Prostate cancer (PC) cells express the androgen receptor (AR) and need the presence of androgens to survive. Androgen suppression is the gold standard first-line therapy for metastatic disease. ...Almost all PC patients initially respond to hormonal therapy, but most of them gradually develop resistance to castration. There is evidence that these tumours that are considered castration-resistant continue to depend on AR signalling. Several mechanisms that enhance AR signalling in an androgen-depleted environment have been elucidated: (1) AR mutations that allow activation by low androgen levels or by other endogenous steroids, (2) AR amplification and/or overexpression, (3) increased local intracrine synthesis of androgens, (4) changes in AR cofactors and (5) cross-talk with cytokines and growth factors. Today, there are a number of novel agents targeting the AR signalling pathway under development, including more effective antiandrogens; inhibitors of CYP17, inhibitors of HSP90, inhibitors of histone deacetylases and inhibitors of tyrosine kinase inhibitors.
Notch signaling has recently emerged as an important regulator of immune responses in autoimmune diseases. The recombination signal-binding protein for immunoglobulin kappa J region (RBPJ) is a ...transcriptional repressor, but converts into a transcriptional activator upon activation of the canonical Notch pathway. Genome-wide association studies of rheumatoid arthritis (RA) identified a susceptibility locus, rs874040(CC), which implicated the RBPJ gene. Here, chromatin state mapping generated using the chromHMM algorithm reveals strong enhancer regions containing DNase I hypersensitive sites overlapping the rs874040 linkage disequilibrium block in human memory, but not in naïve CD4(+) T cells. The rs874040 overlapping this chromatin state was associated with increased RBPJ expression in stimulated memory CD4(+) T cells from healthy subjects homozygous for the risk allele (CC) compared with memory CD4(+) T cells bearing the protective allele (GG). Transcriptomic analysis of rs874040(CC) memory T cells showed a repression of canonical Notch target genes IL (interleukin)-9, IL-17 and interferon (IFN)γ in the basal state. Interestingly, activation of the Notch pathway using soluble Notch ligand, Jagged2-Fc, induced IL-9 and IL-17A while delta-like 4Fc, another Notch ligand, induced higher IFNγ expression in the rs874040(CC) memory CD4(+) T cells compared with their rs874040(GG) counterparts. In RA, RBPJ expression is elevated in memory T cells from RA patients compared with control subjects, and this was associated with induced inflammatory cytokines IL-9, IL-17A and IFNγ in response to Notch ligation in vitro. These findings demonstrate that the rs874040(CC) allele skews memory T cells toward a pro-inflammatory phenotype involving Notch signaling, thus increasing the susceptibility to develop RA.
Expansion of antigen-experienced CD8
T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer
. Interleukin-2 (IL-2) acts as a ...key regulator of CD8
cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability
. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE
), a known negative regulator of immune response in the tumour microenvironment
, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8
TILs via the PGE
receptors EP2 and EP4. Mechanistically, PGE
inhibits IL-2 sensing in TILs by downregulating the IL-2Rγ
chain, resulting in defective assembly of IL-2Rβ-IL2Rγ
membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE
signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE
in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.
To compare the ability of flow cytometry (FCM) and fluorescent in situ hybridization (FISH), using a small set of 4 enumeration chromosome probes to detect aneuploidy in prostate tumors, and to ...correlate it with histological grade and pathological stage.
Among 28 suitable cases, 21 could be analyzed by FISH and FCM techniques. DNA centromeric probes were used in FISH analysis to enumerate chromosomes 7, 8, 10 and 12.
(a) Of the 21 cases studied by FISH, 5 were diploid, 14 aneuploid and 2 were tetraploid. When studied by FCM, these tumors were: 14 diploid, 6 aneuploid, and 1 tetraploid. FISH proved to have a higher ability for detecting DNA aneuploidy than FCM while been equally specific, since all tumors aneuploid by FCM were also found to be aneuploid by FISH. (b) Of the 14 aneuploid tumors, 12 were of high histological grade, while only 2 of the 7 nonaneuploid were of high grade. A statistically significant association was observed between high histological grade and FISH aneuploidy (p = 0.033). (c) All the aneuploid tumors showed chromosome 7 and/or 8 aneusomy. Trisomy 7 and monosomy 8 were the most frequent alterations present in 56 and 42% of the aneuploid tumors, respectively.
FISH analysis of chromosome 7 and 8 alterations proved to be more sensitive than FCM in the detection of aneuploid prostate tumors. This aneuploidy was significantly associated with a poor pathological prognosis.
