Reappraisal of glucocorticoids in castrate-resistant prostate cancer

Recent reports and discussions of .preclinical prostate cancer models have emphasized the possibility that enzalutamide resistance may be mediated by glucocorticoid receptors （GR）.In both in vitro and xenograft animal studies, it is possible to show that the GR is up-regulated in prostate cancer cell lines and that dexamethasone reverses enzalutamide induced growth inhibition. In these model systems, GR agonists can induce a subset of androgen receptor target genes including prostate-specific antigen. These investigators also report a correlation between GR expression in patient-derived prostate cancer specimens and clinical response to enzalutamide. The authors discuss the possibility that these findings have important clinical relevance. We note that the current clinical evidence for GR mediating drug resistance or disease progression in patients with castrate-resistant prostate cancer （CRPC） is very limited at best.     

Glucocorticoids and prostate cancer treatment： friend or foe？

Glucocorticoids have been used in the treatment of prostate cancer to slow disease progression, improve pain control and offset side effects of chemo- and hormonal therapy. However, they may also have the potential to drive prostate cancer growth via mutated androgen receptors or glucocorticoid receptors （GRs）. In this review we examine historical and contemporary use of glucocorticoids in the treatment of prostate cancer, review potential mechanisms by which they may inhibit or drive prostate cancer growth, and describe potential means of defining their contribution to the biology of prostate cancer.     

Next generation patient-derived prostate cancer xenograft models

There is a critical need for more effective therapeutic approaches for prostate cancer. Research in this area, however, has been seriously hampered by a lack of clinically relevant, experimental in vivo models of the disease. This review particularly focuses on the development of prostate cancer xenograft models based on subrenal capsule grafting of patients＇ tumor tissue into nonobese diabetic/ severe combined immunodeficient （NOD/ SCID） mice. This technique allows successful development of transplantable, patient-derived cancer tissue xenograft lines not only from aggressive metastatic, but also from localized prostate cancer tissues. The xenografts have been found to retain key biological properties of the original malignancies, including histopathological and molecular characteristics, tumor heterogeneity, response to androgen ablation and metastatic ability. As such, they are highly clinically relevant and provide valuable tools for studies of prostate cancer progression at cellular and molecular levels, drug screening for personalized cancer therapy and preclinical drug efficacy testing; especially when a panel of models is used to cover a broader spectrum of the disease. These xenograft models could therefore be viewed as next-generation models of prostate cancer.     

Molecular markers in prostate cancer Part Ⅱ： potential roles in management

Predicting treatment responses in advanced prostate cancer （PCa） currently centres on prostate-specific antigen （PSA） kinetics and on being able to visualize measurable changes in imaging modalities. New molecular markers have emerged as potential diagnostic and prognostic indicators; these were summarized in Part I of this review in the Asian Journal ofAndrology. A number of molecular markers are now being used to enhance PCa imaging and staging. However, management options for advanced and hormone-resistant PCa （HRPC） are limited and additional therapeutic options are needed. Molecular markers have been proposed as potential therapeutic targets using gene therapy and immunomodulation. Additionally, markers identified in early PCa and precursor lesions may offer novel targets for chemoprevention and vaccine development. This review summarizes the current advances regarding the roles of these markers in the management of PCa.     

Chromoplexy： a new paradigm in genome remodeling and evolution

Early massively-parallel sequencing stu-dies have revealed the mutational land-scape of protein-coding genes in prostate cancer. However, most of these studies have not explored the extensive influence of geno- mic rearrangement in prostate cancer. In a recent Cell article, Baca and colleagues used whole-genome sequencing to tackle this issue, comprehensively surveying the abun-dance of genomic rearrangements present in a large cohort of 57 prostate cancers. They characterized a wide-spread phenomenon termed ＇chromoplexy＇, which may drive can-cer evolution through the phenomena of punctuated equilibrium by concurrently dys-regulating numerous cancer genes across multiple chromosomes. While the causes of this event still require elucidation, this defin-ing discovery undoubtedly offers an impor- tant glimpse into the evolutionary process of prostate cancer.     

