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Many Cancers (many + cancers)
Selected AbstractsDiagnostic value of GLUT-1 immunoreactivity to distinguish benign from malignant cystic squamous lesions of the head and neck in fine-needle aspiration biopsy materialDIAGNOSTIC CYTOPATHOLOGY, Issue 5 2004Michael F. Weiner M.D. Abstract The distinction of cystic squamous-cell carcinoma (SCC) from benign cystic squamous lesions (BCSLs) of the head and neck can be problematic on fine-needle aspiration biopsy (FNAB) material, particularly when BCSLs display epithelial reactive atypia or when SCC is well differentiated. Glucose transporter 1 (GLUT-1), a facilitative cell surface glucose transport protein, is aberrantly expressed in many cancers including oral and hypopharyngeal SCC. We evaluated the expression of GLUT-1 by immunochemistry on FNAB material to determine its value in distinguishing cystic SCC from BCSL of the head and neck. A 5-yr retrospective review of all head and neck cystic squamous lesions having FNAB specimens with cell block material, radiological studies, and histological confirmation was performed at our institution. Cell block material from 24 cystic squamous lesions, including 8 (33%) BCSL (7 branchial cleft cysts and 1 thyroglossal duct cyst[TDC]) and 16 (67%) metastatic SCCs with cystic/liquefactive degeneration, was retrieved and immunostained with anti-GLUT-1. GLUT-1 expression was considered positive when at least 10% of squamous cells exhibited distinct cell membrane reactivity. Positive GLUT-1 immunostaining was detected in all 16 SCCs and in none of the 8 BCSLs. In the carcinoma cases, the majority of malignant cells exhibited GLUT-1 reactivity; only a minor population of well-differentiated SCC cells displaying keratinization and arranged as squamous pearls did not express GLUT-1. GLUT-1 expression in cell block material can help to distinguish cystic SCCs from BCSLs of the head and neck. In conjunction with clinical and radiological correlation, GLUT-1 immunoreactivity can be an important diagnostic aid when the cytological findings are ambiguous. Diagn. Cytopathol. 2004;31:294,299. © 2004 Wiley-Liss, Inc. [source] Chromosomal fragile sites FRA3B and FRA16D show correlated expression and association with failure of apoptosis in lymphocytes from patients with thyroid cancerGENES, CHROMOSOMES AND CANCER, Issue 5 2006Isabella Sbrana It has been suggested that common fragile sites (cFSs) are related to cancer development. This appears to be the case for FRA3B and FRA16D, localized in two tumor-suppressor genes (FHIT and WWOX, respectively) that are altered by deletions or loss of heterozygosity (LOH) in many cancers. The features responsible for fragility have not yet been identified. Furthermore, it is still unclear whether instability at these regions causes chance deletions and loss of function of the associated genes, or whether the gene function itself is related to the appearance of fragility. In this study, we analyzed cFS expression in lymphocytes from 20 healthy or thyroid cancer,affected subjects exposed to radiation after the Chernobyl accident. The same cells were examined for apoptosis, a principal function of both the FHIT and WWOX genes. Exceptionally elevated chromosome fragility was observed, particularly in cancer patients, affecting FRA3B, FRA16D, and a cluster of less highly expressed cFSs; levels of chromosome fragility were found to be correlated among these cFSs. Interestingly, most expressed cFSs were sites of LOH reported for thyroid tumors; moreover, cells with the highest fragility also had a reduced ability to undergo apoptosis. These findings reveal previously unknown genetic interactions affecting fragile loci, suggestive of a shared function inside mitotic cells. Attenuation of checkpoint control and apoptosis resistance seem to be the cell phenotypes associated with unusual chromosome fragility. We propose that breakage at specific cFS could derive from early epigenetic events at loci involved in radiation carcinogenesis. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. © 2006 Wiley-Liss, Inc. [source] Multiple forms of genetic instability within a 2-Mb chromosomal segment of 3q26.3,q27 are associated with development of esophageal adenocarcinomaGENES, CHROMOSOMES AND CANCER, Issue 4 2006Lin Lin Gene amplification is one of the mechanisms to activate oncogenes in many cancers, including esophageal adenocarcinoma (EA). In the present study, we used two-dimensional restriction landmark genome scanning to clone a NotI/DpnII fragment that showed increased genomic dosage in 1 of 44 EAs analyzed. This fragment maps to 3q26.3,q27, and subsequent experiments identified two intrachromosomal amplicons within a 10-Mb DNA segment in 7 of 75 (9%) EAs. The distal amplified-core region maps centromeric to the PIK3CA locus, and a microsatellite (D3S1754) within this region exhibited significant instability (MSI), in stark contrast to the genomewide microsatellite