Clinical significance of AGE-RAGE axis in colorectal cancer: associations with glyoxalase-I, adiponectin receptor expression and prognosis.

BACKGROUND: Advanced glycation end products (AGEs) and their receptor RAGE emerge as important pathogenic contributors in colorectal carcinogenesis. However, their relationship to the detoxification enzyme Glyoxalase (GLO)-I and Adiponectin receptors (AdipoR1, AdipoR2) in colorectal carcinoma (CRC) is currently understudied. In the present study, we investigated the expression levels of the above molecules in CRC compared to adjacent non-tumoral tissue and their potential correlation with clinicopathological characteristics and patients' survival. METHODS: We analyzed the immunohistochemical expression of AGE, RAGE, GLO-1, AdipoR1 and AdipoR2 in 133 primary CRC cases, focusing on GLO-I. The tumour MSI status was further assessed in mucinous carcinomas. Western immunoblotting was employed for validation of immunohistochemical data in normal and tumoral tissues as well in three CRC cell lines. An independent set of 55 patients was also used to validate the results of univariate survival analysis regarding GLO-I. RESULTS: CRC tissue showed higher intensity of both AGE and RAGE expression compared with normal colonic mucosa which was negative for GLO-I in most cases (78 %). Western immunoblotting confirmed AGE, RAGE and GLO-I overexpression in tumoral tissue. GLO-I expression was directly related to RAGE and inversely related to AGE immunolabeling. There was a trend towards higher expression of all markers (except for RAGE) in the subgroup of mucinous carcinomas which, although of borderline significance, seemed to be more prominent for AdipoR1 and AGE. Additionally, AGE, AdipoR1 and Adipo R2 expression was related to tumor grade, whereas GLO-1 and AdipoR1 to T-category. In survival analysis, AdipoR2 and GLO-I overexpression predicted shortened survival in the entire cohort and in early stage cases, an effect which for GLO-I was reproduced in the validation cohort. Moreover, GLO-I emerged as an independent prognosticator of adverse significance in the patients' cohort. CONCLUSIONS: We herein provide novel evidence regarding the possible interactions between the components of AGE-RAGE axis, GLO-I and adiponectin receptors in CRC. AGE and AdipoR1 are possibly involved in colorectal carcinogenesis, whereas AdipoR2 and GLO-I emerged as novel independent prognostic biomarkers of adverse significance for patients with early disease stage. Further studies are warranted to extend our observations and investigate their potential therapeutic significance.

Polycystin-1 and polycystin-2 are involved in the acquisition of aggressive phenotypes in colorectal cancer.

The polycystins PC1 and PC2 are emerging as major players in mechanotransduction, a process that influences all steps of the invasion/metastasis cascade. We hypothesized that PC1 and PC2 facilitate cancer aggressiveness. Immunoblotting, RT-PCR, semi-quantitative and quantitative real-time PCR and FACS analyses were employed to investigate the effect of polycystin overexpression in colorectal cancer (CRC) cells. The impact of PC1 inhibition on cancer-cell proliferation was evaluated through an MTT assay. In vitro data were analyzed by Student's t-test. HT29 human xenografts were treated with anti-PC1 (extracellular domain) inhibitory antibody and analyzed via immunohistochemistry to determine the in vivo role of PC1 in CRC. Clinical significance was assessed by examining PC1 and PC2 protein expression in CRC patients (immunohistochemistry). In vivo and clinical data were analyzed by non-parametric tests, Kaplan-Meier curves, log-rank test and Cox model. All statistical tests were two-sided. PC1 overexpression promotes epithelial-to-mesenchymal transition (EMT) in HCT116 cells, while PC2 overexpression results in upregulation of the mTOR pathway in SW480 cells. PC1 inhibition causes reduced cell proliferation in CRC cells inducing tumor necrosis and suppressing EMT in HT29 tumor xenografts. In clinical study, PC1 and PC2 overexpression associates with adverse pathological parameters, including invasiveness and mucinous carcinomas. Moreover, PC1 overexpression appears as an independent prognostic factor of reduced recurrence-free survival (HR = 1.016, p = 0.03) and lowers overall survival probability, while aberrant PC2 expression predicts poor overall survival (p = 0.0468). These results support, for the first time, a direct link between mechanosensing polycystins (PC1 and PC2) and CRC progression.

Histone deacetylase (HDAC)-1, -2, -4 and -6 expression in human pancreatic adenocarcinoma: associations with clinicopathological parameters, tumor proliferative capacity and patients' survival.