α1 and β1 integrins enhance the homing and differentiation of cultured prostate cancer stem cells

CD133＋ prostate cancer stem cells （PCSCs） have recently been identified in human prostate cancer tissues. The present study reports the integrin profile of prostate cancer progenitor cells and the role of α1 and β1 integrins in the homing and differentiation of PCSCs in vitro. PCSCs were isolated from the tissue specimens of patients with prostate cancer and the expression of surface integrins and adhesion patterns were determined. Our analysis of the expression of surface integrins and their adhesion patterns of prostate cancer stem cells derived from prostate cancer tissues revealed that the levels of β1 and α2β1 integrins were significantly higher （P 〈 0.05） than those of the other integrins. By contrast, peripheral blood-derived CD 133＋ cells from prostate cancer patients showed a high level of expression （P 〈 0.01） of α2β1,αvβ3, αvβ5, β1 and α1 integrins and a minimal expression of α4β1 integrins. Moreover, CD 133＋ cells derived from both prostate cancer tissues and peripheral blood exhibited an increased degree of attachment to extraceUular matrix proteins （P 〈 0.001） and a high expression level of α2β1 integrin. In vitro experiments using blocking antibodies indicated that α1 and β1 integrins have a role in the homing and differentiation of PCSCs. This is the first report to suggest the importance of integrins in mediating the homing and differentiation of PCSCs.     

Castrate-tolerant cells： what are the implications for the treatment of localized prostate cancer？

More effective treatment of prostate cancer relies on eliminating cellsthat survive androgen withdrawal therapy. The discovery that castrate-tolerant tumour cells pre-exist in localized prostate cancer, prior to androgen withdrawal or progres-sion to castrate-resistant disease, supports the notion that neo-adjuvant therapies might be considered in the management of early stage prostate cancer. Advances in our ability to xenograft human prostate cancer provides a unique model system to study individual patient responses and test the preclinical efficacy of novel compounds for men with localized disease.     

Diagnostic strategies and the incidence of prostate cancer： reasons for the low reported incidence of prostate cancer in China

We have analysed the reasons for the low reported incidence of prostate cancer in China and argue for early diagnosis and treatment of this disease. According to the 2002 database of the International Agency for Research on Cancer （IARC）, the age-standardized incidence of prostate cancer in China is 1.6/105 person years （PY）, with a mortality rate of 1.0/105 PY and mortality-to-incidence rate ratio （MR/IR） = 0.63. The MR/IR ratio of prostate cancer in China was found to be higher than the average in Asia （MR/IR = 0.57） and much higher than that in North America （MR/IR = 0.13）. These data indicate that in China most prostate cancers were in the advanced stages at the time of diagnosis, and that patients had a short survival time thereafter. In 2004, Stamey et al. reported a retrospective American study of prostate cancer for the years 1983-2003. It was shown that most cases of prostate cancer detected by prostate-specific antigen （PSA） screening were in the advanced stage at the start of this 20-year period. These early follow-up data are quite similar to the results obtained from mass PSA screening of elderly men in Changchun, China. However, after the American programmes for early diagnosis and treatment of prostate cancer were accepted, tumours were diagnosed at earlier stages. On the basis of these findings, mass screening should be performed in the whole of China using serum PSA to facilitate early diagnosis and treatment of prostate cancer.     

Phenotypic heterogeneity of mutations in androgen receptor gene

Androgen receptor （AR） gene has been extensively studied in diverse clinical conditions. In addition to the point mutations, trinucleotide repeat （CAG and GGN） length polymorphisms have been an additional subject of interest and controversy among geneticists. The polymorphic variations in triplet repeats have been associated with a number of disorders, but at the same time contradictory findings have also been reported. Further, studies on the same disorder in different populations have generated different results. Therefore, combined analysis or review of the published studies has been of much value to extract information on the significance of variations in the gene in various clinical conditions. AR genetics has been reviewed extensively but until now review articles have focused on individual clinical categories such as androgen insensitivity, male infertility, prostate cancer, and so on. We have made the first effort to review most the aspects of AR genetics. The impact of androgens in various disorders and polymorphic variations in the AR gene is the main focus of this review. Additionally, the correlations observed in various studies have been discussed in the light of in vitro evidences available for the effect of AR gene variations on the action of androgens.     