stability found in EA. D3S1754-MSI arises in premalignant Barrett's dysplastic cells and preceded amplification of the nascent MSI allele in the corresponding EA. Seven ESTs within the amplified-core were overexpressed in amplicon-containing EAs. One of these, EST AW513672, represents a chimeric transcript that initiated from an antisense promoter sequence in the 5,UTR of a full-length LINE-1 element (L1-5,ASP). Similar chimeric transcripts encoding portions of the MET oncogene and the BCAS3 gene also were overexpressed in EAs, suggesting that L1-5,ASP activation may occur at a broad level in primary EAs. Thus, the fine dissection of a 2-Mb amplified DNA segment in 3q26.3,q27 in EA revealed multiple genetic alterations that had occurred sequentially and/or concurrently during EA development. This article has supplementary material, available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. © 2005 Wiley-Liss, Inc. [source] Peripheral tolerance limits CNS accumulation of CD8 T cells specific for an antigen shared by tumor cells and normal astrocytesGLIA, Issue 15 2008Thomas Calzascia Abstract T cell mediated immunotherapies are proposed for many cancers including malignant astrocytoma. As such therapies become more potent, but not necessarily more tumor-specific, the risk of collateral autoimmune damage to normal tissue increases. Tumors of the brain present significant challenges in this respect, as autoimmune destruction of brain tissue could have severe consequences. To investigate local immune reactivity toward a tumor-associated antigen in the brain, transgenic mice were generated that express a defined antigen (CW3170,179) in astroglial cells. The resulting six transgenic mouse lines expressed the transgenic self-antigen in cells of the gastrointestinal tract and CNS compartments, or in the CNS alone. By challenging transgenic mice with tumor cells that express CW3, self/tumor-specific immune responses were visualized within a normal polyclonal T cell repertoire. A large expansion of the endogenous CW3170,179 -specific CD8 T cell population was observed in nontransgenic mice after both subcutaneous and intracerebral implantation of tumor cells. In contrast, CW3170,179 -specific immune responses were not observed in transgenic mice that exhibited extracerebral transgene expression. Importantly, in certain groups of mice in which transgene expression was restricted to the CNS, antigen-specific immune responses occurred when tumor was implanted subcutaneously, but not intracerebrally. This local immune tolerance in the brain was induced via peripheral (extrathymic) rather than central (thymic) tolerance mechanisms. Thus, this study highlights the role of regional immune regulation in the prevention of autoimmunity in the brain, and the potential impact of these mechanisms for brain tumor immunotherapy. © 2008 Wiley-Liss, Inc. [source] Protection against Fas-induced liver apoptosis in transgenic mice expressing cyclooxygenase 2 in hepatocytes,HEPATOLOGY, Issue 3 2007Marta Casado Cyclooxygenase-2 (COX-2) is upregulated in many cancers, and the prostanoids synthesized increase proliferation, improve angiogenesis, and inhibit apoptosis in several tissues. To explore the function of COX-2 in liver, transgenic (Tg) mice were generated containing a fusion gene (LIVhCOX-2) consisting of human COX-2 cDNA under the control of the human ApoE promoter. Six lines were developed; all of them expressed the LIVhCOX-2 transgene selectively in hepatocytes. The Tg mice exhibited a normal phenotype, and the increased levels of PGE2 found were due to the constitutively expressed COX-2. Histological analysis of different tissues and macroscopic examination of the liver showed no differences between wild-type (Wt) and Tg animals. However, Tg animals were resistant to Fas-mediated liver injury, as demonstrated by low levels of plasmatic aminotransferases, a lesser caspase-3 activation, and Bax levels and an increase in Bcl-2, Mcl-1, and xIAP proteins, when compared with the Wt animals. Moreover, the resistance to Fas-mediated apoptosis is suppressed in the presence of COX-2,selective inhibitors, which prevented prostaglandin accumulation in the liver of Tg mice. Conclusion: These results demonstrate that expression of COX-2,dependent prostaglandins exerted a protection against liver apoptosis. (HEPATOLOGY 2007;45:631,638.) [source] Hypoxia increases normal prostate epithelial cell resistance to receptor-mediated apoptosis via AKT activationINTERNATIONAL JOURNAL OF CANCER, Issue 8 2009Sinead Walsh Abstract The aging prostate is associated with changes in its vascular structure, which could lead to changes in oxygen levels. Hypoxia is an important environmental change that leads to the progression of many cancers mediated through a number of cellular changes, which included resistance to apoptosis. The role of hypoxia in initiating tumour development has not been previously investigated. We demonstrate that normal prostate epithelial