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- Adamo, Hanibal Hani, 1984-, et al.
(författare)
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Prostate cancer induces C/EBPβ expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome
- 2019
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Ingår i: The Prostate. - : John Wiley & Sons. - 0270-4137 .- 1097-0045. ; 79:5, s. 435-445
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Tidskriftsartikel (refereegranskat)abstract
- Background: Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating adaptations in the tumor-bearing organ. Similar changes are seen in prostate cancer patients and they are related to outcome. One gene previously found to be upregulated in the non-malignant part of tumor-bearing prostate lobe in rats was the transcription factor CCAAT/enhancer-binding protein- (C/EBP).Methods: To explore this further, we examined C/EBP expression by quantitative RT-PCR, immunohistochemistry, and Western blot in normal rat prostate tissue surrounding slow-growing non-metastatic Dunning G, rapidly growing poorly metastatic (AT-1), and rapidly growing highly metastatic (MatLyLu) rat prostate tumors?and also by immunohistochemistry in a tissue microarray (TMA) from prostate cancer patients managed by watchful waiting.Results: In rats, C/EBP mRNA expression was upregulated in the surrounding tumor-bearing prostate lobe. In tumors and in the surrounding non-malignant prostate tissue, C/EBP was detected by immunohistochemistry in some epithelial cells and in infiltrating macrophages. The magnitude of glandular epithelial C/EBP expression in the tumor-bearing prostates was associated with tumor size, distance to the tumor, and metastatic capacity. In prostate cancer patients, high expression of C/EBP in glandular epithelial cells in the surrounding tumor-bearing tissue was associated with accumulation of M1 macrophages (iNOS+) and favorable outcome. High expression of C/EBP in tumor epithelial cells was associated with high Gleason score, high tumor cell proliferation, metastases, and poor outcome.Conclusions: This study suggest that the expression of C/EBP-beta, a transcription factor mediating multiple biological effects, is differentially expressed both in the benign parts of the tumor-bearing prostate and in prostate tumors, and that alterations in this may be related to patient outcome.
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| 2. |
- Adamo, Hanibal, et al.
(författare)
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Prostate cancer induces C/EBPβ expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating adaptations in the tumor-bearing organ. Similar changes are seen in prostate cancer patients and they are related to outcome. One gene previously found to be upregulated in the non-malignant part of a tumor-bearing prostate lobe in rats was the transcription factor CCAAT/enhancer-binding protein-β (C/EBPβ). To explore this further, we examined C/EBPβ expression by quantitative RT-PCR, immunohistochemistry, and western blot in normal rat prostate tissue surrounding slow-growing non-metastatic Dunning G, rapidly growing poorly metastatic (AT-1), and rapidly growing highly metastatic (MatLyLu) rat prostate tumors―and also by immunohistochemistry in a tissue microarray (TMA) from prostate cancer patients managed by watchful waiting.In rats, C/EBPβ mRNA expression was upregulated in the surrounding tumor-bearing prostate lobe. In tumors and in the surrounding non-malignant prostate tissue, C/EBPβ was detected by immunohistochemistry in some epithelial cells and in infiltrating macrophages. The magnitude of glandular epithelial C/EBPβ expression in the tumor-bearing prostates was associated with tumor size, with distance to the tumor, and with tumor cell metastatic capacity.In prostate cancer patients, high expression of C/EBPβ in glandular epithelial cells in the surrounding tumor-bearing tissue was associated with accumulation of M1 macrophages (iNOS+) and a favorable outcome. High expression of C/EBPβ in tumor epithelial cells was associated with high Gleason score, high tumor cell proliferation, the presence of metastases at diagnosis, and poor outcome.
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| 3. |
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| 4. |
- Assel, Melissa, et al.
(författare)
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Association Between Lead Time and Prostate Cancer Grade : Evidence of Grade Progression from Long-term Follow-up of Large Population-based Cohorts Not Subject to Prostate-specific Antigen Screening
- 2018
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 73:6, s. 961-967
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lead time (LT) is of key importance in early detection of cancer, but cannot be directly measured. We have previously provided LT estimates for prostate cancer (PCa) using archived blood samples from cohorts followed for many years without screening. Objective: To determine the association between LT and PCa grade at diagnosis to provide an insight into whether grade progresses or is stable over time. Design, setting, and participants: The setting was three long-term epidemiologic studies in Sweden including men not subject to prostate-specific antigen (PSA) screening. The cohort included 1041 men with PSA of 3–10 ng/ml at blood draw and subsequently diagnosed with PCa with grade data available. Outcome measurements and statistical analysis: Multivariable logistic regression was used to predict high-grade (Gleason grade group ≥2 or World Health Organization grade 3) versus low-grade PCa at diagnosis in terms of LT, defined as the time between the date of elevated PSA and the date of PCa diagnosis with adjustment for cohort and age. Results and limitations: The probability that PCa would be high grade at diagnosis increased with LT. Among all men combined, the risk of high-grade disease increased with LT (odds ratio 1.13, 95% confidence interval [CI] 1.10–1.16; p < 0.0001), with no evidence of differences in effect by age group or cohort. Higher PSA predicted shorter LT by 0.46 yr (95% CI 0.28–0.64; p < 0.0001) per 1 ng/ml increase in PSA. However, there was no interaction between PSA and grade, suggesting that the longer LT for high-grade tumors is not simply related to age. Limitations include the assumption that men with elevated PSA and subsequently diagnosed with PCa would have had biopsy-detectable PCa at the time of PSA elevation. Conclusions: Our data support grade progression, whereby following a prostate over time would reveal transitions from benign to low-grade and then high-grade PCa. Patient summary: Men with a longer lead time between elevated prostate-specific antigen and subsequent prostate cancer diagnosis were more likely to have high-grade cancers at diagnosis. The probability that a cancer will be of high grade at diagnosis increases with the lead time. Our findings provide evidence of grade progression, whereby a prostate followed over time would exhibit transitions from benign to low-grade to high-grade prostate cancer.
