bluuebunny/crossref_metadata_2025_split huggingface dataset:
Androgen Causes Growth Suppression and Reversion of Androgen-Independent Prostate Cancer Xenografts to an Androgen-Stimulated Phenotype in Athymic Mice
Authors: Chuu Chih-pin , Hiipakka Richard A. , Fukuchi Junichi , Kokontis John M. , Liao Shutsung 
Published: September 2005

Abstract
Most prostate cancer patients develop androgen-independent recurrent prostate tumors a few years after androgen ablation therapy. No therapy, however, has been shown to substantially extend survival in these patients. Previously, we reported that androgen suppresses the growth of androgen-independent LNCaP prostate tumor cells both in vitro and in vivo. In cell culture, androgen receptor (AR)–rich androgen-independent LNCaP 104-R1 cells adapt to growth suppression by androgen and then their growth is androgen stimulated. Because maintaining androgen dependency of prostate tumor cells should prolong the usefulness of androgen ablation therapy, we determined if androgen-independent prostate tumors would revert to an androgen-stimulated phenotype in vivo upon androgen treatment. Growth of the LNCaP 104-R1 tumors was suppressed by androgen, but tumors then adapted to suppression by androgen and growth became androgen stimulated. Tumor AR and prostate-specific antigen mRNA and protein were initially high in 104-R1 tumors but decreased during adaptation. Subsequent removal of androgen decreased the serum prostate-specific antigen level further and stopped the growth of the adapted tumors. Because androgen caused growth suppression and then reversion of androgen-independent tumors to an androgen-stimulated phenotype and because the growth of androgen-stimulated tumors could be restrained by androgen ablation, these results suggest a novel therapy for AR-positive androgen-independent prostate cancer.
Lost in Transcription: p21 Repression, Mechanisms, and Consequences
Authors: Gartel Andrei L. , Radhakrishnan Senthil K. 
Published: September 2005

Abstract
The cyclin-dependent kinase inhibitor p21WAF1/CIP1 is a major player in cell cycle control and it is mainly regulated at the transcriptional level. Whereas induction of p21 predominantly leads to cell cycle arrest, repression of p21 may have a variety of outcomes depending on the context. In this review, we concentrate on transcriptional repression of p21 by cellular and viral factors, and delve in detail into its possible biological implications and its role in cancer. It seems that the major mode of p21 transcriptional repression by negative regulators is the interference with positive transcription factors without direct binding to the p21 promoter. Specifically, the negative factors may either inhibit binding of positive regulators to the promoter or hinder their transcriptional activity. The ability of p21 to inhibit proliferation may contribute to its tumor suppressor function. Because of this, it is not surprising that a number of oncogenes repress p21 to promote cell growth and tumorigenesis. However, p21 is also an inhibitor of apoptosis and p21 repression may also have an anticancer effect. For example, c-Myc and chemical p21 inhibitors, which repress p21, sensitize tumor cells to apoptosis by anticancer drugs. Further identification of factors that repress p21 is likely to contribute to the better understanding of its role in cancer.
E2F-Dependent Repression of Topoisomerase II Regulates Heterochromatin Formation and Apoptosis in Cells with Melanoma-Prone Mutation
Authors: Jiao Wan , Lin Huei-Min , Timmons Jamie , Nagaich Akhilesh K. , Ng Shu-Wing , Misteli Tom , Rane Sushil G. 
Published: September 2005

Abstract
RB pathway mutations, especially at the CDK4 and INK4A loci, are hallmarks of melanomagenesis. It is presently unclear what advantages these alterations confer during melanoma progression and how they influence melanoma therapy. Topoisomerase II inhibitors are widely used to treat human malignancies, including melanoma, although their variable success is attributable to a poor understanding of their mechanism of action. Using mouse and human cells harboring the melanoma-prone p16Ink4a-insensitive CDK4R24C mutation, we show here that topoisomerase II proteins are direct targets of E2F-mediated repression. Drug-treated cells fail to load repressor E2Fs on topoisomerase II promoters leading to elevated topoisomerase II levels and an enhanced sensitivity of cells to apoptosis. This is associated with the increased formation of heterochromatin domains enriched in structural heterochromatin proteins, methylated histones H3/H4, and topoisomerase II. We refer to these preapoptotic heterochromatin domains as apoptosis-associated heterochromatic foci. We suggest that cellular apoptosis is preceded by an intermediary chromatin remodeling state that involves alterations of DNA topology by topoisomerase II enzymes and gene silencing via formation of heterochromatin. These observations provide novel insight into the mechanism of drug action that influence treatment outcome: drug sensitivity or drug resistance.
Antibody against Junctional Adhesion Molecule-C Inhibits Angiogenesis and Tumor Growth
Authors: Lamagna Chrystelle , Hodivala-Dilke Kairbaan M. , Imhof Beat A. , Aurrand-Lions Michel 
Published: September 2005