cells develop a resistance to receptor-mediated apoptosis following 24 hr of 1% hypoxia. This effect is associated with the altered expression of a number of pro- and anti-apoptotic proteins, which leads to inhibition of Cytochrome c release and downstream caspase activation. This is mediated via decreased Bax translocation and upstream Caspase 8 activity. Despite increased expression of cIAP-2, small interfering RNA (siRNA) knockdown does not restore susceptibility to TRAIL-induced apoptosis. Gene expression analysis indicated potential changes in AKT activation, which was confirmed by increased phosphorylation of AKT. Inhibition of this phosphorylation reversed the resistance to TRAIL-induced apoptosis. AKT activation is emerging as a key survival signal in prostate cancer. This study demonstrates that short exposure to low oxygen can increase resistance to immune surveillance mechanisms and might confer a survival advantage onto normal prostate epithelial cells so that they can survive subsequent genomic instability and other carcinogenetic insults leading to the early development of prostate cancer. © 2008 Wiley-Liss, Inc. [source] Somatic mutations of adenomatous polyposis coli gene and nuclear b-catenin accumulation have prognostic significance in invasive urothelial carcinomas: Evidence for Wnt pathway implicationINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Efstathios Kastritis Abstract Wnt pathway signaling is crucial in many cancers and data indicate crosstalk with other key cancer pathways, however in urothelial carcinogenesis it has not been extensively studied. We searched for mutations in adenomatous polyposis coli (APC), a key regulator of the pathway, and studied b-catenin expression and interactions with the expression of other markers of apoptosis, angiogenesis, and proliferation in patients with invasive urothelial cancer. The mutation cluster region of APC was directly sequenced in 70 patients with muscle invasive disease who were treated with surgery and adjuvant chemotherapy. COX-2, p53, Ki67, and b-catenin were studied immunohistochemically and micro vessel density was quantified by CD105 expression. Single somatic amino-acid substitutions (missense) were found in 9 (13%) and frameshift deletions in 2 (3%) tumors, all located in regions adjacent to b-catenin binding sites. Patients having either APC missense mutations or b-catenin nuclear accumulation had less frequent COX-2 overexpression (24% vs. 76%, p = 0.043) and more frequent lymph node involvement (75% vs. 38%, p = 0.023). Patients with either APC mutations or b-catenin accumulation had shorter disease-free interval (13.4 vs. 28 months, p = 0.07), whereas in multivariate analysis they had shorter disease-specific survival (60.5 vs. 20.6 months, p = 0.048). Somatic APC missense mutations are not rare in advanced urothelial neoplasms. Either APC mutations and/or aberrant expression of b-catenin are associated with worse outcome. Further study of the role of the Wnt pathway, potential crosstalk with other pathways and potential candidate therapeutic targets in urothelial cancer is needed. © 2008 Wiley-Liss, Inc. [source] EGFR tyrosine kinase inhibition radiosensitizes and induces apoptosis in malignant glioma and childhood ependymoma xenograftsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2008Birgit Geoerger Abstract Malignant gliomas and childhood ependymomas have a high rate of treatment failure. Epidermal growth factor receptor (EGFR) activation has been implicated in the tumorigenesis and radioresistance of many cancers, including brain tumors. Therefore, combining EGFR targeting with irradiation is a potentially attractive therapeutic option. We evaluated the tyrosine kinase inhibitor gefitinib for its antitumor activity and potential to radio-sensitize in vivo in two xenograft models: an EGFR amplified glioma and an EGFR expressing ependymoma, both derived from primary tumors. When administered at 100 mg/kg for 5 consecutive days, gefitinib-induced partial tumor regression in all treated EGFR amplified IGRG88 glioma xenografts. The addition of 1 Gy of irradiation prior to gefitinib administration resulted in 5 complete and 4 partial regressions for the 9 treated tumors as well as a significant tumor growth delay of 33 days for the combined treatment compared to 19 days for each therapy alone, suggesting additive antitumor activity. Tumor regression was associated with inhibition of AKT and MAPK pathways by gefitinib. In contrast, the ependymoma IGREP83 was sensitive to irradiation, but remained resistant to gefitinib. Combined treatment was associated with inhibition of radiation-induced MAPK phosphorylation and significant induction of apoptotic cell death though radiation-induced AKT phosphorylation was maintained. Depending on the scheduling of both therapies, a trend towards superior antitumor activity was observed with combined treatment. Thus, EGFR targeting through tyrosine kinase inhibition appears to