The aim of this review is to report on the current status of prostate-specific membrane antigen (PSMA)-directed theranostics in prostatecancer (PC) patients. The value of 68 Ga-PSMA-directed PET imaging as a diagnostic procedure for primary and recurrent PC as well as the role of evolving PSMA radioligand therapy (PRLT) in castration-resistant (CR)PC is assessed. The most eminent data from mostly retrospective studies currently available on theranostics of prostatecancer are discussed. The current knowledge on 68 Ga-PSMA PET/CT implicates that primary staging with PET/CT is meaningful in patients with high-risk PC and that the combination with pelvic multi parametric (mp)MR (or PET/mpMR) reaches the highest impact on patient management. There may be a place for 68 Ga-PSMA PET/CT in intermediate-risk PC patients as well, however, only a few data are available at the moment. In secondary staging for local recurrence, 68 Ga-PSMA PET/mpMR is superior to PET/CT, whereas for distant recurrence, PET/CT has equivalent results and is faster and cheaper compared to PET/mpMR. 68 Ga-PSMA PET/CT is superior to 18 F / 11 Choline PET/CT in primary staging as well as in secondary staging. In patients with biochemical relapse, PET/ CT positivity is directly associated with prostate-specific antigen (PSA) increase and amounts to roughly 50% when PSA is raised to ≤0.5 ng/ml and to ≥90% above 1 ng/ml. Significant clinical results have so far been achieved with the subsequent use of radiolabeled PSMA ligands in the treatment of CRPC. Accumulated activities of 30 to 50 GBq of 177 Lu-PSMA ligands seem to be clinically safe with biochemical response and PERCIST/RECIST response in around 75% of patients along with xerostomia in 5 –10% of patients as the only notable side effect. On the basis of the current literature, we conclude that PSMA-directed theranostics do have a major clinical impact in diagnosis and therapy of PC patients. We recommend that 68 Ga-PSMA PET/ CT should be performed in primary staging together with pelvic mpMR in high-risk patients and in all patients for secondary staging, and that PSMA-directed therapy is a potent strategy in CRPC patients when other treatment options have failed. The combination of PSMA-directed therapy with existing therapy modalities (such as 223 Ra-chloride or androgen deprivation ther- apy) has to be explored, and prospective clinical multicenter trials with theranostics are warranted.
ACS, American Cancer Society; ASR, Age-standardized rate; AUA, American Urological Association; BvDU, Professional Association of German Urologists (Berufsverband der Deutschen Urologen); BPH, benign prostatic hyperplasia; DEGAM, German College of General Practice and Family Medicine (Deutsche Gesellschaft für Allgemeinmedizin und Familienmedizin); EAU, European Association of Urology; ERSPC, European Randomized Study of Screening for ProstateCancer; GP, General practitioner; NCCN, National Comprehensive Cancer Network; ng/mL, nanograms per milliliter; PCa, prostatecancer; PLCO, Prostate, Lung, Colorectal and Ovarian study; PSA, pros- tate-speci ﬁc antigen; USPSTF, US Preventive Services Task Force.
Abstract: The idea of using metabolic aberrations as targets for diagnosis or therapeutic intervention has recently gained increasing interest. In a previous study, our group discovered intriguing differences in the oxidative mitochondrial respiration capacity of benign and prostatecancer (PCa) cells. In particular, we found that PCa cells had a higher total respiratory activity than benign cells. Moreover, PCa cells showed a substantial shift towards succinate-supported mitochondrial respiration compared to benign cells, indicating a re-programming of respiratory control. This study aimed to investigate the role of succinate and its main plasma membrane transporter NaDC3 (sodium-dependent dicarboxylate transporter member 3) in PCa cells and to determine whether targeting succinate metabolism can be potentially used to inhibit PCa cell growth. Using high-resolution respirometry analysis, we observed that ROUTINE respiration in viable cells and succinate-supported respiration in permeabilized cells was higher in cells lacking the tumor suppressor phosphatase and tensin-homolog deleted on chromosome 10 (PTEN), which is frequently lost in PCa. In addition, loss of PTEN was associated with increased intracellular succinate accumulation and higher expression of NaDC3. However, siRNA-mediated knockdown of NaDC3 only moderately influenced succinate metabolism and did not affect PCa cell growth. By contrast, mersalyl acid—a broad acting inhibitor of dicarboxylic acid carriers—strongly interfered with intracellular succinate levels and resulted in reduced numbers of PCa cells. These findings suggest that blocking NaDC3 alone is insufficient to intervene with altered succinate metabolism associated with PCa. In conclusion, our data provide evidence that loss of PTEN is associated with increased succinate accumulation and enhanced succinate-supported respiration, which cannot be overcome by inhibiting the succinate transporter NaDC3 alone.