AbstractThe junctional adhesion molecule-C (JAM-C) was recently described as an adhesion molecule localized at interendothelial contacts and involved in leukocyte transendothelial migration. The protein JAM-C interacts with polarity complex molecules and regulates the activity of the small GTPase Cdc42. The angiogenesis process involves rearrangement of endothelial junctions and implicates modulation of cell polarity. We tested whether JAM-C plays a role in angiogenesis using tumor grafts and hypoxia-induced retinal neovascularization. Treatment with a monoclonal antibody directed against JAM-C reduces tumor growth and infiltration of macrophages into tumors. The antibody decreases angiogenesis in the model of hypoxia-induced retinal neovascularization in vivo and vessel outgrowth from aortic rings in vitro. Importantly, the antibody does not induce pathologic side effects in vivo. These findings show for the first time a role for JAM-C in angiogenesis and define JAM-C as a valuable target for antitumor therapies.
The Novel Gene EG-1 Stimulates Cellular Proliferation
Authors: Lu Ming , Zhang Liping , Maul Raymond Scott , Sartippour Maryam R. , Norris Andrew , Whitelegge Julian , Rao Jian Yu , Brooks Mai N. 
Published: September 2005

Abstract
We recently discovered a novel gene and named it endothelial-derived gene 1 (EG-1). Previously, we have shown that the expression of EG-1 is significantly elevated in the epithelial cells of breast cancer, colorectal cancer, and prostate cancer. Here, we report that EG-1 can stimulate cellular proliferation. Transfection experiments which overexpressed the full-length EG-1 gene in human embryonic kidney HEK-293 cells or human breast cancer cell lines resulted in significantly increased in vitro proliferation, in comparison with transfection with empty vectors. On the other hand, small interfering RNA cotransfection resulted in inhibition of proliferation. S.c. xenograft assays were carried out in a severe combined immunodeficient mouse model. We found that injection of high EG-1 expressing HEK-293 clones resulted in significantly larger tumors, in comparison with clones carrying the empty vectors. To further clarify the function of this gene, we investigated its interaction with Src and members of the mitogen-activated protein kinase (MAPK) family. Immunoprecipitation with anti-Src antibody, followed by immunoblotting with anti–EG-1 antibody, showed an association between these two molecules. Overexpression of EG-1 was correlated with activation of the following kinases: extracellular signal-regulated kinases 1 and 2, c-jun-NH2-kinase, and p38. These observations collectively support the hypothesis that the novel gene EG-1 is a positive stimulator of cellular proliferation, and may possibly be involved in signaling pathways involving Src and MAPK activation.
Salivary Gland Tumors in Transgenic Mice with Targeted PLAG1 Proto-Oncogene Overexpression
Authors: Declercq Jeroen , Van Dyck Frederik , Braem Caroline V. , Van Valckenborgh Isabelle C. , Voz Marianne , Wassef Michel , Schoonjans Luc , Van Damme Boudewijn , Fiette Laurence , Van de Ven Wim J.M. 
Published: September 2005