be a promising new approach in the treatment of EGFR-driven glioma, particularly in combination with radiation therapy. © 2008 Wiley-Liss, Inc. [source] The effect of nitric oxide on cyclooxygenase-2 (COX-2) overexpression in head and neck cancer cell linesINTERNATIONAL JOURNAL OF CANCER, Issue 5 2003Seok-Woo Park Abstract The overexpression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) has been previously reported in head and neck squamous cell carcinoma (HNSCC), as well as in many cancers. We hypothesized that endogenous nitric oxide (NO) might increase the expression of COX-2 in cancer cells. Therefore, we investigated the cross-talk between NO and the prostaglandin (PG) pathways in HNSCC cell lines. We found that COX-2 and iNOS expressions were elevated simultaneously. On adding the NO donor, SNAP, the PGE2 level was increased 2,20 times due to increased COX-2 expression. This increase of COX-2 expression by SNAP or PMA (potent inducer of both iNOS and COX-2) was blocked to various degrees by NO scavengers and NOS inhibitors (L-NAME and 1400W). Also, the expression of COX-2 in resting cells was inhibited by NOS inhibitors. Moreover, COX-2 expression, induced by SNAP, was inhibited by ODQ, a soluble guanylate cyclase (sGC) inhibitor. The effect of dibutyryl-cGMP on COX-2 expression was similar to that of SNAP. These results imply that endogenous or exogenous NO activates sGC and that the resulting increase of cGMP induces a signaling that upregulates the expression of COX-2 in HNSCC cell lines. We also observed that NO increased COX-2 expression in different cancer cell lines, including cervic and gastric cancer cell lines. These findings further support the notion that NO can be associated with carcinogenesis through the upregulation of COX-2, and that NOS inhibitor may be also useful for cancer prevention. © 2003 Wiley-Liss, Inc. [source] Role of the metastasis-promoting protein osteopontin in the tumour microenvironmentJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 8 2010Pieter H. Anborgh Abstract Osteopontin (OPN) is a secreted protein present in bodily fluids and tissues. It is subject to multiple post-translational modifications, including phosphorylation, glycosylation, proteolytic cleavage and crosslinking by transglutamination. Binding of OPN to integrin and CD44 receptors regulates signalling cascades that affect processes such as adhesion, migration, invasion, chemotaxis and cell survival. A variety of cells and tissues express OPN, including bone, vasculature, kidney, inflammatory cells and numerous secretory epithelia. Normal physiological roles include regulation of immune functions, vascular remodelling, wound repair and developmental processes. OPN also is expressed in many cancers, and elevated levels in patients' tumour tissue and blood are associated with poor prognosis. Tumour growth is regulated by interactions between tumour cells and their tissue microenvironment. Within a tumour mass, OPN can be expressed by both tumour cells and cellular components of the tumour microenvironment, and both tumour and normal cells may have receptors able to bind to OPN. OPN can also be found as a component of the extracellular matrix. The functional roles of OPN in a tumour are thus complex, with OPN secreted by both tumour cells and cells in the tumour microenvironment, both of which can in turn respond to OPN. Much remains to be learned about the cross-talk between normal and tumour cells within a tumour, and the role of multiple forms of OPN in these interactions. Understanding OPN-mediated interactions within a tumour will be important for the development of therapeutic strategies to target OPN. [source] Nuclear matrix proteins as biomarkers in prostate cancerJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2002Eddy S. Leman Abstract The nuclear matrix (NM) is the structural framework of the nucleus that consists of the peripheral lamins and pore complexes, an internal ribonucleic protein network, and residual nucleoli. The NM contains proteins that contribute to the preservation of nuclear shape and its organization. These protein components better known as the NM proteins have been demonstrated to be tissue specific, and are altered in many cancers, including prostate cancer. Alterations in nuclear morphology are hallmarks of cancer and are believed to be associated with changes in NM protein composition. Prostate cancer is the most frequently diagnosed cancer in American men and many investigators have identified unique NM proteins that appear to be specific for this disease. These NM protein changes are associated with the development of prostate cancer, as well as in some cases being indicative of cancer stage. Identification of these NM proteins specific for prostate cancer provides an insight to understanding the molecular changes associated with this disease. This article reviews the role of NM proteins as tumor biomarkers in prostate cancer and the potential application of these proteins as therapeutic targets in the treatment of this disease. J. Cell. Biochem. 