bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple Familial Trichoepithelioma Caused by Mutations in the Cylindromatosis Tumor Suppressor Gene
Authors: Salhi Aicha , Bornholdt Dorothea , Oeffner Frank , Malik Sajid , Heid Ernest , Happle Rudolf , Grzeschik Karl-Heinz 
Published: September 2005

Abstract
The recessive oncogene cylindromatosis (CYLD) mapping on 16q12-q13 is generally implicated in familial cylindromatosis, whereas a gene region for multiple familial trichoepithelioma has been assigned to 9p21. Markers from both chromosome intervals were subjected to linkage analysis in a large family with multiple hereditary trichoepithelioma (TE) from Algeria. Linkage to 9p21 was excluded, whereas CYLD remained as a candidate. Mutation analysis identified a single bp germ-line deletion expected to result in truncation or absence of the encoded protein, which segregated with the multiple TE phenotype. In individual tumors, loss of heterozygosity at 16q or a somatic point mutation in the CYLD gene was detected. Hence, mutations of the tumor suppressor gene CYLD at 16q12-q13 may give rise to familial TE indistinguishable from the phenotype assigned to 9p21.
Adhesion of Gastric Carcinoma Cells to Peritoneum Mediated by α3β1 Integrin (VLA-3)
Authors: Takatsuki Hironori , Komatsu Shinya , Sano Rikio , Takada Yoshikazu , Tsuji Tsutomu 
Published: September 2005

Abstract
The interaction between gastric carcinoma cells and the peritoneal lining is a key step in peritoneal dissemination. In this study, we examined the roles of the β1 family of integrin receptors in the adhesion of such cells to the peritoneum. The adhesion of several gastric carcinoma cell lines to peritonea excised from mice was inhibited most by an anti-α3 integrin antibody and to a lesser extent by an anti-α2 integrin antibody. In the peritoneal implantation of NUGC-4 human gastric carcinoma cells in athymic mice, treatment of the cells with anti-α2 or anti-α3 integrin antibody reduced the number of disseminated nodules; suppression by the anti-α3 integrin antibody was stronger than that by the anti-α2 integrin antibody. The cDNAs to human α2 and α3 integrins were introduced into K562 leukemic cells, which were positive for the integrin β1 subunit but negative for the α2 or α3 subunit. The α3 integrin-transfected cells adhered to excised peritoneum and to a monolayer of peritoneal mesothelial cells more firmly than did the α2 integrin-transfected cells or the mock transfectant. Reverse transcription-PCR was used to analyze the expression of laminin-5 and laminin-10/11, which have been reported to serve as high-affinity ligands for α3β1 integrin. mRNA for these laminin isoforms was found in mesothelial cells from the diaphragm and parietal peritoneum. These results strongly suggest that α3β1 integrin plays an essential role in mediating the initial attachment of cancer cells to the peritoneum, leading to the formation of peritoneal metastasis.
IRSp53/Eps8 Complex Is Important for Positive Regulation of Rac and Cancer Cell Motility/Invasiveness
Authors: Funato Yosuke , Terabayashi Takeshi , Suenaga Naoko , Seiki Motoharu , Takenawa Tadaomi , Miki Hiroaki 
Published: September 2005

