Michael J Stower

Uludag University, Bursa, Bursa, Turkey

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Publications (15)64.28 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: While chromosomal translocations have a fundamental role in the development of several human leukaemias, their role in solid tumour development has been somewhat more controversial. Recently, it was shown that up to 80% of prostate tumours harbour at least one such gene fusion, and that the most common fusion event, between the prostate-specific TMPRSS2 gene and the ERG oncogene, is a critical, and probably early factor in prostate cancer development. Here we demonstrate the presence and expression of this significant chromosomal rearrangement in prostate cancer stem cells. Moreover, we show that in the prostate epithelial hierarchy from both normal and tumour tissues, TMPRSS2 transcription is subjected to tight monoallelic regulation, which is retained upon asymmetric division and relaxed during epithelial cell differentiation. The presence and expression of TMPRSS2/ERG in prostate stem cells would provide ERG-driven survival advantages, allowing maintenance of this mutated genotype.
    Nature Communications 03/2013; 4(1623). · 10.02 Impact Factor
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    ABSTRACT: While chromosomal translocations have a fundamental role in the development of several human leukaemias, their role in solid tumour development has been somewhat more controversial. Recently, it was shown that up to 80% of prostate tumours harbour at least one such gene fusion, and that the most common fusion event, between the prostate-specific TMPRSS2 gene and the ERG oncogene, is a critical, and probably early factor in prostate cancer development. Here we demonstrate the presence and expression of this significant chromosomal rearrangement in prostate cancer stem cells. Moreover, we show that in the prostate epithelial hierarchy from both normal and tumour tissues, TMPRSS2 transcription is subjected to tight monoallelic regulation, which is retained upon asymmetric division and relaxed during epithelial cell differentiation. The presence and expression of TMPRSS2/ERG in prostate stem cells would provide ERG-driven survival advantages, allowing maintenance of this mutated genotype.
    Nature Communications 03/2013; 4:1623. · 10.02 Impact Factor
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    ABSTRACT: IL-6 overexpression and constitutive STAT3 activation occur in many cancers including prostate cancer. However, their contribution to prostate stem and progenitor cells has not been explored. In this study, we show that stem-like cells from prostate cancer patients secrete higher levels of IL-6 than their counterparts in non-neoplastic prostate. Tumor grade did not influence the levels of expression or secretion. Stem-like and progenitor cells expressed the IL-6 receptor gp80 with concomitant expression of pSTAT3. Blockade of activated STAT3, by either anti-IL-6 antibody siltuximab (CNTO 328) or LLL12, a specific ρSTAT3 inhibitor, suppressed the clonogenicity of the stem-like cells in patients with high grade disease. In a murine xenograft model utilized to determine the in vivo effects of ρSTAT3 suppression, LLL12 treatment effectively abolished outgrowth of a patient-derived castrate-resistant tumor. Our results indicate that the most primitive cells in prostate cancer require ρSTAT3 for survival, rationalizing STAT3 as a therapeutic target to treat advanced prostate cancer.
    Cancer Research 01/2013; 73(16):5288-5298. · 8.65 Impact Factor
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    ABSTRACT: The outcome for patients with advanced metastatic and recurrent prostate cancer is still poor. Therefore, new chemotherapeutics are required, especially for killing cancer stem cells that are thought to be responsible for disease recurrence. In this study, we screened the effect of a novel palladium-based anticancer agent (Pd complex) against six different prostate cancer cell lines, and primary cultures from seven Gleason 6/7 prostate cancer, three Gleason 8/9 prostate cancer and four benign prostate hyperplasia patient samples, as well as cancer stem cells selected from primary cultures. MTT and ATP viability assays were used to assess cell growth and flow cytometry to assess cell cycle status. In addition, immunofluorescence was used to detect γH2AX nuclear foci, indicative of DNA damage, and Western blotting to assess the induction of apoptosis and autophagy. The Pd complex showed a powerful growth-inhibitory effect against both cell lines and primary cultures. More importantly, it successfully reduced the viability of cancer stem cells as first reported in this study. The Pd complex induced DNA damage and differentially induced evidence of cell death, as well as autophagy. In conclusion, this novel agent may be promising for use against the bulk of the tumour cell population as well as the prostate cancer stem cells, which are thought to be responsible for the resistance of metastatic prostate cancer to chemotherapy. This study also indicates that the combined use of the Pd complex with an autophagy modulator may be a more promising approach to treat prostate cancer. In addition, the differential effects observed between cell lines and primary cells emphasise the importance of the model used to test novel drugs including its genetic background, and indeed the necessity of using cells cultured from patient samples.