Abstract
Pleomorphic adenoma gene 1 (PLAG1) proto-oncogene overexpression is implicated in various human neoplasias, including salivary gland pleomorphic adenomas. To further assess the oncogenic capacity of PLAG1, two independent PLAG1 transgenic mouse strains were established, PTMS1 and PTMS2, in which activation of PLAG1 overexpression is Cre mediated. Crossbreeding of PTMS1 or PTMS2 mice with MMTV-Cre transgenic mice was done to target PLAG1 overexpression to salivary and mammary glands, in the P1-Mcre/P2-Mcre offspring. With a prevalence of 100% and 6%, respectively, P1-Mcre and P2-Mcre mice developed salivary gland tumors displaying various pleomorphic adenoma features. Moreover, histopathologic analysis of salivary glands of 1-week-old P1-Mcre mice pointed at early tumoral stages in epithelial structures. Malignant characteristics in the salivary gland tumors and frequent lung metastases were found in older tumor-bearing mice. PLAG1 overexpression was shown in all tumors, including early tumoral stages. The tumors revealed an up-regulation of the expression of two distinct, imprinted gene clusters (i.e., Igf2/H19 and Dlk1/Gtl2). With a latency period of about 1 year, 8% of the P2-Mcre mice developed mammary gland tumors displaying similar histopathologic features as the salivary gland tumors. In conclusion, our results establish the strong and apparently direct in vivo tumorigenic capacity of PLAG1 and indicate that the transgenic mice constitute a valuable model for pleomorphic salivary gland tumorigenesis and potentially for other glands as well.
Plasmacytoid Dendritic Cells Induce CD8+ Regulatory T Cells In Human Ovarian Carcinoma
Authors: Wei Shuang , Kryczek Ilona , Zou Linhua , Daniel Ben , Cheng Pui , Mottram Peter , Curiel Tyler , Lange Andrzej , Zou Weiping 
Published: September 2005

AbstractTo directly dissect the role of each immune component in human tumor immunopathogenesis, we have studied the interaction between dendritic cells and T cells in the tumor environment of patients with ovarian carcinoma. We previously reported that functional plasmacytoid dendritic cells, but not functionally mature myeloid dendritic cells, accumulated in tumor microenvironments. We now show that tumor ascites macrophage-derived dendritic cells induced tumor-associated antigen–specific CD8+ T cells with effector functions. Strikingly, tumor ascites plasmacytoid dendritic cells induced interleukin-10+CCR7+CD45RO+CD8+ regulatory T cells. Four characteristics have been identified in tumor plasmacytoid dendritic cell–induced CD8+ regulatory T cells: (a) induction of CD8+ regulatory T cells is independent of CD4+CD25+ T cells; (b) CD8+ regulatory T cells significantly suppress myeloid dendritic cell–mediated tumor-associated antigen–specific T cell effector functions through interleukin-10; (c) repetitive myeloid dendritic cell stimulation can recover CD8+ regulatory T cell–mediated poor T cell proliferation, but not T cell effector function; (d) CD8+ regulatory T cells express functional CCR7, and efficiently migrate with lymphoid homing chemokine MIP-3β. Primary suppressive CCR7+CD45RO+CD8+ T cells are found in the tumor environment of patients with ovarian cancers. Thus, tumor-associated plasmacytoid dendritic cells contribute to the tumor environmental immunosuppressive network. Collectively, tumors manipulate tumor microenvironmental dendritic cell subset distribution and function to subvert tumor immunity. The data are relevant to understanding tumor immunopathology as well as reevaluating tumor immunotherapeutic strategies.
Proteomic Analysis Reveals Hyperactivation of the Mammalian Target of Rapamycin Pathway in Neurofibromatosis 1–Associated Human and Mouse Brain Tumors
Authors: Dasgupta Biplab , Yi Yijun , Chen David Y. , Weber Jason D. , Gutmann David H. 
Published: September 2005

Abstract
Individuals with the tumor predisposition syndrome, neurofibromatosis 1 (NF1), are prone to development of nervous system tumors, including neurofibromas and pilocytic astrocytomas. Based on the ability of the NF1 gene product (neurofibromin) to function as a GTPase activating protein for RAS, initial biologically based therapies for NF1-associated tumors focused on the use of RAS inhibitors, but with limited clinical success. In an effort to identify additional targets for therapeutic drug design in NF1, we used an unbiased proteomic approach to uncover unanticipated intracellular signaling pathways dysregulated in Nf1-deficient astrocytes. We found that the expression of proteins involved in promoting ribosome biogenesis was increased in the absence of neurofibromin. In addition, Nf1-deficient astrocytes exhibit high levels of mammalian target of rapamycin (mTOR) pathway activation, which was inhibited by blocking K-RAS or phosphatidylinositol 3-kinase activation. This mTOR pathway hyperactivation was reflected by high levels of ribosomal S6 activation in both Nf1 mutant mouse optic nerve gliomas and in human NF1-associated pilocytic astrocytoma tumors. Moreover, inhibition of mTOR signaling in Nf1−/− astrocytes abrogated their growth advantage in culture, restoring normal proliferative rates. These results suggest that mTOR pathway inhibition may represent a logical and tractable biologically based therapy for brain tumors in NF1.
Role of the Ras-Association Domain Family 1 Tumor Suppressor Gene in Human Cancers
Authors: Agathanggelou Angelo , Cooper Wendy N. , Latif Farida 
Published: September 2005