Abstract
IRSp53 has been characterized as an adaptor protein that links Rho-family small GTPases, such as Rac, to reorganization of the actin cytoskeleton. Here, we search for other binding partners for the IRSp53 SH3 domain and identify Eps8 as the major binding protein in fibroblasts and various cancer cell lines. Eps8 has been shown to form a Rac-specific guanine nucleotide exchange factor complex with Abi-1 and Sos-1, which seems essential for ruffling formation induced by oncogenic Ras. We confirm the IRSp53/Eps8 complex formation in vivo and the direct association between Eps8 NH2-terminal proline-rich sequence and IRSp53 SH3 domain. This complex synergistically activates Rac by reinforcing the formation of the Eps8/Abi-1/Sos-1 Rac-guanine nucleotide exchange factor complex, which mediates positive regulation of Rac activity. In addition, IRSp53/Eps8 complex formation as determined by fluorescent resonance energy transfer analysis, occurs at the leading edge of motile cells, and the motility and invasiveness of HT1080 fibrosarcoma cells are suppressed by inhibiting complex formation. These findings implicate the importance of the IRSp53/Eps8 complex in Rac activation and metastatic behavior of the malignant tumor cells.
Array Comparative Genomic Hybridization Analysis of Colorectal Cancer Cell Lines and Primary Carcinomas
Authors: Douglas Eleanor J. , Fiegler Heike , Rowan Andrew , Halford Sarah , Bicknell David C. , Bodmer Walter , Tomlinson Ian P. M. , Carter Nigel P. 
Published: September 2005

Abstract
Array comparative genomic hybridization, with a genome-wide resolution of ∼1 Mb, has been used to investigate copy number changes in 48 colorectal cancer (CRC) cell lines and 37 primary CRCs. The samples were divided for analysis according to the type of genomic instability that they exhibit, microsatellite instability (MSI) or chromosomal instability (CIN). Consistent copy number changes were identified, including gain of chromosomes 20, 13, and 8q and smaller regions of amplification such as chromosome 17q11.2-q12. Loss of chromosome 18q was a recurrent finding along with deletion of discrete regions such as chromosome 4q34-q35. The overall pattern of copy number change was strikingly similar between cell lines and primary cancers with a few obvious exceptions such as loss of chromosome 6 and gain of chromosomes 15 and 12p in the former. A greater number of aberrations were detected in CIN+ than MSI+ samples as well as differences in the type and extent of change reported. For example, loss of chromosome 8p was a common event in CIN+ cell lines and cancers but was often found to be gained in MSI+ cancers. In addition, the target of amplification on chromosome 8q appeared to differ, with 8q24.21 amplified frequently in CIN+ samples but 8q24.3 amplification a common finding in MSI+ samples. A number of genes of interest are located within the frequently aberrated regions, which are likely to be of importance in the development and progression of CRC.
A Role for the RASSF1A Tumor Suppressor in the Regulation of Tubulin Polymerization and Genomic Stability
Authors: Vos Michele D , Martinez Alfredo , Elam Candice , Dallol Ashraf , Taylor Barbara J , Latif Farida , Clark Geoffrey J 
Published: September 2005

Abstract
The high frequency with which the novel tumor suppressor RASSF1A is inactivated by promoter methylation suggests that it plays a key role in the development of many primary human tumors. Yet the mechanism of RASSF1A action remains unknown. We now show that RASSF1A associates with microtubules and that this association is essential for RASSF1A to mediate its growth inhibitory effects. Overexpression of RASSF1A promotes the formation of stable microtubules, whereas a dominant-negative fragment of RASSF1A destabilizes microtubule networks. The RASSF1 protein is expressed as two main isoforms, 1A and 1C. The smaller 1C isoform also associates with microtubules but is less effective at stabilizing them. Because RASSF1A and RASSF1C localize to the mitotic spindle, we examined their effects upon genomic instability. RASSF1A and RASSF1C block activated Ras-induced genomic instability. However, a point mutant of RASSF1C, identified in human tumors, was severely defective for stabilizing tubulin and was unable to block the genomic destabilizing effects of Ras. Thus, we identify a role for RASSF1A/C in the control of microtubule polymerization and potentially in the maintenance of genomic stability.
Heritability and Linkage Analysis of Sensitivity to Cisplatin-Induced Cytotoxicity
Authors: Dolan M. Eileen , Newbold Karla G. , Nagasubramanian Ramamoorthy , Wu Xiaolin , Ratain Mark J. , Cook Edwin H. , Badner Judith A. 
Published: September 2005

