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1.
  • Adamo, Hanibal Hani, et al. (författare)
  • Adaptive (TINT) Changes in the Tumor Bearing Organ Are Related to Prostate Tumor Size and Aggressiveness
  • 2015
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:11
  • Tidskriftsartikel (refereegranskat)abstract
    • In order to grow, tumors need to induce supportive alterations in the tumor-bearing organ, by us named tumor instructed normal tissue (TINT) changes. We now examined if the nature and magnitude of these responses were related to tumor size and aggressiveness. Three different Dunning rat prostate tumor cells were implanted into the prostate of immune-competent rats; 1) fast growing and metastatic MatLyLu tumor cells 2) fast growing and poorly metastatic AT-1 tumor cells, and 3) slow growing and non-metastatic G tumor cells. All tumor types induced increases in macrophage, mast cell and vascular densities and in vascular cell-proliferation in the tumor-bearing prostate lobe compared to controls. These increases occurred in parallel with tumor growth. The most pronounced and rapid responses were seen in the prostate tissue surrounding MatLyLu tumors. They were, also when small, particularly effective in attracting macrophages and stimulating growth of not only micro-vessels but also small arteries and veins compared to the less aggressive AT-1 and G tumors. The nature and magnitude of tumor-induced changes in the tumor-bearing organ are related to tumor size but also to tumor aggressiveness. These findings, supported by previous observation in patient samples, suggest that one additional way to evaluate prostate tumor aggressiveness could be to monitor its effect on adjacent tissues.
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2.
  • Adamo, Hanibal Hani, et al. (författare)
  • Characterization of a Gene Expression Signature in Normal Rat Prostate Tissue Induced by the Presence of a Tumor Elsewhere in the Organ
  • 2015
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating changes in the tumor-bearing organ, for example growth of the vasculature, an altered extracellular matrix, and influx of inflammatory cells. To investigate this response further, we compared prostate morphology and the gene expression profile of tumor-bearing normal rat prostate tissue (termed tumor-instructed/indicating normal tissue (TINT)) with that of prostate tissue from controls. Dunning rat AT-1 prostate cancer cells were injected into rat prostate and tumors were established after 10 days. As controls we used intact animals, animals injected with heat-killed AT-1 cells or cell culture medium. None of the controls showed morphological TINT-changes. A rat Illumina whole-genome expression array was used to analyze gene expression in AT-1 tumors, TINT, and in medium injected prostate tissue. We identified 423 upregulated genes and 38 downregulated genes (p<0.05, >= 2-fold change) in TINT relative to controls. Quantitative RT-PCR analysis verified key TINT-changes, and they were not detected in controls. Expression of some genes was changed in a manner similar to that in the tumor, whereas other changes were exclusive to TINT. Ontological analysis using GeneGo software showed that the TINT gene expression profile was coupled to processes such as inflammation, immune response, and wounding. Many of the genes whose expression is altered in TINT have well-established roles in tumor biology, and the present findings indicate that they may also function by adapting the surrounding tumor-bearing organ to the needs of the tumor. Even though a minor tumor cell contamination in TINT samples cannot be ruled out, our data suggest that there are tumor-induced changes in gene expression in the normal tumor-bearing organ which can probably not be explained by tumor cell contamination. It is important to validate these changes further, as they could hypothetically serve as novel diagnostic and prognostic markers of prostate cancer.
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3.
  • Adamo, Hanibal Hani, 1984-, et al. (författare)
  • Prostate cancer induces C/EBPβ expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome
  • 2019
  • Ingår i: The Prostate. - : John Wiley & Sons. - 0270-4137 .- 1097-0045. ; 79:5, s. 435-445
  • 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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4.
  • Adamo, Hanibal Hani, 1984- (författare)
  • TINT Tumor Indicating Normal Tissue : new field of diagnostic biomarkers for prostate cancer
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Background: Prostate cancer is the most common cancer in Sweden. Due its highly variable behavior, multifocal nature, and insufficient diagnostic methods, prostate cancer is difficult to diagnose and prognosticate. Some patients have an aggressive lethal disease, but the majority of prostate cancer patients have slow-growing, non-lethal disease with long expected survival without treatment. Current diagnostic methods―serum levels of prostate-specific antigen (PSA) and histological grading of biopsied prostate tissue―often do not give the information required to be able to safely differentiate indolent tumors from potentially lethal ones. Many prostate cancers are difficult to detect by imaging, so tissue biopsy cannot be safely guided towards the tumor, and particularly not towards the most aggressive forms. To overcome this problem, multiple needle biopsies are taken from the organ, but biopsies are small and they sample less than 1% of the whole prostate. In this thesis, we explore the non-malignant prostate tissue adjacent to tumors, which is always sampled in biopsies, and we study adaptive changes in this tissue, which may provide new diagnostic and prognostic markers for prostate cancer. We have therefore proposed that this type of tissue should be termed TINT (Tumor Instructed/indicating Normal Tissue). Methods: In our studies, we used orthotopic rat prostate cancer models with tumors of different aggressiveness. We also used clinical materials from patients diagnosed with prostate cancer at transurethral resection (1975‒1990); the majority of these men were followed with watchful waiting. Analyses were performed with whole-genome expression array, quantitative real-time PCR, immunohistochemistry, and western blotting. Results: Using the animal model, we found that the presence of a tumor induces changes in gene expression in the surrounding tumor-bearing organ (TINT). The gene signature of TINT was linked to processes such as extracellular matrix organization, immune responses, and inflammation. We also showed that some of these adaptive TINT changes appear to be related to the aggressiveness and metastatic potential of the growing tumor, such as increases in macrophages, in mast cells, in vascular densities, and in vascular cell-proliferation. Some of these findings were confirmed by our observations in patient samples. We found that high staining of the extracellular matrix component hyaluronan in the stroma of the non-malignant prostate tissue was prognostic for short cancer-specific survival. We also found that an elevated proportion of C/EBP-beta positive epithelial cells in non-malignant (TINT) prostate tissue was associated with a good prognosis. Conclusions: Using animal experiments and patient samples, we showed that the presence of prostate cancer induces changes in the tumor-bearing organ, alterations associated with tumor aggressiveness, and that grading of these changes in TINT can be used to predict outcome in prostate cancer patients. 