Androgen deprivation therapy (ADT) remains a key approach in the treatment of prostatecancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3 0 -triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidences show a higher incidence of PCa in men with elevated thy- roid hormone levels. The thyroid hormone binding protein μ-Crystallin (CRYM) medi- ates intracellular thyroid hormone action by sequestering T3 and blocks its binding to cognate receptors (TR α/TRβ) in target tissues. We show in our study that low CRYM expression levels in PCa patients are associated with early biochemical recurrence and poor prognosis. Moreover, we found a disease stage-specific expression of CRYM in PCa. CRYM counteracted thyroid and androgen signaling and blocked intra- cellular choline uptake. CRYM inversely correlated with [18F]fluoromethylcholine (FMC) levels in positron emission tomography/magnetic resonance imaging of PCa patients. Our data suggest CRYM as a novel antagonist of T3- and androgen- mediated signaling in PCa. The role of CRYM could therefore be an essential control mechanism for the prevention of aggressive PCa growth.
Even though bone metastases in prostatecancer display a predominantly osteoblastic appearance, osteolytic changes usually precede bone formation, and elevated bone breakdown remains a dominant feature of metastatic prostatecancer . Inhibition of bone degradation with anti-resorptive medications has been shown to significantly delay skeletal-related events in patients with advanced prostatecancer, emphasizing the fundamental role of bone resorption in the growth even of osteoblastic metastases . Therefore, findings from a predominantly osteolytic cancer cell line such as PC3 are of clinical relevance for the treatment of osteoblastic tumors . According to the literature, it is important to get at least a 50 % inhibition in tumor growth in mouse models in order to predict clinical responses in patients . The presented thesis fulfills this demand, yet, the neutralizing antibody did not stop the osteolytic process. This is not unexpected. Other factors in addition to IL-6 are also involved in bone resorption and in fact, IL-6 maintains many reciprocal interrelations with other pro- resorptive cytokines, forming a whole network in which they often act in synergism .
Details of participants from the eight countries are shown in Table 1. After an average of 8.7 years of follow-up, 2727 men were diagnosed with prostatecancer among the 142 520 participants included in this study, with a total of 1 236 265 person-years. The median age at diagnosis of prostatecancer was 66 years (range: 44 – 95 years). There was an approximate two-fold variation in the calibrated median intake of total meat and meat products among participating countries, and a three- to six-fold variation in the intake of red meat, poultry, milk and milk beverages, cheese and eggs; the median intake of processed meat and yoghurt varied by more than 10-fold among countries. On the basis of 24-h recall data, protein intake was largely derived from meat (32%), cereals (18%), cheese (9%) and milk (7%). Overall, 17% of protein was derived from dairy products, although this varied from 11% in Spain to 23% in Sweden. Dietary calcium was largely derived from dairy products (53%), with milk, cheese and yoghurt contributing 22, 23 and 8%, respectively. Variation in the proportion of calcium derived from dairy foods ranged from 43% in Germany to 65% in Sweden. There was a very strong correlation between dairy protein and dairy calcium intake (r ¼ 0.98).
