The Association of Death Receptors and TGF-ß1 Expression in Urothelial Bladder Cancer and Their Prognostic Significance.

Death receptor signalization that triggers the extrinsic apoptotic pathway and TGF-ß1 have important roles in urothelial carcinogenesis, with a complex interplay between them. The aim of this research was to assess the association of death receptors DR4, DR5, and FAS as well as TGF-ß1 immunohistochemical expression with the clinicopathological characteristics of urothelial bladder cancer (UBC) and to evaluate their prognostic significance. The decrease or loss of death receptors' expression was significantly associated with muscle-invasive tumors, while non-invasive UBC often retains the expression of death receptors, which are mutually strongly linked. High DR4 expression is a marker of low-grade tumors and UBC associated with exposition to known carcinogens. Conversely, TGF-ß1 was significantly associated with high tumor grade and advanced stage. High expression of DR4 and FAS indicates longer overall survival. High TGF-ß1 signifies an inferior outcome and is an independent predictor of adverse prognosis in UBC patients. This study reveals the expression profile of death receptors in UBC and their possible interconnection with TGF-ß1 and indicates independent prognostic significance of high FAS and TGF-ß1 expression in UBC, which may contribute to deciphering the enigma of UBC heterogeneity in light of the rapid development of novel and effective therapeutic approaches, including targeting of the TRAIL-induced apoptotic pathway.

Expression of Basal Compartment and Superficial Markers in Upper Tract Urothelial Carcinoma Associated with Balkan Endemic Nephropathy, a Worldwide Disease.

The aim of this study was to determine the association of basal compartment and superficial markers, comprising CK5/6, CD44, CK20, and the pathological characteristics of upper tract urothelial carcinoma (UTUC) associated with Balkan endemic nephropathy (BEN). Comparing the expression of the investigated markers in 54 tumors from the BEN region and 73 control UTUC, no significant difference between them was detected. In regression analysis, CK20 expression was not determined with expression of CK5/6, CD44, and the phenotypic characteristics of BEN and control UTUC. Parameters with predictive influence on the expression of CD44 in BEN UTUC included growth pattern (p = 0.010), necrosis (p = 0.019); differentiation (p = 0.001), and lymphovascular invasion (p = 0.021) in control UTUC. Divergent squamous differentiation in BEN tumors (p = 0.026) and stage in control tumors (p = 0.049) had a predictive influence on the expression of CK5/6. This investigation detected a predictive influence of the phenotypic characteristics of UTUC on the expression of basal compartment and superficial markers, with a significant influence of necrosis in BEN tumors (p = 0.006) and differentiation in control UTUC (p = 0.036).

The association between NOTCH3 expression and the clinical outcome in the urothelial bladder cancer patients.

Disrupted NOTCH activity is a driving event in urothelial bladder cancer (UBC). After activation by hypoxia, the NOTCH3 receptor participates in tumor cell proliferation, acquisition of the epithelial-mesenchymal transition phenotype, and angiogenesis. The aim was to analyze the association of NOTCH3 expression with histopathological and clinical parameters, and to determine its predictive impact on the clinical outcome in UBC patients. The present research included 614 UBC samples incorporated in paraffin tissue microarrays, evaluated by immunohistochemistry for NOTCH3 expression. The accrual period was four years, while the follow-up period was two years. The membranous expression was semi-quantified (0-3), and the mean degree was 1.81±0.94. Criteria for semi-quantification the NOTCH3 expression were the intensity of the staining and the percentage of positive cells. The samples with negative (0) and weak (1) NOTCH3 immunohistochemical (IHC) score were considered negative, while the samples that showed moderate (2) and strong (3) expression were considered positive. Higher degree of positivity was associated with higher risk of cancer-specific mortality (p<0.001). Independent predictors for cancer-specific mortality were NOTCH3 expression and high stage (p<0.001). NOTCH3 expression was not a statistically significant predictor of recurrence-free survival (p=0.816). This study indicated that NOTCH3 is a predictor of poor outcome, suggesting that the NOTCH3 could be potentially reliable IHC marker for selecting the UBC patients that would require more intensive follow-up, especially if they diagnosed in higher stage, with divergent differentiation in pathological report, and without recurrences which would lead them to more frequent medical assessments.

Expression and prognostic value of CXCL12/CXCR4/CXCR7 axis in clear cell renal cell carcinoma.

