Biomedical subjects

Uziel Beller

Publications and source records attributed to Uziel Beller.

5 recordsLinked to original sources

PubMed2006

The pattern of Protease Activated Receptor 1 (PAR1) expression in endometrial carcinoma.

OBJECTIVE: Protease Activated Receptors (PARs) form a family of G-protein-coupled proteins uniquely activated by proteolytic cleavage. While the role of either soluble or matrix-immobilized protease in tumor invasion is well established, the part of cell surface PARs is beginning to emerge. We sought to investigate the expression pattern of Protease Activated Receptor 1 (hPar1) in endometrial carcinoma, the most common type of gynecological malignancy. METHODS: Tissue biopsy specimens taken from seventy-four formalin-fixed, paraffin-embedded endometrial tissue blocks were obtained from archival material. Analysis of PAR1 expression was evaluated by riboprobe in situ hybridization for detection of RNA and immunohistochemistry techniques for localization of protein. Histological scoring was performed. RESULTS: The levels of hPar1 mRNA and protein were high and abundant in high-grade endometrial carcinoma, regardless of the histological subtype. In contrast, no hPar1 was detected in endometrial epithelia with conserved glandular structure represented by normal, hyperplastic or low-grade carcinomas. CONCLUSIONS: PAR1 over-expression is selectively confined to the highly aggressive, high-grade endometrial carcinoma and absent in tissue obtained from benign endometrium or low-grade endometrial cancer. This finding highlights the significance of hPar1 gene involvement in invasive endometrial carcinoma and appoints it an attractive candidate for anti-cancer therapy.

Biomarkers, Tumor↗

PubMed2006

The "Sentinel Chain": a new concept for prediction of axillary node status in breast cancer patients.

BACKGROUND AND OBJECTIVES: More than half the breast cancer patients with positive sentinel lymph nodes (SLN) do not harbor additional metastases in non-sentinel nodes (NSN). The aim of this study was to identify a subgroup of patients with positive SLNs and negative NSNs, on the basis of tumor involvement patterns in multiple radioactive nodes. METHODS: Between 2000 and 2004, 290 patients with primary invasive breast cancer and clinically negative axillary nodes had a SLN biopsy in our breast unit. Radiotracer was identified intraoperatively in the axilla. All radioactive nodes were removed and radioactivity was measured in each node extracorporeally. Nodes were ranked according to radioactivity, constituting a "Sentinel Chain", and the histopathological status of each node was reported. The different metastatic involvement patterns of the Sentinel Chain were correlated with the metastatic status of the NSNs after axillary dissection. Information was charted in a prospective database. RESULTS: Of 290 patients, 216 (74.5%) had multiple radioactive nodes. Ninety patients (31%) had SLN metastases. Fifty patients had multiple ranked radioactive nodes and positive SLNs. Twenty-five of these patients had a sequential involvement pattern, with tumor-bearing high radioactivity nodes, and uninvolved low-radioactivity nodes. In the 23 of these 25 patients who had axillary dissection, NSN involvement was detected in only one patient (4.3%), whereas in 24 patients with other involvement patterns of the Sentinel Chain, NSN involvement reached 54.2% (p<0.001). CONCLUSION: Tumor-free status of NSN may be predicted using the Sentinel Chain concept in some breast cancer patients with positive SLNs.

Axilla↗

PubMed2005

Differential expression of protease activated receptor 1 (Par1) and pY397FAK in benign and malignant human ovarian tissue samples.

Protease activated receptors (PAR) form a family of G-protein coupled receptors (GPCR) encoding their own ligands and uniquely activated via proteolytic cleavage. Although proteases in general have been implicated in the remodeling of the extracellular tumor microenvironment, the role of cell surface receptors activated by proteolysis is now emerging. In our present study we investigated the expression pattern of protease activated receptor 1 hPar1 in ovarian carcinoma tissue samples. Abundant hPar1 mRNA and protein were detected in "low malignant potential" and in invasive carcinomas, regardless of the histological subtype. In contrast, no hPar1 expression was detected on the cell surface of normal ovarian epithelium. The differential expression pattern of hPar1 was shown by in situ hybridization, immunohistochemistry and semi-quantitative RT-PCR analyses. In early stages of ovarian carcinoma (Ia), the contra lateral normal ovary showed strong PAR1 expression as opposed to the lack of expression in the ovarian epithelium obtained from normal individuals. In parallel, we analyzed the expression pattern of alphavbeta5 integrin and of activated focal adhesion kinase (FAK), a major focal contact protein, in these tissues. Although abundant expression of alphavbeta5 integrin was observed in all tissues specimens examined, regardless of either normal or malignant, the level of activated FAK was differentially expressed. Phosphorylated FAK was seen in invasive ovarian carcinoma, but not in the normal ovarian epithelium. The abundant hPar1 levels in pathological malignant ovarian carcinoma is likely to transmit signals leading to the phosphorylation of FAK and thereby alterations in the integrin functional state. Altogether our data suggest that hPar1 and FAK cooperate to promote ovarian cancer malignancy.