In case of a high risk tumor (based on PSA measurements and histophatology of prostate biopsies) or when the cancer begins to grow and spread in the tissue around the prostate gland, patients generally undergo surgery or radiation therapy. For surgical treatment the whole prostate along with part of the surrounding tissue, including generally the seminal vesicles and in some cases lymphonodes, is removed via radical prostatectomy, either retropubic or perineal. Radiation therapy is mainly adopted to kill cancer cells or prevent their growth, using high-energy rays or particles. There are two main types of radiation therapy: external beam radiation therapy (EBRT) and internal radiation therapy (brachytherapy). External radiation therapy consists in targeting the prostate gland with an exact dose of radiation generated from a machine outside the body, which is carefully focused in the cancer area to reduce the risk of side effects. Concerning internal radiation therapy, a radioactive substance sealed in small pellets called “seeds”, which are placed directly into or near the cancer, is used (from http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate- cancer-treating-hormone-therapy, 04/2015).
Deletions involving the chromosomal band 5q21 are among the most frequent alterations in prostatecancer. Using single-nucleotide polymorphism (SNP) arrays, we mapped a 1.3 megabase minimally deleted region including only the repulsive guidance molecule B (RGMB) and chromodomain helicase DNA-binding protein 1 (CHD1) genes. Functional analyses showed that CHD1 is an essential tumor suppressor. FISH analysis of 2,093 prostate cancers revealed a strong association between CHD1 deletion, prostate-speciﬁc antigen (PSA) biochemical failure (P ¼ 0.0038), and absence of ERG fusion (P < 0.0001). We found that inactivation of CHD1 in vitro prevents formation of ERG rearrangements due to impairment of androgen receptor (AR)-dependent transcription, a prerequisite for ERG translocation. CHD1 is required for efﬁcient recruitment of AR to responsive promoters and regulates expression of known AR-responsive tumor suppressor genes, including NKX3-1, FOXO1, and PPARg. Our study establishes CHD1 as the 5q21 tumor suppressor gene in prostatecancer and shows a key role of this chromatin remodeling factor in prostatecancer biology. Cancer Res; 73(9); 2795–805. 2013 AACR.
While the differential effects of fibroblast coinjection seen in LuCaP136 and LNCaP xenografts are interesting observations deserving further investigation, this was not the major focus of our study. As we primarily aimed to establish a representative orthotopic in vivo model in which the biological effects of cancer-associated fibroblasts can be further investigated, we further focused on LuCaP136 xenografts in our validation experiments since we observed the strongest effects of CAF coinjection there in the first coinjection experiment. We cannot directly proof if the observed stimulation of metastatic spread in CAF-groups is a direct effect of CAF coinjection or more a consequence of increased primary tumor size. However, though both factors may play a role for the increased incidence of metastases, we believe the first point to be biologically more important. While in some tumors like renal cell carcinoma the incidence of metastases is clearly correlated with primary tumor size 49 this is not the case for prostatecancer. In contrast, it has been shown in several studies that CAFs are able to stimulate metastasis-associated biological features in nearby PCa cells like invasion, epithelial-to-mesenchymal transition (EMT), angiogenesis and stemness traits 33 – 36 , 50 , 51 .
Purpose The aim of the present meta-analysis was to quantify effects of resistance exercise (RE) on physical performance and function, body composition, health-related quality of life (HRQoL), and fatigue in patients with prostatecancer. Methods Trial data were obtained from the databases PubMed, MEDLINE, EMBASE, SCOPUS, and the Cochrane Library as of inception to 31st of December 2016. Thirty-two trials with 1199 patients were included. Results that were measured by using the same assessment method in five or more of the original studies were pooled in a meta- analysis.