BACKGROUND: CXCL12 or stromal-derived factor-1 is a chemokine that binds to two receptors CXCR4 and CXCR7 and takes part in both physiological and pathological cell functions. The disruption of the CXCL12/CXCR4/CXCR7 chemokine axis is seen in various types of cancers. METHODS: We have immunohistochemically analyzed the expression of CXCL12 and its receptors in clear cell renal cell carcinoma patients. The study included 85 tissue samples. Since samples exhibited heterogeneity of expression intensity and staining localization (cytoplasmatic and membranous), histoscores were calculated, and their associations with clinicopathological parameters were analyzed. RESULTS: Both cytoplasmatic CXCR7 and CXCL12 histoscores were associated with greater tumour size, while CXCL12 staining was associated with a higher grade as well. Mortality was associated with tumour size and both membranous and cytoplasmatic CXCL12 histoscores. With each centimetre in tumour size, survival decreases 1.3 times, while CXCL12C histoscore higher than 73 was associated with 2.3 greater risk of mortality. CXCR4 histoscore could only be predicted by female gender and neither cytoplasmatic nor membranous CXCR4 expression was found to be a mortality predictor. CONCLUSION: Our data suggest that regarding overall survival, CXCL12 could be considered a valuable prognostic marker.

Epithelial ovarian cancer with CD117 phenotype is highly aggressive and resistant to chemotherapy.

AIM: CD117 expression has a pathogenic role in many malignancies, including ovarian carcinoma. The aim of the present study was to examine the correlation of stemness-associated marker CD117 with the clinicopathologic features of epithelial ovarian cancer and patient survival. MATERIAL AND METHODS: The analysis included 240 primary ovarian carcinomas (OC) diagnosed during the period from 2005 to 2011 in the region of South Serbia. Age, pathohistological characteristics, presence and size of residual tumor, choice of therapy and response to the therapy were studied. RESULTS: Residual tumors were more frequently present in the patients with positive CD117 expression (18.1% vs 8.0%; P < 0.05). Chemotherapy according to paclitaxel/carboplatin protocol was more frequent in the patients with positive CD117 expression (70.9% vs 54.2%; P < 0.05), while carboplatin monotherapy was more frequent in the patients with negative CD117 expression (18.0% vs 6.4%; P < 0.05). Median survival time in patients with CD117-positive mucinous and endometrioid OC was significantly shorter, at 20 and 26.8 months, respectively. Median survival in serous OC was not related to CD117 expression. CONCLUSION: Residual tumors and chemotherapy treatment were more frequent in patients with positive CD117 expression. The outcome was dependent on the type of OC; a worse outcome, including a shorter survival, was documented in the mucinous and endometrioid OC cases.

Prognostic significance of mucin expression in urothelial bladder cancer.

Urothelial bladder cancer (UBC) is a common genitourinary malignancy, accounting for more than 160.000 deaths per year worldwide. Overexpression and aberrant glycosylation of mucins are frequent traits of many human cancers derived from epithelial cells, and are found to have prognostic significance in various carcinomas. The aim of this study was to further elucidate the features and significance of mucin expression in UBC. We investigated the relationship between mucin expression and clinicopathological characteristics in 539 cases of UBC by immunohistochemical analysis of MUC1, MUC2, MUC4, MUC5AC and MUC6 expression profiles. MUC1 stained 61.8% of the tumors and correlated with high tumor grade (P = 0.013). The expression of MUC2 and MUC6 was associated with low tumor grade (P < 0.000 and P < 0.022, respectively), and low pathologic stage (P < 0.001 and P = 0.001, respectively). MUC2 negative tumors were more frequently associated with the finding of carcinoma in situ in tumor surroundings (P = 0.019). UBC with divergent differentiation correlated with MUC1, MUC4 and MUC5AC staining. MUC4 expression was directly linked to cancer specific death (P = 0.027), while MUC2 and MUC6 showed inverse correlation to cancer-specific death (P < 0.001 and P = 0.005, respectively). Kaplan-Meier analyses showed that expression of MUC2 and MUC6 in UBC was significantly associated with better overall survival of the patients (P < 0.001, respectively). In Cox regression model, the absence of MUC6 expression emerged as independent predictor of death outcome. In conclusion, this study identifies MUC2 and MUC6 expression as markers of UBC with less aggressive behavior and useful predictors of better survival.

Gastric cancer stem cells: therapeutic targets.