IntroductionAs part of the PIONEER (Prostate Cancer Diagnosis and Treatment Enhancement Through the Power of Big Data in Europe) Consortium, we will explore which diagnostic and prognostic factors ...(DPFs) are currently being researched to previously defined clinical and patient-reported outcomes for prostate cancer (PCa).Methods and analysisThis research project will follow the following four steps: (1) a broad systematic literature review of DPFs for all stages of PCa, covering evidence from 2014 onwards; (2) discussion of systematic review findings by a multidisciplinary expert panel; (3) risk of bias assessment and applicability with Prediction model Risk Of Bias Assessment Tool criteria, Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) and the Quality In Prognosis Studies tool (QUIPS) and (4) additional quantitative assessments if required.Ethics and disseminationWe aim to develop an online tool to present the DPFs identified in this research and make them available across all stakeholders. There are no ethical implications.
Notch signaling has recently emerged as an important regulator of immune responses in autoimmune diseases. The recombination signal-binding protein for immunoglobulin kappa J region (RBPJ) is a ...transcriptional repressor, but converts into a transcriptional activator upon activation of the canonical Notch pathway. Genome-wide association studies of rheumatoid arthritis (RA) identified a susceptibility locus, rs874040 super(CC), which implicated the RBPJ gene. Here, chromatin state mapping generated using the chromHMM algorithm reveals strong enhancer regions containing DNase I hypersensitive sites overlapping the rs874040 linkage disequilibrium block in human memory, but not in naive CD4 super(+) T cells. The rs874040 overlapping this chromatin state was associated with increased RBPJ expression in stimulated memory CD4 super(+) T cells from healthy subjects homozygous for the risk allele (CC) compared with memory CD4 super(+) T cells bearing the protective allele (GG). Transcriptomic analysis of rs874040 super(CC) memory T cells showed a repression of canonical Notch target genes IL (interleukin)-9, IL-17 and interferon (IFN) gamma in the basal state. Interestingly, activation of the Notch pathway using soluble Notch ligand, Jagged2-Fc, induced IL-9 and IL-17A while delta-like 4Fc, another Notch ligand, induced higher IFN gamma expression in the rs874040 super(CC) memory CD4 super(+) T cells compared with their rs874040 super(GG) counterparts. In RA, RBPJ expression is elevated in memory T cells from RA patients compared with control subjects, and this was associated with induced inflammatory cytokines IL-9, IL-17A and IFN gamma in response to Notch ligation in vitro. These findings demonstrate that the rs874040 super(CC) allele skews memory T cells toward a pro-inflammatory phenotype involving Notch signaling, thus increasing the susceptibility to develop RA.
Bladder cancer (BC) is a worldwide health problem. In 2006 in Europe, there were an estimated 104,400 incident cases of BC diagnosed (82,800 in men and 21,600 in women) that represent a 6.6% of the ...total cancers in men and 2.1% in women.
Tobacco use is a major preventable cause of death, and especially involved with BC carcinogenesis. Tobacco smoking is the most well-established risk factor for BC, causing around 50%–65% of male cases and 20%–30% of female cases.
Occupational exposure has been considered the second most important risk factor for BC. Work related cases account for a 20%–25% of all BC cases in several series.
In addition, chronic urinary tract infection had been related to BC, particularly, with invasive squamous cell carcinoma. Bladder schistosomiasis has particularlybeen considered by the international agency for research on cancer (IARC) as a definitive cause or urinary BC with an associated fivefold risk.
BC is a disease of the environment and age. Populations are increasing in number, and they are growing old as well.,. Since more people are living longer, more are at potential risk. Furthermore, the changing environments in developed and developing countries are causing more carcinogen concentration than can be associated to genesis of BC. Several carcinogens have been correlated to BC carcinogenesis.
However, it has been proposed that other environmental factors could affect the incidence on urothelial tumors. In fact, as for many other cancers, molecular researchers try to establish genetic alterations linked to carcinogenesis that could justify genetic predisposition.
Cancer is a major public health problem. At the end of the twentieth century, more than 930,000 people died of cancer every year in 15 member countries of the European Union (EU) (Coleman et al.). Using population projections, if the age-specific death rates remain constant, the absolute number of cancer deaths in 2015 will increase to 140,500 (Boyle and Ferlay 2005). BC is a worldwide health problem. In 2006 in Europe, there were an estimated 104,400 incident cases of BC diagnosed (82,800 in men and 21,600 in women) that represent a 6.6% of the total cancers in men and 2.1% in women. The estimated ratio by gender was 3.8:1, respectively. In men BC was the fourth most common cancer. Bladder cancer represents a 4.1% of total deaths for cancer in men and 1.8% of total deaths in women (Ferlay et al. 2007). In the EU overall (27 countries), BC mortality rates were stable up to early 1990s, and declined, thereafter, by 16% in men and 12% in women, to reach values of 6 and 1.3/100,000, respectively, in the early years of the present decade. The only countries without declining mortality are Croatia and Poland in both sexes, Romania in men, and Denmark in women. This documented and quantified reduction in BC mortality seems related to decrease in tobacco smoking, while its relationship with other risk factors remains controversial (Ferlay et al. 2008).
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