    PLoS ONE 01/2013; 8(5):e64278. · 3.73 Impact Factor
  • Joby Taylor, Michael J. Stower
    British Journal of Medical and Surgical Urology 09/2011; 4(5):216.
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    ABSTRACT: Epigenetic control is essential for maintenance of tissue hierarchy and correct differentiation. In cancer, this hierarchical structure is altered and epigenetic control deregulated, but the relationship between these two phenomena is still unclear. CD133 is a marker for adult stem cells in various tissues and tumour types. Stem cell specificity is maintained by tight regulation of CD133 expression at both transcriptional and post-translational levels. In this study we investigated the role of epigenetic regulation of CD133 in epithelial differentiation and cancer. DNA methylation analysis of the CD133 promoter was done by pyrosequencing and methylation specific PCR; qRT-PCR was used to measure CD133 expression and chromatin structure was determined by ChIP. Cells were treated with DNA demethylating agents and HDAC inhibitors. All the experiments were carried out in both cell lines and primary samples. We found that CD133 expression is repressed by DNA methylation in the majority of prostate epithelial cell lines examined, where the promoter is heavily CpG hypermethylated, whereas in primary prostate cancer and benign prostatic hyperplasia, low levels of DNA methylation, accompanied by low levels of mRNA, were found. Moreover, differential methylation of CD133 was absent from both benign or malignant CD133+/α2β1integrinhi prostate (stem) cells, when compared to CD133-/α2β1integrinhi (transit amplifying) cells or CD133-/α2β1integrinlow (basal committed) cells, selected from primary epithelial cultures. Condensed chromatin was associated with CD133 downregulation in all of the cell lines, and treatment with HDAC inhibitors resulted in CD133 re-expression in both cell lines and primary samples. CD133 is tightly regulated by DNA methylation only in cell lines, where promoter methylation and gene expression inversely correlate. This highlights the crucial choice of cell model systems when studying epigenetic control in cancer biology and stem cell biology. Significantly, in both benign and malignant prostate primary tissues, regulation of CD133 is independent of DNA methylation, but is under the dynamic control of chromatin condensation. This indicates that CD133 expression is not altered in prostate cancer and it is consistent with an important role for CD133 in the maintenance of the hierarchical cell differentiation patterns in cancer.
    Molecular Cancer 07/2011; 10:94. · 5.13 Impact Factor
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    ABSTRACT: Objective To quantify the proportion of patients attending for urological investigation of non-visible haematuria who meet criteria for referral to specialist renal services under current UK guidelines.
    British Journal of Medical and Surgical Urology 01/2011; 4(5):197-201.
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    ABSTRACT: ObjectiveTo review patients presenting in a specialist macroscopic (visible) haematuria clinic during 2005, incorporating 3 years of follow-up, and to assess the role of urine cytology.Patients and methodsAll patients attending the 2005 macroscopic haematuria clinic were identified. All subsequent admissions, pathology and imaging for each patient were captured from the hospital IT system during 3 years of follow-up and reviewed retrospectively.ResultsFive hundred and three patients were assessed. No significant abnormalities were diagnosed in 52%, benign disease in 27% and malignant disease in 21% (including 14% urothelial cancer, 3% renal cancer and 4% prostate cancer). All bladder tumours were diagnosed with flexible cystoscopy and the 3 upper-tract urothelial tumours by ultrasound. Overall, cytology had a sensitivity of 66% and specificity 90% but did not diagnose tumours that were not identified with other investigations. Patients with abnormal cytology without apparent cause underwent various investigations including IVU, cystoscopy and biopsy and no tumours were identified. After 3 years no occult diseases became apparent.ConclusionsHalf of all those attending with visible haematuria had significant urological diagnoses (21% urological cancer). Urine cytology did not appear to add significant information in the initial assessment of visible haematuria.