Abstract
In recent years, the list of tumor suppressor genes (or candidate TSG) that are inactivated frequently by epigenetic events rather than classic mutation/deletion events has been growing. Unlike mutational inactivation, methylation is reversible and demethylating agents and inhibitors of histone deacetylases are being used in clinical trails. Highly sensitive and quantitative assays have been developed to assess methylation in tumor samples, early lesions, and bodily fluids. Hence, gene silencing by promoter hypermethylation has potential clinical benefits in early cancer diagnosis, prognosis, treatment, and prevention. The hunt for a TSG located at 3p21.3 resulted in the identification of the RAS-association domain family 1, isoform A gene (RASSF1A). RASSF1A falls into the category of genes frequently inactivated by methylation rather than mutational events. This gene is silenced and frequently inactivated by promoter region hypermethylation in many adult and childhood cancers, including lung, breast, kidney, gastric, bladder, neuroblastoma, medulloblastoma, gliomas and it has homology to a mammalian Ras effector (i.e., Nore1). RASSF1A inhibits tumor growth in both in vitro and in vivo systems, further supporting its role as a TSG. We and others identified the gene in 2000, but already there are over a 150 publications demonstrating RASSF1A methylation in a large number of human cancers. Many laboratories including ours are actively investigating the biology of this novel protein family. Thus far, it has been shown to play important roles in cell cycle regulation, apoptosis, and microtubule stability. This review summarizes our current knowledge on genetic, epigenetic, and functional analysis of RASSF1A tumor suppressor gene and its homologues.
Gene Expression Profiling Identifies Molecular Subtypes of Inflammatory Breast Cancer
Authors: Bertucci François , Finetti Pascal , Rougemont Jacques , Charafe-Jauffret Emmanuelle , Cervera Nathalie , Tarpin Carole , Nguyen Catherine , Xerri Luc , Houlgatte Rémi , Jacquemier Jocelyne , Viens Patrice , Birnbaum Daniel 
Published: September 2005

Abstract
Breast cancer is a heterogeneous disease. Comprehensive gene expression profiles obtained using DNA microarrays have revealed previously indistinguishable subtypes of noninflammatory breast cancer (NIBC) related to different features of mammary epithelial biology and significantly associated with survival. Inflammatory breast cancer (IBC) is a rare, particular, and aggressive form of disease. Here we have investigated whether the five molecular subtypes described for NIBC (luminal A and B, basal, ERBB2 overexpressing, and normal breast-like) were also present in IBC. We monitored the RNA expression of ∼8,000 genes in 83 breast tissue samples including 37 IBC, 44 NIBC, and 2 normal breast samples. Hierarchical clustering identified the five subtypes of breast cancer in both NIBC and IBC samples. These subtypes were highly similar to those defined in previous studies and associated with similar histoclinical features. The robustness of this classification was confirmed by the use of both alternative gene set and analysis method, and the results were corroborated at the protein level. Furthermore, we show that the differences in gene expression between NIBC and IBC and between IBC with and without pathologic complete response that we have recently reported persist in each subtype. Our results show that the expression signatures defining molecular subtypes of NIBC are also present in IBC. Obtained using different patient series and different microarray platforms, they reinforce confidence in the expression-based molecular taxonomy but also give evidence for its universality in breast cancer, independently of a specific clinical form.
Hypoxia Stimulates Carcinoma Invasion by Stabilizing Microtubules and Promoting the Rab11 Trafficking of the α6β4 Integrin
Authors: Yoon Sang-Oh , Shin Sejeong , Mercurio Arthur M. 
Published: September 2005

