Abstract
CD24 is a glycosyl phosphatidylinositol (GPI)-anchored membrane protein that is frequently over-expressed in a variety of human carcinomas and is correlated with poor prognosis. In cancer ...cell lines, changes of CD24 expression can alter several cellular properties like invasion, proliferation and adhesion in vitro and tumor growth in vivo. However, little is known about the mechanisms by which CD24 mediates these effects. Here we have analyzed functional consequences of CD24 knock-down or over-expression in human cancer cell lines of different tumor entities (ovarian, lung, glioma). We show that presence or absence of CD24 was crucial to regulate the amount and activity of c-Src in lipid rafts. CD24-mediated effects on tyrosine-phosphorylated c-Src had impact on regulation of target genes affecting tumor cell invasion, proliferation and apoptosis. Invasive potential of tumor cells was controlled by the expression of the tissue factor pathway inhibitor-2 (TFPI-2), a potent inhibitor of extracellular matrix degradation that can block tumor cell invasion and metastasis. Silencing of CD24 or c-Src enhanced TFPI-2 expression and diminished invasion of SKOV3ip and A549 cells into matrigelTM. Conversely, over-expression of CD24 reduced TFPI-2 expression and enhanced invasion. Furthermore, an inverse correlation between expression of CD24 and TFPI-2 was observed by immunohistochemical analysis of primary breast cancers (N = 1174). TFPI-2 expression was highest in CD24 negative samples and lowered with increasing CD24 expression. Patients with a CD24 low/TFPI-2 high phenotype showed significantly better survival compared to CD24 high/TFPI-2 low patients (p=0.001). Additionally, STAT3 expression and phosphorylation were reduced by CD24 silencing. Diminished STAT3 activity was confirmed by specific reporter assays. Src depletion abrogated levels of p-STAT3 (Y705). In line with that, expression of classical STAT3 target genes like MCL-1, Cyclin D1 and Survivin was reduced after CD24 knock-down. Suppressed cell proliferation and enhanced apoptosis were observed in CD24 knock-down cells, suggesting a pivotal role of regulated target genes. An antibody to CD24 was effective in reducing tumor growth of lung- and pancreatic cancer xenografts in mice. Antibody treatment affected the level of Src-activity in the tumor and altered expression of STAT3 target genes. Our results provide evidence that CD24 regulates TFPI-2 and STAT3 activity via the c-Src non receptor tyrosin kinase. Targeting of CD24 by antibodies could represent a novel strategy for anti tumor therapy.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3087. doi:1538-7445.AM2012-3087
Yes-associated protein 1 (YAP1), the nuclear effector of the Hippo pathway, plays an important role in many tumor entities. We evaluated staining and clinical significance of YAP1 and phosphorylated ...YAP1 (pYAP1) in urothelial bladder cancer (BCA).
We used a tissue micorarray with samples of patients with muscle-invasive bladder cancer (MIBC, n = 192), non-muscle-invasive bladder cancer (NMIBC, n = 192) and normal urothelial bladder tissue (CTRL, n = 38) to determine the immunhistochemical staining of YAP1 and pYAP1. Cytoplasmatic and nuclear levels were evaluated. The t test was used for comparative analysis. Overall survival and progression-free survival were evaluated by Kaplan-Meier estimates and the Cox proportional hazard regression model.
Nuclear YAP1 as well as cytoplasmatic pYAP1 levels were higher in CTRL than in BCA, whereby both--NMIBC and MIBC--had lower levels than CTRL. Among patients with MIBC, cytoplasmatic YAP1 and pYAP1 staining decreased with advanced stage. YAP1 and pYAP1 staining did not correlate with the recurrence rate, progression-free, cancer-specific or overall survival.
Immunhistochemical staining and subcellular localization of YAP1 and pYAP1 are different for BCA, NMIBC, MIBC and CTRL, indicating that the Hippo pathway is involved in urothelial carcinogenesis.