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5.
  • Adamo, Hanibal, et al. (författare)
  • Prostate cancer induces C/EBPβ expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome
  • 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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6.
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7.
  • Alexeyev, Oleg, et al. (författare)
  • Association between the presence of bacterial 16S RNA in prostate specimens taken during transurethral resection of prostate and subsequent risk of prostate cancer (Sweden)
  • 2006
  • Ingår i: Cancer Causes and Control. - Dordrecht : Kluwer Academic Publishers. - 0957-5243 .- 1573-7225. ; 17:9, s. 1127-1133
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To study bacterial 16S RNA in archival prostate samples from 352 patients with benign prostate hyperplasia (BPH) and evaluate whether the presence of bacterial DNA was different in those who later developed prostate cancer (n = 171) and in the matched controls that did not progress to cancer (n = 181).Methods: 16S DNA PCR followed by cloning and sequencing the positive samples.Results: In 96/352 (27%) of the prostate tissue specimens 16S RNA were detected. Sequence analysis revealed Propionibacterium acnes as the predominant microorganism (23% of 16S RNA positive patients). The second most frequent isolate—Escherichia coli was found in 12 (12%) patients. The other isolates included Pseudomonas sp. (3 patients), Actinomyces sp. (2), Streptococcus mutans (1), Corynebacterium sp. (2),Nocardioides sp. (1), Rhodococcus sp. (1) Veillonella sp. (2). In P. acnes positive samples 62% exhibited severe histological inflammation versus 50% in the bacteria-negative group (p = 0.602). The presence of P. acnes in the prostate was associated with prostate cancer development (OR 2.17, 95% CI 0.77–6.95).Conclusions: This study has revealed P. acnes as the most common bacteria in the prostate in BPH. Further studies are needed to clarify its role in contributing to the development of prostatic inflammation and prostate cancer.
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8.
  • Aripaka, Karthik, et al. (författare)
  • TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer
  • 2019
  • Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 45, s. 192-207
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Tumour necrosis factor receptor associated factor 6 (TRAF6) promotes inflammation in response to various cytokines. Aberrant Wnt3a signals promotes cancer progression through accumulation of β-Catenin. Here we investigated a potential role for TRAF6 in Wnt signaling.Methods: TRAF6 expression was silenced by siRNA in human prostate cancer (PC3U) and human colorectal SW480 cells and by CRISPR/Cas9 in zebrafish. Several biochemical methods and analyses of mutant phenotype in zebrafish were used to analyse the function of TRAF6 in Wnt signaling.Findings: Wnt3a-treatment promoted binding of TRAF6 to the Wnt co-receptors LRP5/LRP6 in PC3U and LNCaP cells in vitro. TRAF6 positively regulated mRNA expression of β-Catenin and subsequent activation of Wnt target genes in PC3U cells. Wnt3a-induced invasion of PC3U and SW480 cells were significantly reduced when TRAF6 was silenced by siRNA. Database analysis revealed a correlation between TRAF6 mRNA and Wnt target genes in patients with prostate cancer, and high expression of LRP5, TRAF6 and c-Myc correlated with poor prognosis. By using CRISPR/Cas9 to silence TRAF6 in zebrafish, we confirm TRAF6 as a key molecule in Wnt3a signaling for expression of Wnt target genes.Interpretation: We identify TRAF6 as an important component in Wnt3a signaling to promote activation of Wnt target genes, a finding important for understanding mechanisms driving prostate cancer progression.
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9.
  • Assel, Melissa, et al. (författare)
  • 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
  • Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 73:6, s. 961-967
  • 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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10.
  • Bergh, Anders (författare)
  • Characterization and functional role of the stroma compartment in prostate tumors.
  • 2009
  • Ingår i: Future Oncology. - London : Future Medicine Ltd. - 1479-6694 .- 1744-8301. ; 5:8, s. 1231-1235
  • Tidskriftsartikel (refereegranskat)abstract
    • Prostate tumors are composed of many cell types, yet the biological significances of the different nonepithelial cells have been largely overlooked. According to recent studies, however, the stroma, which constitutes a substantial part of the tumor volume, plays an important role during the initiation, progression, metastasis and metastatic growth of prostate cancers. To explore this further, Dakhova and co-workers compared gene expression in laser microdissected normal peripheral zone stroma with stroma in peripheral zone cancers (only those with reactive stroma grade 3). A total of 544 genes were upregulated and 606 genes downregulated in tumor stroma. The cancer stroma showed signs of formation of nerves, increased number of stem cells, and responses to DNA damage. Further studies are needed to explore the functional consequences of this, particularly the role of nerves. If these stroma changes can be used as prognostic markers, as targets for therapy, and if similar changes occur in metastases also need to be explored.
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