BACKGROUND: Histone deacetylases (HDACs) have been associated with malignant tumor development and progression in humans. HDAC inhibitors (HDACIs) are currently being explored as anti-cancer agents in clinical trials. The present study aimed to evaluate the clinical significance of HDAC-1, -2, -4 and -6 protein expression in pancreatic adenocarcinoma. METHODS: HDAC-1, -2, -4 and -6 protein expression was assessed immunohistochemically on 70 pancreatic adenocarcinoma tissue specimens and was statistically analyzed with clinicopathological characteristics and patients' survival. RESULTS: Enhanced HDAC-1 expression was significantly associated with increased tumor proliferative capacity (p = 0.0238) and borderline with the absence of lymph node metastases (p = 0.0632). Elevated HDAC-4 expression was significantly associated with the absence of organ metastases (p = 0.0453) and borderline with the absence of lymph node metastases (p = 0.0571) and tumor proliferative capacity (p = 0.0576). Enhanced HDAC-6 expression was significantly associated with earlier histopathological stage (p = 0.0115) and borderline with smaller tumor size (p = 0.0864). Pancreatic adenocarcinoma patients with enhanced HDAC-1 and -6 expression showed significantly longer survival times compared to those with low expression (p = 0.0022 and p = 0.0113, respectively), while a borderline association concerning HDAC-2 expression was noted (p = 0.0634). CONCLUSIONS: The present study suggested that HDACs may be implicated in pancreatic malignant disease progression, being considered of clinical utility with potential use as therapeutic targets.

Radioisotopic and anatomical imaging approach of a primary non functioning liver paraganglioma.

Paragangliomas, also described as ectopic pheochromocytomas are infrequent neuroectodermal neoplasms that could be found wherever paraganglionic tissue exists. We present a rare case of a manifold non-functional primary hepatic paraganglioma in a 71 years old female. The combination of structural computed tomography and magnetic resonance imaging and of a functional modality, octreotide scan supported diagnosis. The role of nuclear medicine is crucial because it may help to determine future treatment in cases where there is suspicion of this tumour. However it has certain limitations, largely related to the physiological radionuclidic biodistribution. This case is described because of its relative rarity and also to emphasize the need to be studied by multidisciplinary collaboration.

Evaluation of a conventional ELISA (Novitec) and a near patient immunochromatographic test (Stick H. pyl) for Helicobacter pylori antigen detection in stool.

BACKGROUND/AIMS: The detection of Helicobacter pylori (H. pylori) antigen in stool by conventional ELISA is a reliable non-invasive method for the diagnosis of H. pylori infection in untreated patients. Recently, rapid in-office stool tests have been developed for the same purpose. METHODOLOGY: We have prospectively evaluated the performances of a commercially available enzyme-linked immunoassay (Novitec EIA) and a rapid near-patient immunochromatographic stool test (Stick H. pyl) for the detection of H. pylori stool antigen. Fifty H. pylori positive and 50 negative patients were included. H. pylori infection was diagnosed by using histology, rapid urease test and urea breath test. Patients were classified as positive if two of the three tests were positive and negative if all the three tests were negative. Testing was carried out according to the manufacturer's instructions. RESULTS: Novitec EIA had 8% equivocal results. If they were interpreted as negative the sensitivity, specificity, positive predictive value, negative predictive value and overall diagnostic accuracy were 82%, 86%, 86%, 83% and 84% and if as positive 88%, 76%, 79%, 86% and 82% respectively. ROC curve analysis showed a cut-off value of 0.144 for our population. The corresponding numbers for this cut-off value were: 82%, 94%, 93%, 84% and 88%. The respective numbers for Stick H. pyl were 78%, 78%, 76%, 78% and 79%. CONCLUSIONS: Novitec EIA performed well in this cohort of Greek patients and demonstrated a high specificity and positive predictive value when we adjusted the cut-off at 0.144. Performance of Stick H. pyl was sub-optimal.

Pregnane X Receptor Expression in Human Pancreatic Adenocarcinoma: Associations With Clinicopathologic Parameters, Tumor Proliferative Capacity, Patients' Survival, and Retinoid X Receptor Expression.