86: 213,223, 2002. © 2002 Wiley-Liss, Inc. [source] Detection of carcinomas in an asymptomatic Chinese population: advantage of screening with multiple tumor markersJOURNAL OF CLINICAL LABORATORY ANALYSIS, Issue 2 2006Kuo-Chien Tsao Abstract A total of 73,443 asymptomatic individuals were screened on a voluntary basis for cancer at Chang Gung Memorial Hospital in Taiwan using a panel of tumor markers, including alpha fetoprotein (AFP), CA 125, CA 15-3, CA 19-9, carcinoembryonic antigen (CEA), prostate specific antigen (PSA), chromogranin A (CgA), and squamous cell specific antigen (SCC). The results are derived from data collected from January 1998 to October 2003. A total of 210 cancers (approximately 0.3%) were detected, including cancers of the liver, lung, colon, prostate, stomach, pancreas, breast, cervix, ovary, and bladder. Of the tumor markers monitored, elevated CA 19-9, CEA, and CA 125 were the most frequently detected in a variety of cancers. It was surprising to find that many cancers were not detected by their dominant markers but by the elevation of tumor markers not recommended for monitoring their tumor activity. Screening with multiple circulating tumor markers provides improved sensitivity for cancer detection in asymptomatic individuals before they reach the fatal advanced stage. Screening with multiple tumor markers also allows cancers to be detected in the absence of their dominant markers. If we had not measured the multiple tumor markers, these cancers would have gone undetected. J. Clin. Lab. Anal. 20:42,46, 2006. © 2006 Wiley-Liss, Inc. [source] Bmi-1 is critical for the proliferation and invasiveness of gastric carcinoma cellsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 3 2010Wei Li Abstract Background and Aim:, Bmi-1 is a transcriptional repressor belonging to the Polycomb group and is associated with the cell proliferation and carcinogenesis of a variety of human cancers. The level of Bmi-1 expression correlates with the aggressiveness of many cancers, and is considered an important marker for cancer diagnosis. However, its role in gastric carcinoma is unknown. Methods:, We used lentiviral mediated interfering short hairpin RNA to knockdown Bmi-1 expression in gastric carcinoma human gastric cancer cell line (AGS cells), then tested the cell proliferation by MTT assay, rate of colony formation by colony formation assay, cell cycle distribution by fluorescence-activated cell sorting and cell invasiveness by cell invasion assay. To analyze the expression and localization of Bmi-1 in gastric tumor tissues, we further performed the immunohistochemistry analysis on a gastric cancer tissue array. Results:, We found that knocking down Bmi-1 led to slower cell growth, lesser cell invasiveness, decelerated colony formation, and altered cell cycle progression. In addition, a positive relationship between nuclear expression of Bmi-1 and gastric cancer was observed, suggesting that nucleus localization of Bmi-1 in the cells may be a novel marker of gastric cancer. Conclusions:, Our study highlights critical roles for Bmi-1 in gastric cancer, and suggests that Bmi-1 nuclear localization could be an important marker for the diagnosis of gastric cancer. [source] Is lymph node count an ideal quality indicator for cancer care?JOURNAL OF SURGICAL ONCOLOGY, Issue 4 2009*Article first published online: 21 NOV 200, Nancy N. Baxter MD Abstract Although lymph node count has substantial appeal as a quality indicator because of the ease of measurement, the presence of variation in the population, the association with survival for many cancers, and the previous success of quality intervention programs, improvements in patient outcome by increasing lymph node counts have not yet been demonstrated. This article discusses potential pitfalls in the use of lymph node count as a quality indicator. J. Surg. Oncol. 2009;99:265,268. © 2008 Wiley-Liss, Inc. [source] A Bayesian hierarchical mixture model for platelet-derived growth factor receptor phosphorylation to improve estimation of progression-free survival in prostate cancerJOURNAL OF THE ROYAL STATISTICAL SOCIETY: SERIES C (APPLIED STATISTICS), Issue 1 2010Satoshi Morita Summary., Advances in understanding the biological underpinnings of many cancers have led increasingly to the use of molecularly targeted anticancer therapies. Because the platelet-derived growth factor receptor (PDGFR) has been implicated in the progression of prostate cancer bone metastases, it is of great interest to examine possible relationships between PDGFR inhibition and therapeutic outcomes. We analyse the association between change in activated PDGFR (phosphorylated PDGFR) and progression-free survival time based on large within-patient samples of cell-specific phosphorylated PDGFR values taken before and after treatment from each of 88 prostate cancer patients. To utilize these paired