Identification of speckle-type POZ protein somatic mutations in African American prostate cancer

The speckle-type POZ protein （SPOP） is a tumor suppressor in prostate cancer （PCa）. SPOP somatic mutations have been reported in up to 15% of PCa of those of European descent. However, the genetic roles of SPOP in African American （AA）-PCa are currently unknown. We sequenced the SPOP gene to identify somatic mutations in 49 AA prostate tumors and identified three missense mutations （p.Y87C, p.F102S, and p.G111E） in five AA prostate tumors （10%） and one synonymous variant （p.11061） in one tumor. Intriguingly, all of mutations and variants clustered in exon six, and all of the mutations altered conserved amino acids. Moreover, two mutations （p.F102S and p.G111E） have only been identified in AA-PCa to date. Quantitative real-time polymerase chain reaction analysis showed a lower level of SPOP expression in tumors carrying SPOP mutations than their matched normal prostate tissues. In addition, SPOP mutations and novel variants were detected in 5 of 27 aggressive PCa and one of 22 less aggressive PCa （P 〈 0.05）. Further studies with increased sample size are needed to validate the clinicopathological significance of these SPOP mutations in AA-PCa.     

Apogossypolone, a novel inhibitor of anfiapoptotic Bcl-2 family proteins, induces autophagy of PC-3 and LNCaP prostate cancer cells in vitro

Limited treatment options are available for aggressive prostate cancer. Gossypol has been reported to have a potent anticancer activity in many types of cancer. It can increase the sensitivity of cancer cells to alkylating agents, diminish multidrug resistance and decrease metastasis. Whether or not it can induce autophagy in cancer cells has not yet been determined. Here we investigated the antiproliferative activity of apogossypolone （ApoG2） and （-）-gossypol on the human prostate cancer cell line PC3 and LNCaP in vitro. Exposure of PC-3 and LNCaP cells to ApoG2 resulted in several specific features characteristic of autophagy, including the appearance of membranous vacuoles in the cytoplasm and formation of acidic vesicular organelles. Expression of autophagy-associated LC3-Ⅱ and beclin-1 increased in both cell lines after treatment. Inhibition of autophagy with 3-methyladenine promoted apoptosis of both cell types. Taken together, these data demonstrated that induction of autophagy could represent a defense mechanism against apoptosis in human prostate cancer cells.     

Immunotherapy and therapeutic vaccines in prostate cancer： an update on current strategies and clinical implications

In recent years, immunotherapy has emerged as a viable and attractive strategy for the treatment of prostate cancer. While there are multiple ways to target the immune system, therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in late-stage clinical trials. The landmark Food and Drug Administration approval of sipuleuceI-T for asymptomatic or minimally symptomatic metastatic prostate cancer set the stage for ongoing phase III trials with the cancer vaccine PSA-TRICOM and the immune checkpoint inhibitor ipilimumab. A common feature of these immune-based therapies is the appearance of improved overall survival without short-term changes in disease progression. This class effect appears to be due to modulation of tumor growth rate kinetics, in which the activated immune system exerts constant immunologic pressure that slows net tumor growth. Emerging data suggest that the ideal population for clinical trials of cancer vaccines is patients with lower tumor volume and less aggressive disease. Combination strategies that combine immunotherapy with standard therapies have been shown to augment both immune response and clinical benefit.     

