to the sprouting of new blood vessels from pre-existing ones, involving proliferation of endothelial cells and migration towards pro-angiogenic molecules. The expansion of the existing vasculature also relies on the accumulation of circulating...

New therapeutic approaches in targeting PCSCs

Despite progress in the therapeutic approaches that significantly increased the survival rate of PC patients, most prostate aggressive tumors become resistant to currently used treatment protocols. PC that initially responded well to a standard chemotherapy often recur with selective outgrowth of tumor cell subpopulations and get resistant not only to the original chemotherapeutic agent but also to other therapeutics. Thus, for most patients with relapse of castration-resistant metastatic PC...

Abiraterone and galeterone

As previously mentioned, abiraterone acetate 3 (Fig. 1) constitutes the first and still the only steroidal CYP17 inhibitor approved by the FDA in 2011, being indicated for the treatment of mCRPC after chemotherapy 14 . This drug was developed at the Institute of Cancer Research (UK) considering the known efficacy and limitations of ketoconazole in this field and following the observation that nonsteroidal 3-pyridyl esters had improved selectivity for the inhibition of CYP17. This led to the...

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 lt 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...

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...

PI3KAKT and AR Signalling axis

The role of the PI3K AKT pathway in CaP cell proliferation, survival and progression from AD to AI disease has been linked to androgen receptor AR transcriptional activity, stability and expression. This section of the review will discuss the various modes of crosstalk between the PI3K-Akt and AR axis. The activation of Akt has provided a mechanistic link between PI3K and AR transactivation. However, other modes of interaction have been shown. AR can directly interact with the p85 regulatory...

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...

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

It is well known that the tumor suppressor gene p53 is a key player in controlling the genetic stability in breast tumor cells 86 . More recently, it was reported that inhibition of PARP-1 by veliparib enhances DNA damage in BRCA-proficient cancer cells, a process that appears to be regulated by p53. Although a diverse response was observed in p53-mutant or -null cells, the veliparib and topotecan combination enhanced DNA damage response and cell death in these type of cells 87 . Similarly,...