samples as covariate data in a regression model for progression-free survival time, and be cause the phosphorylated PDGFR distributions are bimodal, we first employ a Bayesian hierarchical mixture model to obtain a deconvolution of the pretreatment and post-treatment within-patient phosphorylated PDGFR distributions. We evaluate fits of the mixture model and a non-mixture model that ignores the bimodality by using a supnorm metric to compare the empirical distribution of each phosphorylated PDGFR data set with the corresponding fitted distribution under each model. Our results show that first using the mixture model to account for the bimodality of the within-patient phosphorylated PDGFR distributions, and then using the posterior within-patient component mean changes in phosphorylated PDGFR so obtained as covariates in the regression model for progression-free survival time, provides an improved estimation. [source] Liver tumors: Pediatric population,LIVER TRANSPLANTATION, Issue 11 2008Milton J. Finegold Liver tumors in childhood are rare and are typically not detected clinically until they reach a large size and often spread within the organ or metastasize. This can make surgical resection problematic, and almost all of them require extirpation for cure. With very effective chemotherapy for hepatoblastoma and to some extent for sarcomas, many cancers can be shrunk to permit partial hepatectomy, but for most hepatocarcinomas, some of the other malignancies, and even some benign proliferations, their location at the hilum and multiplicity of masses in multiple lobes make transplantation the treatment of choice. Major advances in diagnostic imaging, especially enhanced computed tomography and magnetic resonance imaging, permit a preoperative choice of resection versus transplantation to be achieved in almost all instances, and for the remainder, intraoperative ultrasonography can further help to determine the most desirable approach. The outcome is very much better in the case of hepatoblastoma when transplantation is a primary modality rather than following unsuccessful attempts at resection. In this review, transplantation for liver tumors in children is considered from all aspects, including the importance of screening for tumors whenever possible to avoid the need for transplantation. Liver Transpl 14:1545,1556, 2008. © 2008 AASLD. [source] The PTEN gene in locally progressive prostate cancer is preferentially inactivated by bi-allelic gene deletionTHE JOURNAL OF PATHOLOGY, Issue 5 2006PCMS Verhagen Abstract PTEN is frequently inactivated during the development of many cancers, including prostate cancer, and both bi-allelic and mono-allelic PTEN inactivation may contribute to tumorigenesis. PTEN mutations in clinical cancer specimens can easily be recorded but mono- or bi-allelic gene deletions are often difficult to assess. We performed a comprehensive study to detect PTEN inactivation in 40 locally progressive clinical prostate cancer specimens obtained by transurethral resection of the prostate, utilizing a variety of complementary technical approaches. The methods to detect PTEN deletion included allelotype analysis, dual-colour FISH and array-based CGH. We also applied a novel semi-quantitative approach, assessing the PTEN-WT (wild-type): PTEN- , (pseudogene) ratio (WPR). Structural analysis of PTEN was performed by single-strand conformational polymorphism (PCR-SSCP) and sequencing. PTEN protein expression was assessed by immunohistochemistry. Our data predict complete PTEN inactivation in 12 samples (30%), nine of these by bi-allelic deletion. Loss of one PTEN copy was also detected by several methodologies but the number could not be accurately assessed. Immunohistochemistry indicated the absence of PTEN protein in 15 samples, and heterogeneous expression of the protein in eight tumours. Taken together, these data show that bi-allelic deletion is a major mechanism of PTEN inactivation in locally progressive prostate cancer. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Overexpression of hepatocyte nuclear factor-3, induces apoptosis through the upregulation and accumulation of cytoplasmic p53 in prostate cancer cells,THE PROSTATE, Issue 4 2010Hyun Joo Lee Abstract BACKGROUND Hepatocyte nuclear factor-3, (HNF-3,) has been known to act as a repressor in the pathogenesis of many cancers. Herein, we investigated the effect of HNF-3, overexpression in prostate cancer cells. METHODS HNF-3, was overexpressed in prostate cancer cells using an adenovirus recombinant expressing wild-type HNF-3,. The apoptosis of prostate cancer cells was determined by TUNEL, FACS, and caspase activity analyses. RESULTS Adenovirus-mediated overexpression of HNF-3, caused cell death in prostate cancer cells as assessed by changes in cellular and nuclear morphology, TUNEL analysis, and caspase activations. Furthermore, FACS analysis showed an increased sub-G1 phase of cell cycle as well as the G2/M phase with a corresponding