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| 5. |
- Bovinder Ylitalo, Erik, et al.
(författare)
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Subgroups of castration-resistant prostate cancer bone metastases defined through an inverse relationship between androgen receptor activity and immune response
- 2017
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 71:5, s. 776-787
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Tidskriftsartikel (refereegranskat)abstract
- Background: Novel therapies for men with castration-resistant prostate cancer (CRPC) are needed, particularly for cancers not driven by androgen receptor (AR) activation. Objectives: To identify molecular subgroups of PC bone metastases of relevance for therapy.Design, setting, and participants: Fresh-frozen bone metastasis samples from men with CRPC (n = 40), treatment-naïve PC (n = 8), or other malignancies (n = 12) were characterized using whole-genome expression profiling, multivariate principal component analysis (PCA), and functional enrichment analysis. Expression profiles were verified by reverse transcription–polymerase chain reaction (RT-PCR) in an extended set of bone metastases (n = 77) and compared to levels in malignant and adjacent benign prostate tissue from patients with localized disease (n = 12). Selected proteins were evaluated using immunohistochemistry. A cohort of PC patients (n = 284) diagnosed at transurethral resection with long follow-up was used for prognostic evaluation.Results and limitations: The majority of CRPC bone metastases (80%) was defined as AR-driven based on PCA analysis and high expression of the AR, AR co-regulators (FOXA1, HOXB13), and AR-regulated genes (KLK2, KLK3, NKX3.1, STEAP2, TMPRSS2); 20% were non–AR-driven. Functional enrichment analysis indicated high metabolic activity and low immune responses in AR-driven metastases. Accordingly, infiltration of CD3+ and CD68+ cells was lower in AR-driven than in non–AR-driven metastases, and tumor cell HLA class I ABC immunoreactivity was inversely correlated with nuclear AR immunoreactivity. RT-PCR analysis showed low MHC class I expression (HLA-A, TAP1, and PSMB9 mRNA) in PC bone metastases compared to benign and malignant prostate tissue and bone metastases of other origins. In primary PC, low HLA class I ABC immunoreactivity was associated with high Gleason score, bone metastasis, and short cancer-specific survival. Limitations include the limited number of patients studied and the single metastasis sample studied per patient.Conclusions: Most CRPC bone metastases show high AR and metabolic activities and low immune responses. A subgroup instead shows low AR and metabolic activities, but high immune responses. Targeted therapy for these groups should be explored. Patient summary: We studied heterogeneities at a molecular level in bone metastasis samples obtained from men with castration-resistant prostate cancer. We found differences of possible importance for therapy selection in individual patients.
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| 6. |
- Bylund, Annika, et al.
(författare)
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Anticancer effects of a plant lignan 7-hydroxymatairesinol on a prostate cancer model in vivo.
- 2005
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Ingår i: Experimental biology and medicine. - 1535-3702 .- 1535-3699. ; 230:3, s. 217-223
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Tidskriftsartikel (refereegranskat)abstract
- Clinical intervention studies and experimental studies with lignan-rich diets suggest that lignans may have inhibitory effects on prostate cancer, but no clinical or experimental studies with purified lignans have been published. The purpose of this study was to investigate the effect of a plant lignan 7-hydroxymatairesinol (HMR) on LNCaP human prostate cancer xenografts in athymic mice. Athymic nude male mice were injected subcutaneously with LNCaP cells. Starting 3 days after tumor cell injections, a control diet or a control diet supplemented with 0.15% or 0.30% of HMR was administered to mice and the tumor take rate and growth was observed for 9 weeks. HMR diet inhibited the growth of LNCaP tumors. Mice treated with HMR had smaller tumor volume, lower tumor take rate, increased proportion of nongrowing tumors, and higher tumor cell apoptotic index compared with controls. Furthermore, the cell proliferation index was reduced in mice receiving the 0.30% HMR diet compared with mice receiving the control diet. Our results suggest that dietary HMR started at the early phase of the tumor development inhibits the growth of the LNCaP human prostate cancer xenografts in athymic male mice.