    British Journal of Medical and Surgical Urology. 01/2010;
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    ABSTRACT: The tumor-initiating capacity of many cancers is considered to reside in a small subpopulation of cells (cancer stem cells). We have previously shown that rare prostate epithelial cells with a CD133+/alpha2beta1hi phenotype have the properties of prostate cancer stem cells. We have compared gene expression in these cells relative to their normal and differentiated (CD133-/alpha2beta1low) counterparts, resulting in an informative cancer stem cell gene-expression signature. Cell cultures were generated from specimens of human prostate cancers (n = 12) and non-malignant control tissues (n = 7). Affymetrix gene-expression arrays were used to analyze total cell RNA from sorted cell populations, and expression changes were selectively validated by quantitative RT-PCR, flow cytometry and immunocytochemistry. Differential expression of multiple genes associated with inflammation, cellular adhesion, and metastasis was observed. Functional studies, using an inhibitor of nuclear factor kappaB (NF-kappaB), revealed preferential targeting of the cancer stem cell and progenitor population for apoptosis whilst sparing normal stem cells. NF-kappaB is a major factor controlling the ability of tumor cells to resist apoptosis and provides an attractive target for new chemopreventative and chemotherapeutic approaches. We describe an expression signature of 581 genes whose levels are significantly different in prostate cancer stem cells. Functional annotation of this signature identified the JAK-STAT pathway and focal adhesion signaling as key processes in the biology of cancer stem cells.
    Genome biology 02/2008; 9(5):R83. · 10.30 Impact Factor
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    ABSTRACT: Giant bladder calculi are rare and giant vaginal stones are an exceptional finding. We report the case of a 76-year-old female who presented with bilateral hydronephrosis and was discovered to have giant bladder calculus with a synchronous giant vaginal stone. The vaginal stone was broken into fragments and removed with the discovery of a copper intrauterine contraceptive device at the core whilst the bladder calculus required a planned open cystolithotomy. Subsequently two cystograms were conducted with the initial one not showing any vesico-vaginal communication how-ever the second cysrtogram showed the contrary and subsequently the patient underwent further surgery to correct this fistula.
    Current Urology. 01/2008; 2(4):206-207.
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    ABSTRACT: Three-dimensional epithelial culture models are widely used to emulate a more physiologically relevant microenvironment for the study of genes and signaling pathways. Prostate epithelial cells can grow into solid cell masses or acinus-like spheroids in Matrigel. To test if the ability to form acinus-like spheroids in Matrigel is dependent on how undifferentiated a cell is or whether it is tumor or nontumor, we established six novel epithelial cell lines. Primary prostate epithelial cells were immortalized using HPV16 E6 gene transduction and were named Shmac 2, 3, and 6 (nontumor); Shmac 4, Shmac 5, and P4E6 (tumor). All cell lines were phenotyped in monolayer culture, and their ability to form acinus-like spheroids in Matrigel investigated. The cell lines exhibited a wide range of population doubling times and all showed an intermediate phenotype in monolayer culture ((luminal)CK(+)/(basal)CK(+)/CD44(+)/PSA(+)/AR(-)). Only Shmac 5 cells formed acinus-like spheroids when cultured in Matrigel. Co-culture of the spheroids with fibroblasts advanced differentiation by inducing androgen receptor expression and epithelial polarization. Our findings indicate that tumor cells can form acinus-like spheroids in Matrigel.
    In Vitro Cellular & Developmental Biology - Animal 08/2006; 42(8-9):273-80. · 1.29 Impact Factor
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    ABSTRACT: Existing therapies for prostate cancer eradicates the bulk of cells within a tumor. However, most patients go on to develop androgen-independent disease that remains incurable by current treatment strategies. There is now increasing evidence in some malignancies that the tumor cells are organized as a hierarchy originating from rare stem cells that are responsible for maintaining the tumor. We report here the identification and characterization of a cancer stem cell population from human prostate tumors, which possess a significant capacity for self-renewal. These cells are also able to regenerate the phenotypically mixed populations of nonclonogenic cells, which express differentiated cell products, such as androgen receptor and prostatic acid phosphatase. The cancer stem cells have a CD44+/alpha2beta1hi/CD133+ phenotype, and we have exploited these markers to isolate cells from a series of prostate tumors with differing Gleason grade and metastatic states. Approximately 0.1% of cells in any tumor expressed this phenotype, and there was no correlation between the number of CD44+/alpha2beta1hi/CD133+ cells and tumor grade. The identification of a prostate cancer stem cell provides a powerful tool to investigate the tumorigenic process and to develop therapies targeted to the stem cell.