decrease in S phases. HNF-3, overexpression caused the upregulation of p53 protein and its accumulation, together with HNF-3,, in the cytoplasm. It also causes Bax protein to localize to the mitochondria-enriched fraction. These findings suggest that multiple apoptotic pathways seem to be involved in the HNF-3,-induced cell death: pathways involving the accumulation of p53 protein in the cytoplasm and subsequent cytochrome c release, and other pathways involving death receptor signaling and caspase-8 activation. CONCLUSIONS The results of the current study suggest a novel function of HNF-3, as a killer of malignant prostate cancer cells, which reveals HNF-3, as a promising therapeutic molecule for prostate cancers. Prostate 70: 353,361, 2010. © 2009 Wiley-Liss, Inc. [source] Expression of human telomerase reverse transcriptase and cyclin-D1 in olfactory neuroblastoma,APMIS, Issue 1 2007SHENG-LAN WANG Olfactory neuroblastoma is an uncommon neoplasm. Typically, these tumors are indolent with long-standing symptomatology, but the fact that the lesions are indeed malignant has been proven by the repeated demonstration that they can metastasize to distant organs. Suitable prognostic factors are lacking and therapeutic strategy still remains controversial. Expression of human telomerase reverse transcriptase (hTERT) is associated with most human malignancies and high levels have been correlated with poor prognosis in many cancers. In comparison, overexpression of cyclin-D1 occurs in several malignancies and has been associated with aggressive tumor behavior and poorer prognosis. In this study, we collected 16 olfactory neuroblastomas from the Kaohsiung Medical University Hospital. The aim was to investigate the value of immunoexpression of hTERT and cyclin-D1 in correlation with clinicopathologic features of olfactory neuroblastoma. Low and high cyclin-D1 expression was found in 6 and 10 cases, respectively. For hTERT, low and high protein expression was detected in 5 and 11 tumors, respectively. Cyclin-D1 expression was not correlated with selected parameters. However, high hTERT expression was significantly correlated with high Kadish stage. In conclusion, high hTERT expression can be considered a potential indicator of aggressive olfactory neuroblastoma. [source] Crystallization of the receptor-binding domain of parathyroid hormone-related protein in complex with a neutralizing monoclonal antibody Fab fragmentACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 4 2009William J. McKinstry Parathyroid hormone-related protein (PTHrP) plays an important role in regulating embryonic skeletal development and is abnormally regulated in the pathogenesis of skeletal complications observed with many cancers and osteoporosis. It exerts its action through binding to a G-protein-coupled seven-transmembrane cell-surface receptor (GPCR). Structurally, GPCRs are very difficult to study by X-ray crystallography. In this study, a monoclonal antibody Fab fragment which recognizes the same region of PTHrP as its receptor, PTH1R, was used to aid in the crystallization of PTHrP. The resultant protein complex was crystallized using the hanging-drop vapour-diffusion method with polyethylene glycol as a precipitant. The crystals belonged to the orthorhombic space group P21212, with unit-cell parameters a = 72.6, b = 96.3, c = 88.5,Å, and diffracted to 2.0,Å resolution using synchrotron radiation. The crystal structure will shed light on the nature of the key residues of PTHrP that interact with the antibody and will provide insights into how the antibody is able to discriminate between PTHrP and the related molecule parathyroid homone. [source] SERPINE1 intron polymorphisms affecting gene expression are associated with diffuse-type gastric cancer susceptibilityCANCER, Issue 18 2010Hyoungseok Ju PhD Abstract BACKGROUND: A primary inhibitor of plasminogen activators, SERPINE1 (serpin peptidase inhibitor 1, clade E, member 1, also known as plasminogen activator inhibitor type 1), is an important regulator in tumorigenesis and is highly expressed in many cancers. METHODS: Five tag single nucleotide polymorphisms (SNPs) and 1 insertion polymorphism within SERPINE1 were genotyped in 1101 unrelated Korean individuals (a case group of 612 patients with gastric cancer and a control group of 489 healthy individuals). Associations with susceptibility to diffuse-type gastric cancer (DGC) and intestinal-type gastric cancer were assessed using multivariate logistic regression analyses adjusted for age and sex. Allelic differences in the contribution to gene expression were measured using luciferase assays. RESULTS: SNP c.1162+162C>T (rs2227692) in intron 7 was associated with susceptibility to DGC but not with susceptibility to intestinal-type gastric cancer. The minor allele-carrying genotypes C/T and T/T had 1.6-fold greater odds of DGC than the C/C genotype (P = .00084). This SNP was linked to a repeat-number variation c.1162+604AAAG(11_17), a