During the past decade, a growing body of evidence has implied that cancer stem cells (CSCs) play an important role in the development of gastric cancer (GC). The notion that CSCs give rise to GC and may be responsible for invasion, metastasis, and resistance to treatment has profound implications for anti-cancer therapy. Recent major advances in the rapidly evolving field of CSCs have opened novel exciting opportunities for developing CSC-targeted therapies. Discovery of specific markers and signaling pathways in gastric CSCs (GCSCs), with the perfecting of technologies for identification, isolation, and validation of CSCs, may provide the basis for a revolutionary cancer treatment approach based on the eradication of GCSCs. Emerging therapeutic tools based on specific properties and functions of CSCs, including activation of self-renewal signaling pathways, differences in gene expression profiles, and increased activity of telomerase or chemoresistance mechanisms, are developing in parallel with advances in nanotechnology and bioengineering. The addition of GCSC-targeted therapies to current oncological protocols and their complementary application may be the key to successfully fighting GC.

Malakoplakia mimics urinary bladder cancer: a case report.

INTRODUCTION: Malakoplakia is an unusual and very rare chronic inflammatory disease. In bladder especially it can mimic malignancy and lead to serious misdiagnosis. CASE REPORT: We presented a case of a middle-aged woman with persistent macrohematuria and cystoscopically polypoid bladder mass that resembled a neoplastic process. The final diagnosis was based on cystoscopic biopsy and microscopic findings of acidophilic, foamy histiocytes with the presence of Michaelis-Gutmann inclusions which are characteristic for diagnosis of malakoplakia. Immunohistochemistry confirmed diagnosis by demonstrating CD68-positive macrophages. CONCLUSION: Urinary bladder malakoplakia should be considered in patients with persistent urinary tract infections and tumor mass at cystoscopy. Early identification with prompt antibiotic treatment can be helpful in avoiding unnecessary surgical interventions and in preventing development of possible complications.

Angiogenesis in upper tract urothelial carcinoma associated with Balkan endemic nephropathy.

Upper tract urothelial carcinoma (UTUC) associated with Balkan endemic nephropathy (BEN) is characterized by a number of aberrations in cell-cycle regulation and apoptosis. The aim of this study was to detect angiogenesis-related marker(s) specific for BEN UTUC, and to examine the influence of HIF 1α upon angiogenesis and apoptosis in UTUC. Present investigation included 110 patients with UTUC, 50 from BEN region and 60 control tumors. Altered expression of VEGFR1 was more often present in control UTUC than in BEN tumors (p<0.005). It was associated with high grade, low and high stage, solid growth, and metaplastic change of control UTUC. Microvessel density assessed by CD31 (MVD CD31) was significantly higher in UTUC with lymphovascular invasion (p<0.05), and in BEN tumors with papillary growth (p<0.05). Discriminant analysis indicated that BEN and control tumors do not differ significantly in expression of angiogenesis related markers. The most important discriminant variable that determined control UTUC was expression of VEGFR1 (p=0.002). HIF 1α in UTUC significantly correlated with the low stage, papillary growth and expression of Bcl-2, Caspase-3 index, and MVD CD34 (p<0.001; 0.0005; 0.01; 0.005; 0.01, respectively). HIF-1α may be helpful marker in evaluation of UTUC, especially when combined with angiogenesis and apoptosis.

Pro- and antiapoptotic markers in upper tract urothelial carcinoma associated with Balkan endemic nephropathy.

The role of aristolochic acid in the etiology of Balkan endemic nephropathy (BEN) and associated upper-tract urothelial carcinoma (UTUC) has been recently confirmed. The aim of this study was to determine apoptosis-related marker(s) specific for BEN-associated UTUC. Present investigation included 105 patients with UTUC, 44 from BEN region and 61 control tumors. Altered expression of Survivin was more often present in BEN UTUC with high grade and solid growth (P < 0.005; P < 0.05) than in control tumors. Significantly lower expression of proapoptotic marker Bax was found in BEN tumors with high grade, high stage, necrosis, and without metaplastic change (P < 0.05; 0.05; 0.05; 0.05) compared to control tumors with the same features. Group (BEN-related/control), stage, growth pattern, and caspase 3 activity were significantly associated with the expression of Bax (P = 0.002, 0.034, 0.047, 0.028, resp.,). This investigation identifies Bax as specific marker of BEN-associated UTUC. Decrease of pro-apoptotic protein Bax together with alteration of Survivin may be indicative for specific disturbances of intrinsic apoptotic pathway in UTUC arising in endemic areas.