Prostatecancer is characterised by structural rearrangements. Most frequently translocations occur between androgen-responsive genes and members of the ETS family. Hereby, the most common translocation is the TMPRSS2:ERG-Fusion. In a recent sequency study we could detect 140 gene fusions without ETS-genes. Hence, aim of the study was to measure the prevalence of some of these non-ets gene fusions. In a randomized study, 27 of the 140 non-ets genes were analyzed by FISH in 500 prostate cancers in tissue microarray regarding chromosomal rearrangements. Using break-apart FISH probes for one fusion partner each, we found rearrangements of 13 (48%) of the 27 analyzed genes in 300-400 analyzable cancers per gene. Recurrent breakage, often accompanied by partial deletion of the genes, was found for NCKAP5,
Another well-known effect of PMA is the release of TNFα and other factors from LNCaP cells. Therefore, the question whether bryostatin 1 affects the composition of the conditioned medium (CM) was addressed. Indeed, whereas CM- PMA was capable of inducing apoptosis in naïve LNCaP cells, CM-Bryo1 and, more importantly, CM-Bryo1+PMA failed to induce apoptosis. As with cells that are directly treated with PMA and bryostatin 1, cells that received CM-Bryo1+PMA still exhibited phosphorylation of p38, which was maintained over several hours, as well as phosphorylation of JNK and dephosphorylation of pAkt. Taken together, these data are in favor with the hypothesis that bryostatin 1 prevents PMA from triggering the release of pro-apoptotic factors to the CM, while others are still being secreted and are capable of triggering a cascade that leads ultimately to the phosphorylation of p38 and JNK and dephosphorylation of pAkt, respectively. Although a cytokine array did not reveal any obvious difference in the secretion of pro-apoptotic factors, probably due to issues of sensitivity , a more accurate measurement employing ELISA revealed that PMA-induced secretion of TNFα is essentially blunted by bryostatin 1. PMA, in turn, depends on the autocrine secretion of this cytokine for killing prostatecancer cells . The impaired TNFα secretion by PMA when cells are simultaneously treated with bryostatin 1 seems to fully account for the functional antagonism. Indeed, adding back this cytokine at similar final concentrations as those normally observed in CM-PMA fully restores the apoptotic activity. It is interesting that bryostatin 1 promotes apoptosis and TNFα release from leukemia cells [115, 116], suggesting a strict cell type dependency for the differential killing ability of this agent.
cycle regulators contributing to the growth of many sporadic cancers (Zoncu et al., 2011b; Porta et al., 2014). αATA(8,24) was shown to strongly inhibit the Akt/mTORC1 signaling and the expression of different cell cycle regulatory proteins. Accordingly, αATA(8,24) significantly impedes the cell cycle progression of prostatecancer cells. The inhibition of the Akt/mTOR pathway by αATA(8,24) was obvious already 6 h after treatment, before the appearance of any mitochondrial or lysosomal dysfunction. Under nutrient-rich conditions, mTOR as well as Akt, strongly suppress autophagy, and mTOR inhibitors, such as rapamycin, are strong autophagic inducers (Zoncu et al., 2011b). Similarly, accumulation of the acidic vesicular organelles in cells treated with αATA(8,24) might be also a result of Akt/mTOR inhibition. Rapamycin, a canonical inhibitor of mTOR, forms a gain-of-function complex with the intracellular immunoplilin 12-kDa FK506-binding protein (FKBP12) protein and the formed complex binds near the mTOR kinase domain, partially inhibiting mTORC1 (Tao et al., 2010; Laplante and Sabatini, 2012). This partial inhibition of mTORC1 by rapamycin was, however, not sufficient to trigger apoptosis in prostatecancer cells (Zoncu et al., 2011b; Morad et al., 2013). Rapamycin, which induces autophagy, protects cells against a range of proapoptotic insults. It is believed that autophagy has a prosurvival function by enhancing clearance of mitochondria and subsequently reducing cytosolic cytochrome c release and downstream caspase activation (Repnik et al., 2013). Different types of autophagy, in turn, depend on subsequent lysosomal degradation of their cargo. Under conditions of oxidative stress, excess ROS diffusing into lysosomes and autolysosomes fully loaded with autophagic cargo can easily destabilize membranes leading to lysosomal membrane permeabilization. The lysosomal membrane dysfunction not only leads to the release of lysosomal proteases into cytosol to exacerbate cell death but also reduces the degradation rate of the endocytotic system impairing the cytoprotective role of autophagy and lowering the apoptotic threshold (Repnik et al., 2013). In fact, the increased ROS and superoxide production in cells treated with αATA(8,24) might be amplified by the positive feedback loop between mitochondria and acidic vesicular organelles, whereas the ROS production and the feedback loop were absent in cells treated with rapamycin.