Efficacy of maximal androgen blockade versus castration alone in the treatment of advanced prostate cancer： a retrospective clinical experience from a Chinese medical centre

In this retrospective study, we evaluated and compared the efficacy and toxicities of maximal androgen blockade （MAB） versus castration alone in Chinese patients with advanced prostate cancer. From 1996 to 2004, 608 patients with advanced prostate cancer were included in the study. Patients were retrospectively divided into two groups according to different therapeutic regimens. Of the 608 patients, 300 patients were treated with MAB （castration plus nonsteroidal antiandrogens） and the remaining 308 were treated with castration alone. The 2- and 5-year overall survival rates of these patients were 73.7% and 56%, respectively. Multivariate analysis showed that, in patients with metastatic prostate cancer, MAB was associated with not only the improvement of progression-free survival （PFS） （increased by 10 months） but also a 20.6% reduction in mortality risk compared with castration alone. In contrast, the efficacy of MAB was not superior to castration alone for patients with nonmetastatic prostate cancer. Interestingly, among patients with MAB, those using bicalutamide had a longer PFS than those using flutamide; this was especially so in patients with metastatic prostate cancer. Almost all of the toxicities due to the hormone therapy were mild to moderate and manageable. To conclude, in China, hormone therapies, including MAB and castration alone, have been standard treatments for advanced prostate cancer. For patients with nonmetastatic prostate cancer, castration alone might be adequately practical and efficient. In patients with metastatic prostate cancer, however, MAB has superior efficacy over castration alone. It is clear that MAB should be considered the first-line standard treatment for patients with metastatic prostate cancer.     

New developments in the treatment of castration resistant prostate cancer

In the past 5 years, the treatment and understanding of metastatic castrate resistant prostate cancer （CRPC） have improved dramatically. Our understanding of the mechanisms of castration resistance has allowed for the development of new drugs to target prostate cancer, and our understanding of genetic mutations may give us new tools with which to more accurately diagnose and be able to predict the course of this heterogeneous disease. This article summarizes the recent advances in the understanding of the development of CRPC, as well as the new drugs and targets, which have evolved from this basic research.     

Human epidermal growth factor receptor type 2 protein expression in Chinese metastatic prostate cancer patients correlates with cancer specific survival and increases after exposure to hormonal therapy

Aim： To investigate human epidermal growth factor receptor type 2 （HER2） protein expression and gene amplification in Chinese metastatic prostate cancer patients and their potential value as prognostic factors. Methods： Immunohistochemistry （IHC） was performed to investigate HER2 protein expression in prostate biopsy specimens from 104 Chinese metastatic prostate cancer patients. After 3-11 months of hormonal therapy, 12 patients underwent transurethral resection of the prostate （TURP）. HER2 protein expression of TURP specimens was compared with that of the original biopsy specimens. Of these, 10 biopsy and 4 TURP specimens with HER2 IHC staining scores ≥ 2＋ were investigated for HER2 gene amplification status by fluorescent in situ hybridization （FISH）. Results： Of the 104 prostate biopsy specimens, HER2 protein expression was 0, 1＋, 2＋ and 3＋ in 49 （47.1%）, 45 （43.3%）, 8 （7.7%） and 2 （1.9%） cases, respectively. There was a significant association between HER2 expression and Gleason score （P = 0.026）. HER2 protein expression of prostate cancer tissues increased in 33.3% of patients after hormonal therapy. None of the 14 specimens with HER2 IHC scores 〉 2＋ showed HER2 gene amplification. Patients with HER2 scores 〉 2＋ had a significantly higher chance of dying from prostate cancer than those with HER2 scores of 0 （P = 0.004） and 1＋ （P = 0.034）. Multivariate Cox regression analysis showed that HER2 protein expression intensity was an independent predictor of cancer-related death （P = 0.039）. Conclusion： An HER2 IHC score 〉 2＋ should be defined as HER2 protein overexpression in prostate cancer. Overexpression of HER2 protein in cancer tissue might suggest an increased risk of dying from prostate cancer. HER2 protein expression increases in some individual patients after hormonal therapy.     