OBJECTIVES: Pregnane X receptor (PXR) has been involved in human malignancy, either by directly affecting carcinogenesis or by inducing drug-drug interactions and chemotherapy resistance. The present study aimed to assess the clinical significance of PXR in pancreatic adenocarcinoma. METHODS: Pregnane X receptor and its heterodimers' PXR/retinoid X receptor α (RXR-α), RXR-ß, and RXR-γ expression were assessed immunohistochemically on tumoral samples from 55 pancreatic adenocarcinoma patients and were associated with clinicopathologic parameters, tumor proliferative capacity, and patients' survival. RESULTS: Enhanced PXR expression was noted in 24 (43.6%) of 55 pancreatic adenocarcinoma cases. Pancreatic adenocarcinoma patients presenting increased histological grade of tumor differentiation showed a significant increased incidence of elevated PXR expression (P = 0.023). Enhanced PXR/RXR-ß expression was significantly associated with smaller tumor size and earlier clinical stage (P = 0.005 and P = 0.003, respectively). Elevated PXR/RXR-γ expression was significantly associated with smaller tumor size and earlier clinical stage (P = 0.012 and P = 0.014, respectively) and borderline with the absence of lymph node metastases (P = 0.056). In addition, pancreatic adenocarcinoma patients presenting enhanced PXR/RXR-γ expression showed marginally longer survival times compared with those with decreased expression (log-rank test, P = 0.053). CONCLUSIONS: This study supported evidence that PXR and its copartners' overexpression may be associated with favorable clinicopathologic parameters and better outcome in pancreatic adenocarcinoma.

Clinical significance of ephrin (eph)-A1, -A2, -a4, -a5 and -a7 receptors in pancreatic ductal adenocarcinoma.

Ephrin (Eph) receptors have been reported to be frequently overexpressed in a wide variety of cancer types, being associated with tumor growth, invasion, metastasis and angiogenesis. The aim of the present study was to evaluate the clinical significance of Eph-A1, -A2, -A4, -A5 and -A7 expression in pancreatic ductal adenocarcinoma. Eph-A1, -A2, -A4, -A5 and -A7 expression and staining intensity were assessed immunohistochemically in tumoral samples of 67 pancreatic adenocarcinoma patients and were statistically analyzed in relation to clinicopathological characteristics, tumor proliferative capacity and patients' survival. Eph receptors were abundantly expressed in pancreatic ductal adenocarcinoma cases examined. Eph-A1 staining intensity was significantly associated with tumor size (pT, p = 0.008) and tumor histopathological stage (pStage, p = 0.012). Eph-A2 expression was significantly associated with patients' age (p = 0.007), while Eph-A4 and Eph-A5 with tumor proliferative capacity (p = 0.019 and p = 0.011, respectively). Pancreatic adenocarcinoma patients with moderate/intense Eph-A5 or Eph-A7 staining presented significantly shorter survival times compared to those with negative/mild one (log-rank test, p = 0.024 and p = 0.009, respectively). Multivariate analysis identified Eph-A5 and Eph-A7 staining intensity as independent prognostic factors (p = 0.048 and p = 0.004, respectively). In conclusion, the present study revealed that Eph receptors were associated with pancreatic cancer characteristics, supporting evidence for their potential clinical application in management and prognosis of pancreatic adenocarcinoma patients.

Clinical significance of tumor-associated antigen RCAS1 expression in human pancreatic ductal adenocarcinoma.

Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a human tumor-associated antigen that induces cell cycle arrest and/or apoptosis in RCAS1 receptor-expressing immune cells. The aim of the present study was to evaluate the clinical significance of RCAS1 expression in human pancreatic adenocarcinoma. Immunohistochemical analysis of RCAS1 expression was performed on paraffin-embedded tissue sections obtained from 76 pancreatic adenocarcinoma patients. RCAS1 positivity and overexpression and intensity of the staining were correlated with clinicopathological parameters, proliferative capacity and patient survival. Of the 76 adenocarcinoma patients, 65 (86%) tested positive for RCAS1; of these 65 RCAS1-positive cases, 36 (55%) showed RCAS1 overexpression. RCAS1 positivity was statistically significantly correlated with the histopathological grade of the tumor (P = 0.026), and it showed a trend to be correlated with tumor size (P = 0.071). RCAS1 intensity and overexpression of staining showed a trend to be correlated with the histopathological grade of the tumor (P = 0.061 and P = 0.089, respectively), whereas RCAS1 positivity and the overexpression and intensity of staining were not statistically significantly correlated with the proliferative capacity of the tumor or any other clinicopathological parameter examined nor with patients' survival. Our data provide evidence for the implication of RCAS1 in pancreatic neoplasia. However, the prediction of survival using RCAS1 expression as a marker seems uncertain for this type of cancer.