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| 7. |
- Chung, Sui Chu, et al.
(författare)
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A high cannabinoid CB(1) receptor immunoreactivity is associated with disease severity and outcome in prostate cancer
- 2009
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 45:1, s. 174-182
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Tidskriftsartikel (refereegranskat)abstract
- In the light of findings indicating that cannabinoids can affect the proliferation of a number of cancer cell types and that cannabinoid receptor expression is higher in prostate cancer cell lines than in non-malignant cells, we investigated whether the level of cannabinoid 1 receptor immunoreactivity (CB(1)IR) in prostate cancer tissues is associated with disease severity and outcome. Formalin-fixed paraffin-embedded non-malignant and tumour tissue samples from patients who were diagnosed with prostate cancer at a transurethral resection for voiding problems were used. CB(1)IR, which was scored in a total of 399 cases, was associated with the epithelial cell membranes, with little staining in the stroma. Patients with a tumour CB(1)IR score greater or equal to the median (2) had a significantly higher proportion of Gleason scores 8-10, metastases at diagnosis, tumour size and rate of cell proliferation at diagnosis than patients with a score<2. For 269 cases, tumour CB(1)IR was measured for patients who only received palliative therapy at the end stages of the disease, allowing the influence of CB(1)IR upon the disease outcome to be determined. Receiver operating characteristic (ROC) curves showed an area under the curve of 0.67 (95% confidence limits 0.59-0.74) for CB(1)IR in the tumour. CB(1)IR in non-malignant tissue was not associated with disease outcome. A tumour CB(1)IR score >or=2 was associated with a significantly lower disease specific survival. A Cox proportional hazards regression indicated that the tumour CB(1)IR score and the Gleason score were independent prognostic variables. It is concluded that a high tumour CB(1)IR score is associated with prostate cancer severity and outcome.
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| 8. |
- Halin Bergström, Sofia, et al.
(författare)
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Extratumoral Heme Oxygenase-1 (HO-1) Expressing Macrophages Likely Promote Primary and Metastatic Prostate Tumor Growth.
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- Aggressive tumors induce tumor-supporting changes in the benign parts of the prostate. One factor that has increased expression outside prostate tumors is hemoxygenase-1 (HO-1). To investigate HO-1 expression in more detail, we analyzed samples of tumor tissue and peritumoral normal prostate tissue from rats carrying cancers with different metastatic capacity, and human prostate cancer tissue samples from primary tumors and bone metastases. In rat prostate tumor samples, immunohistochemistry and quantitative RT-PCR showed that the main site of HO-1 synthesis was HO-1+ macrophages that accumulated in the tumor-bearing organ, and at the tumor-invasive front. Small metastatic tumors were considerably more effective in attracting HO-1+ macrophages than larger non-metastatic ones. In clinical samples, accumulation of HO-1+ macrophages was seen at the tumor invasive front, almost exclusively in high-grade tumors, and it correlated with the presence of bone metastases. HO-1+ macrophages, located at the tumor invasive front, were more abundant in bone metastases than in primary tumors. HO-1 expression in bone metastases was variable, and positively correlated with the expression of macrophage markers but negatively correlated with androgen receptor expression, suggesting that elevated HO-1 could be a marker for a subgroup of bone metastases. Together with another recent observation showing that selective knockout of HO-1 in macrophages reduced prostate tumor growth and metastatic capacity in animals, the results of this study suggest that extratumoral HO-1+ macrophages may have an important role in prostate cancer.
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| 9. |
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| 10. |
- Hammarsten, Peter, et al.
(författare)
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High Caveolin-1 Expression in Tumor Stroma Is Associated with a Favourable Outcome in Prostate Cancer Patients Managed by Watchful Waiting
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:10
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Tidskriftsartikel (refereegranskat)abstract
- In the present study we have investigated whether Caveolin-1 expression in non-malignant and malignant prostate tissue is a potential prognostic marker for outcome in prostate cancer patients managed by watchful waiting. Caveolin-1 was measured in prostate tissues obtained through transurethral resection of the prostate from 395 patients diagnosed with prostate cancer. The majority of the patients (n = 298) were followed by watchful waiting after diagnosis. Tissue microarrays constructed from malignant and non-malignant prostate tissue were stained with an antibody against Caveolin-1. The staining pattern was scored and related to clinicopathologic parameters and outcome. Microdissection and qRT-PCR analysis of Cav-1 was done of the prostate stroma from non-malignant tissue and stroma from Gleason 3 and 4 tumors. Cav-1 RNA expression was highest in non-malignant tissue and decreased during cancer progression. High expression of Caveolin-1 in tumor stroma was associated with significantly longer cancer specific survival in prostate cancer patients. This association remained significant when Gleason score and local tumor stage were combined with Caveolin-1 in a Cox regression model. High stromal Caveolin-1 immunoreactivity in prostate tumors is associated with a favourable prognosis in prostate cancer patients managed by watchful waiting. Caveolin-1 could possibly become a useful prognostic marker for prostate cancer patients that are potential candidates for active surveillance.
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