PSA screening for prostate cancer： why so muc ：ontroversy？

Since prostate cancer reaches the advanced and non curable stage in the absence of any specific symptom or sign, it seems reasonable to diagnose this cancer at an early and curable stage. Screening by prostate-specific antigen （PSA） has been the common technology used. The last follow-up of the first two prospective and randomized screening studies for prostate cancer, namely the Quebec and ERSPC （European Randomized Study of Screening for Prostate Cancer） clinical trials started in 1988 and 1991, respectively, have shown reductions of prostate cancer death of 62% （P〈0.002） and 21% （P〈0.001） （38% in the tenth and eleventh years of follow-up, P〈0.003）, respectively, while the PLCO （Prostate Lung Colorectal and Ovarian Cancer） screening trial reported no benefit. It has been estimated, however, that 85% of men in the planned ＇non-screened＇ group of the US study have been screened. With such a serious flaw, the PLCO study does not have the statistical power to reach any valid conclusion. In the Quebec study, only 7.3% of men were screened in the control arm. The important benefit observed in the ERSPC study was achieved using a less than optimal 4-year PSA screening interval which misses a significant number of cancers while the Quebec study used the optimal 1-year interval. With proper information obtained from their physicians or otherwise using data collected only from the clinical trials having the required statistical power, men should be in a good position to decide about being or not being screened for prostate cancer.     

Speckle-type POZ protein mutations interrupt tumor suppressor function of speckle-type POZ protein in prostate cancer by affecting androgen receptor degradation

Large scale exome sequencing studies have ＇revealed regions of the genome, which contribute to the castrate resistant prostate cancer （CRPC） phenotype.1-3 Such studies have identified mutations in genes, which may have diagnostic/prognostic potential, or which may be targeted therapeutically. Two of these genes include the androgen receptor （AR） and speckle-type POZ protein （SPOP） genes. However, the findings from these exome sequencing studies can only be translated therapeutically once the functional consequences of these mutations have been determined. Here, we highlight the recent study by An et al.4 which investigated the functional effects of mutations in the SPOP gene that were identified in the aforementioned exome sequencing studies, particnlarly in the context of SPOP-mediated degradation of the AR.     

Uptake of resveratrol and role of resveratrol-targeting protein,quinone reductase 2, in normally cultured human prostate cells

Resveratrol is a dietary polyphenol espoused to have chemopreventive activity against a variety of human cancer types. We first reported that resveratrol significantly decreases the proliferation of both androgen-dependent and hormone-refractory prostate cancer cells. However, the effects of resveratrol in normal prostate epithelial and stromal cells, particularly with regard to its uptake, subcellular distribution and intracellular targets, have not been investigated. To advance the knowledge on accessibility and cellular disposition of resveratrol in prostate cells, [3H] resveratrol, fractionation of cell extracts into subcellular compartments, Western blot analysis, resveratrol affinity column chromatography and flow cytometry were used to study the uptake and intracellular distribution of resveratrol in normally cultured prostate stromal （PrSCs） and epithelial cells （PrECs）. Pretreatment of both PrSCs and PrECs for 2 days with resveratrol modulated its uptake and selectively increased its distribution to the membrane and organelle compartments. Resveratrol affinity column chromatography studies showed differential expression of a previously identified resveratrol-targeting protein, quinone reductase 2 （QR2）, in PrSCs and PrECs. Flow cytometric analysis comparing resveratrol-treated and untreated PrSCs showed a large decrease in G1-phase and a concomitant increase in S and G2/M-phases of the cell cycle. These results suggest that resveratrol suppresses PrSC proliferation by affecting cell cycle phase distribution, which may involve the participation by QR2.     

Role of androgen receptor in prostate cancer

The growth of prostate cancer is sensitive to androgen, and hormonal therapy has been used for treatment of ad-vanced cancer. About 80 % of prostate cancers initially respond to hormonal therapy, howcrver, more than half of the re-sponders gradtmlly become resistant to this therapy. Changes in tumors from an androgen-responsive to an androgen-unre-sponsive state have been widely discussed. Since androgen action is mediated by androgen receptor (AR), abnonnalitiesof AR is believed to play an important role of the loss of androgen responsiveness in prostate cancer. “Ilais article focusedon the role of AR in the progression of prostate cancer.