    Cancer Research 01/2006; 65(23):10946-51. · 8.65 Impact Factor
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    J R Wilson, G H Urwin, M J Stower
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    ABSTRACT: Uraemia as a result of malignant ureteric obstruction is a recognised event in those with advanced malignancy, usually of pelvic origin, which, if left untreated, is quickly a terminal event. Palliative decompression of the obstructed urinary system, either by percutaneous nephrostomy (PCN), ureteric stent or a combination of both is a recognised method of improving renal function, with presumed low morbidity. The aims of the study were to assess whether PCN placement in malignant ureteric obstruction provided any additional survival benefit or patient morbidity. The case notes of 32 patients with a mean age of 68.1 years (16 male, 16 female) who underwent PCN drainage for malignant ureteric obstruction were retrospectively analysed. Data on the site of primary malignancy, mode of presentation, improvement in renal function, median survival, conversion to internal ureteric stents and intervention-related complications were collected for analysis. The median survival following PCN insertion was 87 days and was unrelated to the patient's age and renal function. Those patients with primary underlying gynaecological malignancies appeared to survive almost 4 times as long as those with underlying primary bladder cancer. Renal function took a mean of 16.8 days to reach a nadir. Almost 79% of patients were able to be discharged from hospital--each patient, however, being re-admitted back to hospital on average 1.6 times prior to their death through PCN or internal ureteric stent related events. Retrospective "useful quality of life" was seen in less than half of the patient cohort. In the presence of malignant ureteric obstruction, palliative percutaneous urinary diversion may be performed and is effective in improving renal function. However, long-term survival is limited and should, therefore, be performed only when the views and wishes of the patient and carers are taken into account and if there is a definitive treatment plan available for the patient as quality of life can be suboptimal.
    Annals of The Royal College of Surgeons of England 02/2005; 87(1):21-4. · 1.33 Impact Factor
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    J R Wilson, G H Urwin, M J Stower
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    ABSTRACT: Transurethral resection of the prostate (TURP) is considered by many to be the 'gold standard' treatment for benign prostatic enlargement. However, with the relatively recent introduction of pharmacological and other surgical treatment modalities, the performance of TURP appears to be in decline. A retrospective casenote analysis of 200 patients who underwent TURP in 1990 and the year 2000 with the aim of identifying changes in the incidence and practice of TURP. There was a decline in the number of TURPs performed of 31.6% over the 10-year period, with more being carried out because of urinary retention. In 2000, the patient was older and the operative procedure took statistically longer than 10-years earlier, but the weight of prostate tissue resected, patient satisfaction and complication rates were similar. At present, TURP is in decline, with urinary retention being the commonest indication. The population at present is older but this does not carry additional co-morbidity. The weight of resection has not altered, although surgery currently takes longer to perform.
    Annals of The Royal College of Surgeons of England 12/2004; 86(6):428-31. · 1.33 Impact Factor
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    ABSTRACT: The metastatic potential of a series of prostate cell lines was analysed by measuring motility and invasiveness, and further correlated to the expression of epithelial differentiation markers. Invasion and motility were measured using in vitro assays. Immunohistochemistry of cell lines and tissues was used to identify expression of cytokeratins 8 and 1, 5, 10, 14, vimentin, prostate specific antigen, prostate specific membrane antigen, androgen receptor, desmoglein, E-cadherin, beta1 integrin, CD44, hmet, vinculin and actin. Expression of vimentin was the only marker to correlate with motility, no markers correlated to invasion. Lower vimentin expression was observed in cells with low motility (PNT2-C2) and high expression in cells with high motility (P4E6, PNT1a, PC-3). Vimentin expression was not detected in well differentiated tumours, moderately differentiated tumours contained vimentin positive cells (1/9 bone scan negative, 2/5 bone scan positive), but the majority of poorly differentiated cancers (4/11 bone scan negative, 9/14 bone scan positive) and bone metastases (7/8) had high vimentin expression in tumour cells. Motile prostate cancer cell lines express vimentin. In tissue sections, the presence of vimentin positive tumour cells correlated positively to poorly differentiated cancers and the presence of bone metastases.
    The Prostate 10/2002; 52(4):253-63. · 3.84 Impact Factor

Publication Stats

1k Citations
64.28 Total Impact Points

Institutions

  • 2013
    • Uludag University
      • Department of Medical Biochemistry
      Bursa, Bursa, Turkey
  • 2002–2013
    • The University of York
      • • Department of Biology
      • • Yorkshire Cancer Research Unit
      York, ENG, United Kingdom
  • 2002–2011
    • York Hospital
      York, Pennsylvania, United States