Abstract
Little is known about the genetic determinants explaining variation in sensitivity to chemotherapeutic cytotoxicity. We characterized the degree of cisplatin sensitivity, using lymphoblastoid cell lines derived from 10 Centre d’Etude du Polymorphisme Humain pedigrees. We estimated the heritability for susceptibility to cisplatin-induced cytotoxicity to be ∼0.47; therefore, sensitivity to the cytotoxic effects of cisplatin is under appreciable genetic influence. Linkage analysis was performed, and the strongest signal (lod score, 2.16; empirical P = 0.0005) was found on chromosome 1 at 44 cM. Susceptibility to cisplatin-induced cytotoxicity is likely due to multiple loci, with low locus-specific heritability contributing to the trait. These data show the power of using large pedigrees that have been extensively genotyped for evaluating the genetic contribution to sensitivity to cell growth inhibition by anticancer agents.
A Novel Founder CHEK2 Mutation is Associated with Increased Prostate Cancer Risk
Authors: Cybulski Cezary , Huzarski Tomasz , Górski Bohdan , Masojć Bartłomiej , Mierzejewski Marek , Dębniak Tadeusz , Gliniewicz Bartłomiej , Matyjasik Joanna , Złowocka Elżbieta , Kurzawski Grzegorz , Sikorski Andrzej , Posmyk Michał , Szwiec Marek , Czajka Ryszard , Narod Steven A. , Lubiński Jan 
Published: September 2005

Abstract
Variants in the CHEK2 have been found to be associated with prostate cancer risk in the United States and Finland. We sequenced CHEK2 gene in 140 Polish patients with prostate cancer and then genotyped the three detected variants in a larger series of prostate cancer cases and controls. CHEK2 truncating mutations (IVS2 + 1G&gt;A or 1100delC) were identified in 9 of 1921 controls (0.5%) and in 11 of 690 (1.6%) unselected patients with prostate cancer [odds ratio (OR) = 3.4; P = 0.004]. These mutations were found in 4 of 98 familial prostate cases (OR = 9.0; P = 0.0002). The missense variant I157T was also more frequent in men with prostate cancer (7.8%) than in controls (4.8%), but the relative risk was more modest (OR = 1.7; P = 0.03). I157T was identified in 16% of men with familial prostate cancer (OR = 3.8; P = 0.00002). Loss of the wild-type CHEK2 allele was not observed in any of prostate cancers from five men who carried CHEK2-truncating mutations. Our results provide evidence that the two truncating mutations of CHEK2 confer a moderate risk of prostate cancer in Polish men and that the missense change appears to confer a modest risk.
Oncogenic H-Ras Up-Regulates Expression of ERCC1 to Protect Cells from Platinum-Based Anticancer Agents
Authors: Youn Cha-Kyung , Kim Mi-Hwa , Cho Hyun-Ju , Kim Hong-Beum , Chang In-Youb , Chung Myung-Hee , You Ho Jin 
Published: September 2005

Abstract
Tumors frequently contain mutations in the ras genes, resulting in the constitutive activation of the Ras-activated signaling pathway. The activation of Ras is involved not only in tumor progression but also in the development of resistance of the tumor cells to platinum-based chemotherapeutic agents. To investigate the potential mechanisms underlying this resistance, we analyzed the effect of activated H-Ras on the expression of the nucleotide excision repair genes. Here we identified ERCC1, which is one of the key enzymes involved in nucleotide excision repair, as being markedly up-regulated by the activated H-Ras. From promoter analysis of ERCC1, an increase in the Ap1 transcriptional activity as a result of the expression of the oncogenic H-Ras was found to be crucial for this induction. In addition, ERCC1 small interfering RNA expression was shown to reduce the oncogenic H-Ras-mediated increase in the DNA repair activity as well as to suppress the oncogenic H-Ras-mediated resistance of the cells to platinum-containing chemotherapeutic agents. These results suggest that the oncogenic H-Ras-induced ERCC1, which activates the DNA repair capacity, may be involved in the protection of the cells against platinum-based anticancer agents.
p53 Heterozygosity Results in an Increased 2-Acetylaminofluorene-Induced Urinary Bladder but not Liver Tumor Response in DNA Repair-Deficient
Xpa
Mice
Authors: Hoogervorst Esther M. , van Oostrom Conny Th. M. , Beems Rudolf B. , van Benthem Jan , Gielis Siska , Vermeulen Jolanda P. , Wester Piet W. , Vos Joseph G. , de Vries Annemieke , van Steeg Harry 
Published: September 2005