Gross cystic disease fluid protein (GCDFP-15) and mammaglobin are both widely used and accepted markers for epithelia of breast origin. We aimed to evaluate their relation of expression on parallel ...whole tissue sections in primary breast cancer by immunohistochemistry and also to correlate it with clinico-pathological parameters including patient survival. Primary breast carcinomas from 165 patients with a mean clinical follow-up of 73 months were immunostained using commercially available antibodies against GCDFP-15 and mammaglobin. An immunoreactive score (IRS) was calculated based on the cytoplasmic staining intensity and the number of cells stained. Cytoplasmic expression of GCDFP-15 and mammaglobin was observed in 73.3% and 72.1% of invasive breast carcinomas respectively. 91.8% of breast cancer cases expressed at least one of both markers. Both markers strongly correlated with each other and were significantly associated with lower tumour grading. Additionally, GCDFP-15 negativity was significantly associated with shortened disease-free survival times in univariate and multivariate analyses. We demonstrated the strong correlation of GCDFP-15 and mammaglobin with each other and showed that only very few primary breast cancers are completely negative for both markers. The significantly longer disease free survival times for patients with GCDFP-15 positive tumours clearly warrants further study.
Objective:
The aim of this study was to assess the behavior of the matrix metalloproteinases (MMPs) 2 and 9 and the tissue inhibitor of metalloproteinases 1 (TIMP-1) in human prostate cancer.
...Methods:
mRNA and protein expression patterns of MMP-2, MMP-9, and TIMP-1 were studied in cancerous and noncancerous parts of 17 prostates removed by radical prostatectomy. Competitive RT-PCR, gelatin-substrate zymography, and ELISA techniques were used for quantification.
Results:
On the mRNA level, MMP-2 expression was decreased and MMP-9, TIMP-1, the ratios of MMP-2 and MMP-9 to TIMP-1 were unchanged in cancerous tissue compared to the normal counterparts. On the protein level, expression of MMP-9 was significantly higher and TIMP-1 expression was significantly lower, MMP-2 was unchanged and the ratios of MMP-2 and MMP-9 to TIMP-1 were increased in tumor tissue.
Conclusions:
The higher concentration of MMP-9 as well as the increased ratios of MMP-2 and MMP-9 to TIMP-1 in malignant tissue prove the proteolytic dysbalance in prostate cancer, which does not seem to be associated with the stage and grade of the tumor. Comparison of mRNA and protein expression of MMP-2, MMP-9 and TIMP-1, respectively, did not show any significant relationships illustrating the necessity to study these components at both molecular levels.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A putative hilus interstitial cell has been proposed as the cell of origin for testicular tumors of adrenogenital syndrome, but its normal histology is not documented. We present hitherto undescribed ...nodular steroid cell nests associated with the rete testis that are distinctive in their morphology and immunohistochemical profile from Leydig cells and do not have the morphology of typical extra-adrenal cortical rests. These nodules measured 1, 1, 1.8, 2, and 2.5 mm in size with a distinct sinusoidal vasculature. Individual cells were rounded to polygonal with evenly distributed moderate-to-abundant eosinophilic cytoplasm. The nuclei were homogenous and round, with fine chromatin and ocasionally with prominent nucleoli. The differential diagnosis included adrenocortical rests, testicular adnexal Leydig cells, carcinoid tumorlets, paraganglionic rests, and adenomatoid mesothelial proliferation. Immunohistochemistry showed positivity for melan A (5/5), inhibin (3/5), and calretinin (2/4), although the immunoreactivity was distinctively different from the concurrent intratesticular Leydig cells and testicular adnexal Leydig cells in all cases. The unique morphology, immunophenotype, and distinctive location of these cells in the testicular mediastinum raises the possibility that these cells represent testicular hilus steroid cells, the putative histogenetic cell implicated for testicular tumors of adrenogenital syndrome. We propose to name these proliferations rete testis-associated nodular steroid cell nests.