deletion (del) variation c.1162+664_1162+673del, and another SNP c.1162+859T>A (rs2070683) in intron 7 based on the sequencing of 5 patients and 5 controls. The risk haplotype of the 4 variations exhibited a 30% greater gene expression level than the nonrisk haplotype in luciferase reporter assays (P = .025). In contrast, DGC susceptibility was not associated with the c.,1969_,1968insG polymorphism (rs1799768) in the promoter, commonly known as 4G/5G, in which the minor 5G allele is less active in transcription than the major 4G allele. CONCLUSIONS: An association between SERPINE1 and DGC susceptibility was observed with 4 correlated polymorphisms in intron 7 rather than the 4G/5G polymorphism in the promoter, although all polymorphisms affected gene expression. Cancer 2010. © 2010 American Cancer Society. [source] Cancer epigenomics: Implications of DNA methylation in personalized cancer therapyCANCER SCIENCE, Issue 5 2009Minoru Toyota Genetic alterations in cancer can provide information for predicting a tumor's sensitivity to chemotherapeutic drugs. But although such information is certainly useful, the relatively low frequency of mutations seen in many cancers limits the utility of pharmacogenomics in large numbers of cancer patients, necessitating consideration of other approaches. Epigenetic changes such as DNA methylation are a hallmark of human cancers. Methylation of genes involved in DNA repair and maintaining genome integrity (e.g. MGMT, hMLH1, WRN, and FANCF), and cell-cycle checkpoint genes (e.g. CHFR and 14-3-3 ,, CDK10, and p73), all reportedly influence the sensitivity to chemotherapeutic drugs, suggesting that DNA methylation could serve as a molecular marker for predicting the responsiveness of tumors to chemotherapy. However, the comprehensive study of pharmacoepigenomics awaits the advent of genome-wide analysis of DNA methylation using microarrays and next-generation sequencers. (Cancer Sci 2009; 100: 787,791) [source] Organometallic Ruthenium Inhibitors of Glutathione- S -Transferase P1-1 as Anticancer DrugsCHEMMEDCHEM, Issue 12 2007Han Ang Dr. Abstract Ruthenium,arene complexes conjugated to ethacrynic acid were prepared as part of a strategy to develop novel glutathione- S -transferase (GST) inhibitors with alternate modes of activity through the organometallic fragment, ultimately to provide targeted ruthenium-based anticancer drugs. Enzyme kinetics and electrospray mass spectrometry experiments using GST P1-1 and its cysteine-modified mutant forms revealed that the complexes are effective enzyme inhibitors, but they also rapidly inactivate the enzyme by covalent binding at Cys,47 and, to a lesser extent, Cys,101. They are highly effective against the GST Pi-positive A2780 and A2780cisR ovarian carcinoma cell lines, are among the most effective ruthenium complexes reported so far, and target ubiquitous GST Pi overexpressed in many cancers. [source] Detection of Overexpressed COX-2 in Precancerous Lesions of Hamster Pancreas and Lungs by Molecular Imaging: Implications for Early Diagnosis and PreventionCHEMMEDCHEM, Issue 6 2006Hildegard Abstract The enzyme cyclooxygenase-2 (COX-2) is overexpressed in many cancers, cardiovascular disease, neurodegenerative disorders, and arthritis. Selective inhibitors of COX-2 have been developed as therapeutics or preventive agents for these diseases. However, recent reports have revealed a significant increase in cardiovascular mortality in long-term users of the COX-2 inhibitors Vioxx and Celebrex, emphasizing the need for noninvasive tests that allow the identification of individuals whose COX-2 levels are overexpressed prior to assignment to treatment with these drugs. In this study, we have prepared a radioiodinated analogue of the selective COX-2 inhibitor celecoxib, and verified its binding to the COX-2 enzyme in,vitro. Biodistribution studies in hamsters demonstrated significantly higher levels of radiotracer in animals treated with the tobacco carcinogen NNK in lung, pancreas, and liver. Assessment of COX-2 levels by whole-body planar nuclear imaging two hours after injection of the radiotracer was suggestive of a distinct increase in COX-2 in the pancreas and liver of a hamster treated for 10 weeks with NNK, in the lungs and liver of a second animal, and in the liver only, in two additional animals from the same treatment group. Immunostains showed selective overexpression of COX-2 in pre-neoplastic lesions of the pancreas and lungs in only those animals that showed tracer accumulation in these organs and in the livers of all NNK-treated hamsters. Immunostains for COX-1 yielded detectable reactions in the intestinal epithelium but not in pancreas, lungs, or liver, supporting the specificity of the tracer for COX-2. Our data provide proof of principle for the hypothesis that molecular imaging with radiolabeled COX-2 inhibitors can be used for the noninvasive monitoring of overexpressed COX-2 levels. [source] | |||||||||||||||||||||||||||||||