Abstract
Both nucleotide excision repair (NER) and the p53 tumor suppressor protein play crucial roles in the prevention of cells becoming cancerous. This is clearly demonstrated by the fact that NER-deficient xeroderma pigmentosum patients and Li-Fraumeni patients who carry a germ-line p53 mutation are highly tumor prone. The NER-deficient Xpa and the p53+/− mouse models clearly mimic their human counterparts, because they are both tumor prone as well. The aim of the study presented here was to analyze the relative contribution of these two pathways in tumor suppression and to analyze a possible link between NER and p53 activation in vivo. For this, we exposed Xpa, p53+/−, and Xpa/p53+/− mice to 2-acetylaminofluorene (2-AAF). We show that 2-AAF-induced urinary bladder tumor suppression is dependent on p53 status, because p53+/− mice were highly tumor prone. Xpa/p53+/− mice were even more tumor prone, whereas no increased tumor response was found in Xpa mice. Short-term assays revealed a decreased apoptotic response in Xpa/p53+/− mice, pointing in vivo toward a link between NER and p53-mediated apoptosis. In contrast, liver tumor response was primarily dependent on appropriate DNA repair, because Xpa-deficient mice were liver tumor prone. p53 heterozygosity had no influence on liver tumor incidences, in line with the results obtained from the short-term 2-AAF studies revealing no altered cellular response in p53+/− or Xpa/p53+/− mice. Interestingly, however, mice completely deficient in both NER and p53 (Xpa/p53−/− mice) showed a dramatic increase of hepatocellular proliferation accompanied by lacZ reporter gene mutations.
Accumulation of the Oxidative Base Lesion 8-Hydroxyguanine in DNA of Tumor-Prone Mice Defective in Both the
Myh
and
Ogg1
DNA Glycosylases
Authors: Russo Maria Teresa , De Luca Gabriele , Degan Paolo , Parlanti Eleonora , Dogliotti Eugenia , Barnes Deborah E. , Lindahl Tomas , Yang Hanjing , Miller Jeffrey H. , Bignami Margherita 
Published: September 2005

Abstract
The OGG1 and MYH DNA glycosylases prevent the accumulation of DNA 8-hydroxyguanine. In Myh−/− mice, there was no time-dependent accumulation of DNA 8-hydroxyguanine in brain, small intestine, lung, spleen, or kidney. Liver was an exception to this general pattern. Inactivation of both MYH and OGG1 caused an age-associated accumulation of DNA 8-hydroxyguanine in lung and small intestine. The effects of abrogated OGG1 and MYH on hepatic DNA 8-hydroxyguanine levels were additive. Because there is an increased incidence of lung and small intestine cancer in Myh−/−/Ogg1−/− mice, these findings support a causal role for unrepaired oxidized DNA bases in cancer development.
Suppression of Colorectal Cancer Liver Metastasis and Extension of Survival by Expression of Apolipoprotein(a) Kringles
Authors: Yu Hyun-Kyung , Kim Jang-Seong , Lee Ho-Jeong , Ahn Jin-Hyung , Lee Suk-Keun , Hong Soon-Won , Yoon Yeup 
Published: September 2005