Resistance to docetaxel is a major clinical problem in advanced prostatecancer (PCa). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance. In this study, we aim to elucidate the role of the GR in docetaxel-resistant PCa in order to improve the current PCa therapies. GR expression was analyzed in a tissue microarray of primary PCa specimens from chemonaive and docetaxel- treated patients, and in cultured PCa cell lines with an acquired docetaxel resistance (PC3-DR, DU145-DR, and 22Rv1-DR). We found a robust overexpression of the GR in primary PCa from docetaxel-treated patients and enhanced GR levels in cultured docetaxel-resistant human PCa cells, indicating a key role of the GR in docetaxel resistance. The capability of the GR antagonists (RU-486 and cyproterone acetate) to revert docetaxel resistance was
We should also emphasize that in the study in focus, nutrition was not associated with risk factors. However, other studies should be conducted due to the importance of micronutrients for genetic stability. Considering cancer as a multifactorial genetic disease, with strong influences of age, ethnicity, socioeconomic factors, lifestyle, family history, micronutrients and epigenetic factors associated with occupational and environmental risk, the findings obtained in this epidemiological study corroborate as the main risk factors that guide the etiology of prostatecancer. The results obtained can be used as indicators of public policies related to the treatment and prevention of prostatecancer.
Prostatecancer (PCa) is a major mortality cause for men around the world and therefore there is a high demand for reliable diagnostic solutions. Prostate-specific antigen (PSA) is currently the representative biomarker for pre-screening of PCa, necessarily followed by biopsy examinations for confirmatory diagnosis. In the biomedical market, equipment to detect PSA in its relevant clinical concentration is already commercialized. These devices are accurate, but the bench-top systems are bulky, expensive, have a long response time, and rely on optical labels. To eliminate these drawbacks, point-of-care (POC) devices are under development, aiming at cost-effective, precise, portable, disposable and environmentally friendly designs with a fast response time. Most of the devices are utilizing conventional biosensing principles. However, the miniaturization of these approaches directly induces performance variations and a drastic decrease of the sensing accuracy. It is noteworthy that no biomarker is ideal, and no definite diagnostic decision can be based on a single biomarker. Thus, the detection of a combination of various biomarkers is recommended to provide multi-variable information for accurate diagnosis in the early stage of cancer development. Some biomarkers are more specific for PCa than others, but of a relatively low concentration in the clinical samples. Therefore, new biosensing concepts with multiplexing capability are under intensive investigation.
effects of that treatment in prostatecancer cells on myeloid cells (Figure 1 a). In the first setup, prostatecancer cells were exposed to the plasma, and the cell culture supernatants were collected after four hours and added to myeloid cells. At 1 h, immediate effects such as ROS production and mitochondrial activity were determined. At 24 h, the metabolic activity and cell proliferation of the myeloid cells were investigated. At 96 h, the cell surface marker expression profile and cytokine release were assessed. In the direct co-culture approach, the prostatecancer cells were exposed to the plasma, and myeloid cells were added 1 h later. The co-cultures were imaged at 24 h, 48 h, 72 h, and 96 h, with an additional investigation of the cell surface marker profile of myeloid cells and the cytokine release in the supernatants of the co-cultures at 96 h. An image of the plasma treatment procedure is shown in Figure 1 b. Based on previous studies, it was hypothesized that the plasma treatment decelerates tumor cell growth. Investigating the impact on the metabolic activity of the cancer cells 4 h after plasma treatment, the treatment led to a significant reduction in both prostatecancer cell lines investigated (Figure 1 c). The plasma labeling denotes cells that were treated with the gas plasma directly. The argon control indicates conditions where the inert argon gas was not ignited into plasma but instead was merely blown onto the cell suspension as a mock treatment to exclude any biological effects of the noble gas alone. Similar to other plasma jets, the kINPen generates ROS in the plasma gas phase that subsequently diffuse into the treated liquid [ 31 ]. From there, the species further diffuse to cells [ 16 ] with some of the species possibly accumulating in the cytosol, as has been suggested for H 2 O 2 passing through aquaporin channels in the membrane [ 32 ]. As the purpose was to investigate the immunomodulatory potential of supernatants from the untreated and plasma-treated prostatecancer cells, we also investigate residual ROS in these suspensions. Only a minor presence of ROS was observed in the plasma-treated LNCaP cultures 1 h after exposure, while residual ROS were absent for plasma-treated PC3 cells at 1 h (Figure 1 d). At 4 h after plasma treatment, supernatants of the prostatecancer cells were collected and used for subsequent experiments with myeloid cells. Altogether, plasma treatment decelerated prostatecancer cell growth, and the majority of plasma-derived ROS have reacted with the cancer cells.