Abstract
Hypoxia plays a key role in tumor cell survival, invasion, and metastasis. Here we show that hypoxia increases tumor cell invasion by the modulation of Rab11, an important molecule for vesicular trafficking, especially membrane protein recycling and translocation of proteins from trans-Golgi network to plasma membrane. Dominant-negative Rab11 dramatically decreased hypoxia-induced invasion of MDA-MB-231 breast carcinoma cells without affecting cell apoptosis. Hypoxia-induced Rab11 trafficking is regulated by microtubule stability, as evidenced by the findings that hypoxia increases Glu tubulin and that colchicine blocks Rab11 trafficking and invasion. Inhibition of GSK-3β activity by hypoxia seems to be central to microtubule stabilization and invasion. In fact, expression of a dominant-negative GSK-3β was sufficient to stimulate invasion in normoxia. One target of Rab11-mediated trafficking that contributes to invasion is the integrin α6β4. Hypoxia induced a significant increase in α6β4 surface expression but it had no effect on the surface expression of α3β1. This increase is dependent on Rab11 and stable microtubules. In summary, we identify vesicle trafficking as a novel target of hypoxic stimulation that is important for tumor invasion.
Cytochrome P450 2J2 Promotes the Neoplastic Phenotype of Carcinoma Cells and Is Up-regulated in Human Tumors
Authors: Jiang Jian-Gang , Chen Chun-Lian , Card Jeffrey W. , Yang Shilin , Chen Ji-Xiong , Fu Xiang-Ning , Ning Yao-Gui , Xiao Xiao , Zeldin Darryl C. , Wang Dao Wen 
Published: September 2005

Abstract
Cytochrome P450 (CYP) arachidonic acid epoxygenase 2J2 converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids, which exert diverse biological activities in cardiovascular system and endothelial cells. However, it is unknown whether this enzyme highly expresses and plays any role in cancer. In this study, we found that very strong and selective CYP2J2 expression was detected in human carcinoma tissues in 101 of 130 patients (77%) as well as eight human carcinoma cell lines but undetectable in adjacent normal tissues and nontumoric human cell lines by Western, reverse transcription-PCR, and immunohistochemical staining. In addition, forced overexpression of CYP2J2, and CYP BM3F87V or addition of epoxyeicosatrienoic acids (EET) in cultured carcinoma cell lines in vitro markedly accelerated proliferation by analyses of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, cell accounts, and cell cycle analysis, and protected carcinoma cells from apoptosis induced by tumor necrosis factor α (TNF-α) in cultures. In contrast, antisense 2J2 transfection or addition of epoxygenase inhibitors 17-ODYA inhibited proliferation and accelerated cell apoptosis induced by TNF-α. Examination of signaling pathways on the effects of CYP2J2 and EETs revealed activation of mitogen-activated protein kinases and PI3 kinase-AKT systems and elevation of epithelial growth factor receptor phosphorylation level. These results strongly suggest that CYP epoxygenase 2J2 plays a previously unknown role in promotion of the neoplastic cellular phenotype and in the pathogenesis of a variety of human cancers.
Antivascular Therapy of Human Follicular Thyroid Cancer Experimental Bone Metastasis by Blockade of Epidermal Growth Factor Receptor and Vascular Growth Factor Receptor Phosphorylation
Authors: Younes Maher Nabil , Yigitbasi Orhan Gazi , Park Young Wook , Kim Sun-Jin , Jasser Samar A. , Hawthorne Valerie Stone , Yazici Yasemin Dakak , Mandal Mahitosh , Bekele Benjamin Nebiyou , Bucana Corazon D. , Fidler Isaiah J. , Myers Jeffrey N. 
Published: September 2005

Abstract
Patients suffering from bone metastases of follicular thyroid carcinoma (FTC) have a poor prognosis because of the lack of effective treatment strategies. The overexpression of epidermal growth factor receptor (EGFR) associated with increased vascularity has been implicated in the pathogenesis of FTC and subsequent bone metastases. We hypothesized that inhibiting the phosphorylation of the EGFR and vascular endothelial growth factor receptor (VEGFR) by AEE788, a dual tyrosine kinase inhibitor of EGFR and VEGFR, in combination with paclitaxel would inhibit experimental FTC bone lesions and preserve bone structure. We tested this hypothesis using the human WRO FTC cell line. In culture, AEE788 inhibited the EGF-mediated phosphorylation of EGFR, VEGFR2, mitogen-activated protein kinase, and Akt in culture. AEE788, alone and in combination with paclitaxel, inhibited cell growth and induced apoptosis. When WRO cells were injected into the tibia of nude mice, tumor and endothelial cells within the lesions expressed phosphorylated EGFR, VEGFR, Akt, and mitogen-activated protein kinase that were inhibited by the oral administration of AEE788. Therapy consisting of orally given AEE788 and i.p. injected paclitaxel induced a high level of apoptosis in tumor-associated endothelial cells and tumor cells with the inhibition of tumor growth in the bone and the preservation of bone structure. Collectively, these data show that blocking the phosphorylation of EGFR and VEGFR with AEE788 combined with paclitaxel can significantly inhibit experimental human FTC in the bone of nude mice.