Adenocarcinoma, Clear Cell↗

PubMed2003

The RASSF1A tumor suppressor gene is commonly inactivated in adenocarcinoma of the uterine cervix.

PURPOSE: Development of adenocarcinoma (AC) of the uterine cervix, as well as squamous cell carcinoma (SCC), is strongly linked to infection by high-risk human papillomavirus (HPV) types. Human HPV E6 and E7 proteins inactivate the tumor suppressor genes p53 and retinoblastoma, respectively. However, additional genetic alterations may be required to maintain a malignant phenotype. Allelic loss at the short arm of chromosome 3 is one of the most frequent genetic changes found in cervical cancer and various other types of human cancer, including lung, breast, and ovarian cancer. This implies that a resident tumor-suppressor gene in this region is involved in the genesis of these tumors. RASSF1A, which is located at 3p21.3, is rarely inactivated by mutations but has been suggested as a target tumor suppressor gene on the basis of its frequent inactivation through promoter hypermethylation and loss of heterozygosity in a variety of primary human cancers. In the present study, we sought to determine whether epigenetic silencing of RASSF1A caused by hypermethylation of the promoter region plays a role in the development of uterine cervical cancer. EXPERIMENTAL DESIGN: We studied 51 uterine cervical carcinoma samples. These 51 cases were comprised of 31 SCCs and 20 ACs. Real-time methylation-specific PCR system was used for the detection and quantitation of the bisulfite-converted methylated version of the RASSF1A promoter region. The 20 cases of cervical AC were also analyzed for the presence of oncogenic HPV 16 DNA using a PCR-based method. RESULTS: We found complete methylation of the RASSF1A promoter in 45% (9 of 20 samples) of AC cases. There was no promoter methylation observed in any of the 31 cases of SCC. We also correlated RASSF1A promoter hypermethylation to oncogenic HPV 16 infection. HPV 16 DNA was found in 3 of 9 (33%) AC tumors with RASSF1A promoter hypermethylation and 5 of 11 (45%) AC tumors without RASSF1A promoter hypermethylation. We could not demonstrate an inverse correlation between RASSF1A methylation and HPV 16 infection in AC of the uterine cervix. CONCLUSIONS: Hypermethylation of the RASSF1A promoter region is common in AC of the uterine cervix and rare in squamous carcinoma of uterine cervix. HPV infection does not correlate with RASSF1A methylation status in AC of the uterine cervix, but the absence of RASSF1A methylation in SCC of the uterine cervix coupled with the high incidence of HPV 16 infection in this subtype is in accord with previous reports. Our results suggest that epigenetic silencing of RASSF1A may play a role in the development of AC of the uterine cervix.

Adenocarcinoma↗

PubMed2003

BRAF mutation in papillary thyroid carcinoma.

The BRAF gene has been found to be activated by mutation in human cancers, predominantly in malignant melanoma. We tested 476 primary tumors, including 214 lung, 126 head and neck, 54 thyroid, 27 bladder, 38 cervical, and 17 prostate cancers, for the BRAF T1796A mutation by polymerase chain reaction (PCR)-restriction enzyme analysis of BRAF exon 15. In 24 (69%) of the 35 papillary thyroid carcinomas examined, we found a missense thymine (T)-->adenine (A) transversion at nucleotide 1796 in the BRAF gene (T1796A). The T1796A mutation was detected in four lung cancers and in six head and neck cancers but not in bladder, cervical, or prostate cancers. Our data suggest that activating BRAF mutations may be an important event in the development of papillary thyroid cancer.

Adenine↗