One of the prostatecancer candidate genes is the CYP17 gene. A thymidine (T) to cytosine (C) transition (designated A2 variant) in the promoter region of the CYP17 gene has been used in several studies in order to determine a possible association with the prostatecancer risk. A recent meta-analysis found no effect of the CYP17 polymorphism for the sporadic prostatecancer (74). The question still remained unresolved for familial cases, since only two investigators included prostatecancer families (22;93). In order to evaluate the role of the CYP17 A2 allele in familial aggregation of prostatecancer we performed an association study. A putative influence of the A2 allele on disease risk was investigated by designing a dominant and a recessive model. In our study we realized a slight difference of CYP17 genotypes between sporadic cases and controls. However, this unequal distribution was not significant. Although a certain trend can be seen, that the A2 allele increases susceptibility to prostatecancer, our results are consistent with the conclusion, that CYP17 has no effect on prostatecancer risk in general. To investigate the involvement of this polymorphism in familial prostatecancer we performed comparison of the familial cases with controls. Our results showed no evidence that the CYP17 genotype might predispose for a familial aggregation of prostatecancer neither under the dominant nor under the recessive model. Our results do not suggest a role of CYP17 as a high-risk susceptibility gene for familial prostatecancer nor as a modifier for the disease risk.
An isoform shift from the expression of nCLU to sCLU was reported and theorized to be important for progression of various malignancies, including colon cancer (Pucci et al., 2004). Also, over-expression of CLU was closely associated with disease progression in bladder cancer (Miyake et al., 2001) and prostatecancer acceleration (Miyake et al., 2004). While nCLU is mostly found in the nucleus, sCLU is present in the cytoplasmic cell compartment (reviewed in Shannan et al., 2006, b). Therefore, we evaluated the immunohistochemical staining pattern in primary cutaneous malignant melanomas and metastases to assess any differences between nuclear and cytoplasmic staining patterns in the progression of malignant melanoma and whether these differences could be detected. There were no detectable differences between nuclear (nCLU) and cytoplasmic (sCLU) CLU staining. Thus, our immunohistochemical results do not support the hypothesis that a pattern shift of CLU isoforms may be of importance during progression of malignant melanoma. A major caveat in our interpretation of these data is that we did not have a positive control for nCLU expression and therefore we can not be completely certain we were detecting nuclear versus secretory CLU expression in the samples examined in our study. Based on the above, we document that both CLU mRNA and protein expressions vary in human melanomas and melanoma cell lines, however, unlike other tumours, CLU expression does not seem of importance for the progression and/or pathogenesis of malignant melanoma.
Publikation 3: Tahir Durmus, Carsten Stephan, Maria Grigoryev, Gerd Diederichs, Musaab Saleh, Torsten Slowinski, Andreas Maxeiner, Anke Thomas, Thomas Fischer; Detection of prostatecancer by real-time MR/Ultrasound fusion guided biopsy: 3T MRI and state of the art sonography techniques; Rofo. 2013 May;185(5):428-33.: Dateninterpretation. Verfassen einzelner Passagen und kritisches Überarbeiten des Manuskripts. Finale Zustimmung der zu publizierenden Version des Artikels