Abstract
The formation of hepatic metastases in colorectal cancer is the main cause of patient death. Current therapies directed at hepatic metastasis of colorectal cancer have had minimal impact on outcome. Therefore, alternative treatment strategies for liver metastasis require development. The present study was performed to evaluate the application of cDNA of LK68 encoding apolipoprotein(a) kringles IV-9, IV-10, and V as possible candidates for gene therapy treatment of this life-threatening disease. The murine colorectal cancer cell line CT26 was transduced ex vivo with LK68 cDNA via retroviral gene transfer, and an experimental model of hepatic metastasis was established by injecting LK68-expressing and control cells into the spleens of BALB/c mice. Expression of LK68 did not affect the growth characteristics and viability of transduced CT26 cells in vitro. LK68 produced from CT26 cells substantially inhibited the migration of endothelial cells in vitro. In vivo, substantial suppression of liver metastasis and prolonged survival were observed in mice bearing LK68-expressing CT26 cells, compared with controls. LK68-expressing liver metastases were restricted to smaller sizes and displayed decreased microvessel density and increased tumor cell apoptosis. Our data collectively indicate that LK68 suppresses angiogenesis-dependent progression of prevascular micrometastases to macroscopic tumors and their growth, which are clinically accessible and biologically relevant therapeutic targets. We propose that antiangiogenic gene therapy with LK68 is a promising strategy for the treatment of colorectal cancer liver metastasis.
A Novel Role for Carcinoembryonic Antigen-Related Cell Adhesion Molecule 6 as a Determinant of Gemcitabine Chemoresistance in Pancreatic Adenocarcinoma Cells
Authors: Duxbury Mark S. , Ito Hiromichi , Benoit Eric , Waseem Talat , Ashley Stanley W. , Whang Edward E. 
Published: September 2005

AbstractMost patients with pancreatic adenocarcinoma present with surgically incurable disease. Gemcitabine, the principal agent used to treat such patients, has little impact on outcome. Overexpression of carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 6, a feature of this malignancy, is associated with resistance to anoikis and increased metastasis. The purpose of this study was to determine the role of CEACAM6 in cellular chemoresistance to gemcitabine. CEACAM6 was stably overexpressed in Capan2 cells, which inherently express very low levels of the protein. Suppression of CEACAM6 expression was achieved in BxPC3 cells, which inherently overexpress CEACAM6, by stable transfection of a CEACAM6 small interfering RNA-generating vector. The effects of modulating CEACAM6 expression on gemcitabine-induced cytotoxicity were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cytotoxicity assay, flow cytometric apoptosis quantification, caspase profiling, and Western analysis of cytoplasmic cytochrome c release. The roles of Akt and c-Src kinases as downstream targets of CEACAM6 signaling were examined. Stable overexpression of CEACAM6 in Capan2 increased gemcitabine chemoresistance, whereas CEACAM6 gene silencing in BxPC3 markedly increased the sensitivity of these cells to gemcitabine. Differential expression of CEACAM6 modulates Akt activity in a c-Src-dependent manner, and CEACAM6 overexpression appears to protect cells from cytochrome c-induced caspase 3 activation and apoptosis.
Noninvasive Imaging of the Transcriptional Activities of Human Telomerase Promoter Fragments in Mice
Authors: Groot-Wassink Thomas , Aboagye Eric O. , Wang Yaohe , Lemoine Nicholas R. , Keith W. Nicol , Vassaux Georges 
Published: September 2005

Abstract
We have assessed the feasibility of positron emission tomography (PET) and ex vivo γ-counting to measure the pattern of expression of telomerase promoter fragments in vivo. Promoter fragments from either the RNA [human telomerase RNA (hTR)] or the catalytic components [human telomerase reverse transcriptase (hTERT)] of the telomerase genes were used to drive the expression of the sodium iodide symporter PET reporter gene in recombinant adenoviruses. Both promoter fragments provided cancer-selective expression that could be visualized and quantitated by PET. The transcriptional activity of the hTR promoter was found to be consistently stronger than that of the hTERT promoter. Both promoters appear therefore to be good candidates for safe use in gene therapy, and PET imaging can be used to assess the selectivity of promoters in vivo. Given that this methodology is directly scalable to humans, imaging gene expression using the sodium iodide symporter PET reporter gene could be applied to measure telomerase promoter activity in humans.
Pathophysiological Effects of Vascular Endothelial Growth Factor Receptor-2-Blocking Antibody plus Fractionated Radiotherapy on Murine Mammary Tumors
Authors: Fenton Bruce M. , Paoni Scott F. , Ding Ivan 
Published: September 2005

Abstract
Although clinical trials of antiangiogenic strategies have been disappointing when administered as single agents, such approaches can play an important role in cancer treatment when combined with conventional therapies. Previous studies have shown that DC101, an antiangiogenic monoclonal antibody against vascular endothelial growth factor receptor-2, can produce significant growth inhibition in spontaneous and transplanted tumors but can also induce substantial hypoxia. Because DC101 appears to potentiate radiotherapy in some tumors, the present studies were undertaken to characterize pathophysiological changes following combined therapy and to determine whether radioresponse is enhanced despite the induction of hypoxia. MCa-4 and MCa-35 mammary carcinomas were treated with: (a) DC101; (b) 5 × 6 Gy radiation fractions; or (c) the combination. Image analysis of frozen tumor sections was used to quantitate: (a) hypoxia; (b) spacing of total and perfused blood vessels; and (c) endothelial and tumor cell apoptosis. For MCa-4, combination treatment schedules produced significant and prolonged delays in tumor growth, whereas single-modality treatments had minor effects. For MCa-35, radiation or the combination led to equivalent growth inhibition. In all tumors, hypoxia increased markedly after either radiation or DC101 alone. Although combination therapy produced no immediate pathophysiological changes, hypoxia ultimately increased after cessation of therapy. Preferential increases in endothelial apoptosis following combination treatment suggest that in addition to blocking tumor angiogenesis, DC101 enhances radiotherapy by specifically sensitizing endothelial cells, leading to degeneration of newly formed blood vessels.
Peptides Derived from the Histidine-Proline Domain of the Histidine-Proline-Rich Glycoprotein Bind to Tropomyosin and Have Antiangiogenic and Antitumor Activities
Authors: Doñate Fernando , Juarez Jose C. , Guan Xiaojun , Shipulina Natalya V. , Plunkett Marian L. , Tel-Tsur Ziva , Shaw David E. , Morgan William T. , Mazar Andrew P. 
Published: September 2005

Abstract
The antiangiogenic activity of the multidomain plasma protein histidine-proline-rich glycoprotein (HPRG) is localized to its histidine-proline–rich (H/P) domain and has recently been shown to be mediated, at least partially, through binding to cell-surface tropomyosin in fibroblast growth factor-2-activated endothelial cells (X. Guan et al., Thromb Haemost, in press). HPRG and its H/P domain, but not the other domains of HPRG, bind specifically and with high affinity to tropomyosin. In this study, we characterize the interaction of the H/P domain with tropomyosin and delineate the region within the H/P domain responsible for that interaction. The H/P domain of HPRG consists mostly of repetitions of the consensus sequence [H/P][H/P]PHG. Applying an in vitro tropomyosin binding assay, we demonstrate that the synthetic peptide HHPHG binds to tropomyosin in vitro and inhibits angiogenesis and tumor growth in vivo. The affinity for tropomyosin increases exponentially upon multimerization of the HHPHG sequence, with a concurrent increase in antiangiogenic activity. Specifically, the tetramer (HHPHG)4 has significant antiangiogenic activity in the Matrigel plug model (IC50 ∼600 nm) and antitumor effects in two syngeneic mouse tumor models. Thus, we show that a 16-mer peptide analogue mimics the antiangiogenic activity of intact HPRG and is also able to inhibit tumor growth, suggesting that cell surface tropomyosin may represent a novel antiangiogenic target for the treatment of cancer.