Aims
The
G
leason scoring system underwent revision at the
I
nternational
S
ociety of
U
rological Pathology (
ISUP
) conference in 2005. It is not known how uropathologists have interpreted its ...recommendations.
Method and results
A web‐based survey to
E
uropean
N
etwork of
U
ropathology members received replies from 266 pathologists in 22 countries. Eighty‐nine per cent claimed to follow
ISUP
recommendations. Key areas of disagreement included the following. Smoothly rounded cribriform glands were assigned
G
leason pattern (
GP
) 3 by 51% and
GP
4 by 49%. Necrosis was diagnosed as
GP
5 by 62%. Any amount of secondary pattern of higher grade in needle biopsies was included in the
G
leason score by 58%. Tertiary
GP
of higher grade on needle biopsies was included in the
G
leason score by only 58%. If biopsy cores were embedded separately, only 56% would give a
G
leason score for each core/slide examined; 68% would give a concluding
G
leason score and the most common method was a global
G
leason score (77%). Among those who blocked multiple biopsy cores together, 46% would only give an overall
G
leason score for the case.
Conclusion
Misinterpretation of
ISUP
2005 is widespread, and may explain the variation in
G
leason scoring seen. Clarity and uniformity in teaching
ISUP
2005 recommendations is necessary.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Alpha-methylacyl-CoA racemase (AMACR) is involved in the cellular metabolism of fatty acids. It is a prognostic factor in prostate and colorectal cancer. So far, little is known about its expression ...and prognostic role in ovarian cancer. We investigated the expression of AMACR in a total of 420 ovarian tumors (388 carcinomas, 32 borderline tumors) by immunohistochemistry on tissue microarrays of two independent patient cohorts. In both cohorts, cytoplasmic AMACR expression was identified in 11.8% (16/136) and 5.4% (13/239), respectively, of the ovarian carcinomas. In contrast, borderline tumors did not show any AMACR expression. AMACR expression was significantly associated with histological subtype, FIGO stage, and grade in one cohort and low estrogen receptor levels in the other cohort. In univariate analysis, AMACR expression was significantly associated with poor overall survival (log rank,
p
= 0.006) and an independent prognostic factor in a multivariate analysis (HR 3.3; CI 1.3–7.9;
p
= 0.008) but could not be verified in the second cohort. Unlike in other tumor entities, AMACR expression does not seem to have an unequivocal prognostic impact in ovarian cancer. The prevalence may limit the value of AMACR for the differential diagnosis between metastatic colorectal carcinomas and primary ovarian carcinomas, whereas the association with estrogen receptor expression deserves further studies.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Prostate cancer is among the most common cancers. Although it has a relatively good prognosis, 15 to 30% of men with prostate cancer experience a relapse after radical prostatectomy. Identifying ...patients with an aggressive tumor will therefore help to improve prostate cancer management. DNA methylation of PITX2 has been established in several studies as a prognostic biomarker for breast and prostate cancer. These case control studies were conducted using research assay components; to facilitate its use in a diagnostic setting, the PITX2 biomarker was transferred to a validated diagnostic platform, the Affymetrix GeneChip System. A customized microarray (Epichip PITX2 ) was designed using features in high redundancy to ensure a robust determination of the methylation state of the PITX2 promoter. The developed method allowed for accurate assessment of prognosis in prostate cancer patients who underwent radical prostatectomy. Determination of PITX2 methylation in formalin-fixed and paraffin-embedded tissue samples from a cohort of 157 prostatectomy patients resulted in an excellent level of concordance of the clinical classification, as well as the measured output between the research assay and the Epichip PITX2 . These analytical performance results describe the Epichip PITX2 as a robust and reliable diagnostic tool for assessing the methylation status of PITX2 , enabling an improved outcome prediction in cancer patients following radical prostatectomy.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF