bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cocarcinogenic Effects of Islet Hormones and N-Nitrosomorpholine in Hepatocarcinogenesis after Intrahepatic Transplantation of Pancreatic Islets in Streptozotocin-Diabetic Rats
Authors: Dombrowski Frank , Jost Christina Maria , Manekeller Steffen , Evert Matthias 
Published: September 2005

Abstract
In contrast to high local insulin levels obtained after low-number transplantation (n = 350) of islets of Langerhans into the livers of diabetic rats, low insulin levels after high-number transplantation (n = 1,000) do not suffice to induce hepatocarcinogenesis. Herein, we investigated the possible cocarcinogenic potential of high and, in particular, low insulin levels, combining this in vivo model with a chemical model of hepatocarcinogenesis after administration of N-nitrosomorpholine (NNM). In three main experiments, different schemes of single or continuous NNM administration were combined with different transplantation procedures in diabetic or nondiabetic animals, i.e., low-number and high-number islet transplantation, transplantation of polystyrene particles, and sham transplantation. Animals were sacrificed between 3 and 53 weeks after transplantation procedures. Evidence for the cocarcinogenic effects of NNM and insulin was provided in each main experiment. NNM treatment after low-number islet transplantation resulted in an increase in the number of preneoplastic hepatocellular foci, and a significant increase in the number and an earlier appearance of hepatocellular adenomas and carcinomas compared with controls. Most intriguing was the increase in preneoplastic foci after combined NNM treatment and high-number islet transplantation, proving that insulin, even in lower doses, has at least cocarcinogenic effects on the downstream hepatocytes and thus promotes an otherwise initiated hepatocarcinogenic process. Conclusively, intrahepatic transplantation of pancreatic islets acts as a strong cocarcinogenic factor together with NNM in streptozotocin-diabetic rats.
A Human- and Male-Specific Protocadherin that Acts through the Wnt Signaling Pathway to Induce Neuroendocrine Transdifferentiation of Prostate Cancer Cells
Authors: Yang Xuezhen , Chen Min-Wei , Terry Stephane , Vacherot Francis , Chopin Dominique K. , Bemis Debra L. , Kitajewski Jan , Benson Mitchell C. , Guo Yinglu , Buttyan Ralph 
Published: September 2005

Abstract
Protocadherin-PC (PCDH-PC)is a gene on the human Y chromosome that is selectively expressed in apoptosis- and hormone-resistant human prostate cancer cells. The protein encoded by PCDH-PC is cytoplasmically localized and has a small serine-rich domain in its COOH terminus that is homologous to the β-catenin binding site of classical cadherins. Variants of prostate cancer cells that express PCDH-PC have high levels of nuclear β-catenin protein and increased wnt-signaling. In this study, we show that transfection of human prostate cancer cells (LNCaP) with PCDH-PC or culture of these cells in androgen-free medium (a condition that up-regulates PCDH-PC expression) activates wnt signaling as assessed by nuclear accumulation of β-catenin, increased expression of luciferase from a reporter vector promoted by Tcf binding elements and increased expression of wnt target genes. Moreover, LNCaP cells transfected with PCDH-PC or grown in androgen-free medium transdifferentiate to neuroendocrine-like cells marked by elevated expression of neuron-specific enolase and chromogranin-A. Neuroendocrine transdifferentiation was also observed when LNCaP cells were transfected by stabilized β-catenin. Increased wnt signaling and neuroendocrine transdifferentiation of LNCaP cells induced by culture in androgen-free medium was suppressed by short interfering RNAs that target PCDH-PC as well as by dominant-negative Tcf or short interfering RNA against β-catenin, supporting the hypothesis that increased expression of PCDH-PC is driving neuroendocrine transdifferentiation by activating wnt signaling. These findings have significant implications for the process through which prostate cancers progress to hormone resistance in humans.
A Novel Carbohydrate-Based Therapeutic GCS-100 Overcomes Bortezomib Resistance and Enhances Dexamethasone-Induced Apoptosis in Multiple Myeloma Cells
Authors: Chauhan Dharminder , Li Guilan , Podar Klaus , Hideshima Teru , Neri Paola , He Deli , Mitsiades Nicholas , Richardson Paul , Chang Yan , Schindler Joanne , Carver Bradley , Anderson Kenneth C. 
Published: September 2005

Abstract
Human multiple myeloma is a presently incurable hematologic malignancy, and novel biologically based therapies are urgently needed. GCS-100 is a polysaccharide derived from citrus pectin in clinical development for the treatment of cancer. Here we show that GCS-100 induces apoptosis in various multiple myeloma cell lines, including those resistant to dexamethasone, melphalan, or doxorubicin. Examination of purified patient multiple myeloma cells showed similar results. Specifically, GCS-100 decreases viability of bortezomib/PS-341–resistant multiple myeloma patient cells. Importantly, GCS-100 inhibits multiple myeloma cell growth induced by adhesion to bone marrow stromal cells; overcome the growth advantage conferred by antiapoptotic protein Bcl-2, heat shock protein-27, and nuclear factor-κB; and blocks vascular endothelial growth factor–induced migration of multiple myeloma cells. GCS-100–induced apoptosis is associated with activation of caspase-8 and caspase-3 followed by proteolytic cleavage of poly(ADP-ribose) polymerase enzyme. Combined with dexamethasone, GCS-100 induces additive anti-multiple myeloma cytotoxicity associated with mitochondrial apoptotic signaling via release of cytochrome c and Smac followed by activation of caspase-3. Moreover, GCS-100 + dexamethasone–induced apoptosis in multiple myeloma cells is accompanied by a marked inhibition of an antiapoptotic protein Galectin-3, without significant alteration in Bcl-2 expression. Collectively, these findings provide the framework for clinical evaluation of GCS-100, either alone or in combination with dexamethasone, to inhibit tumor growth, overcome drug resistance, and improve outcome for patients with this universally fatal hematologic malignancy.
Signaling Intricacies Take Center Stage in Cancer Cells
Authors: Kumar Rakesh , Hung Mien-Chie 
Published: September 2005

Abstract
After many years of productive study on the signaling networks, posttranslational regulatory control of effector molecules remains an intensely investigated and continuously evolving field of research to connect signaling with phenotypic changes. In recent years, there have been intriguing results on the interaction of critical molecules to control the growth of cancer cells. This review article will focus on two critical convergence signaling nodules, Akt and p21-activated kinase, two integral components of phenotypic signaling during tumorigenesis. Here we will summarize the recent findings on how these master signaling nodules regulate their targets and alter the subcellular localization of their effectors to control their functionality. Based on the laboratory advances in the Akt and p21-activated kinase signaling pathways, it is conceivable to start defining novel avenues to develop targeted anticancer therapies.
Retinoid Targeting of Different D-Type Cyclins through Distinct Chemopreventive Mechanisms
Authors: Ma Yan , Feng Qing , Sekula David , Diehl J. Alan , Freemantle Sarah J. , Dmitrovsky Ethan 
Published: September 2005

Abstract
D-type cyclins (cyclins D1, D2, and D3) promote G1-S progression and are aberrantly expressed in cancer. We reported previously that all-trans-retinoic acid chemoprevented carcinogenic transformation of human bronchial epithelial (HBE) cells through proteasomal degradation of cyclin D1. Retinoic acid is shown here to activate distinct mechanisms to regulate different D-type cyclins in HBE cells. Retinoic acid increased cyclin D2, decreased cyclin D3 and had no effect on cyclin D1 mRNA expression. Retinoic acid decreased cyclin D1 and cyclin D3 protein expression. Repression of cyclin D3 protein preceded that of cyclin D3 mRNA. Proteasomal inhibition prevented the early cyclin D3 degradation by retinoic acid. Threonine 286 (T286) mutation of cyclin D1 stabilized cyclin D1, but a homologous mutation of cyclin D3 affecting threonine 283 did not affect cyclin D3 stability, despite retinoic acid treatment. Lithium chloride and SB216763, both glycogen synthase kinase 3 (GSK3) inhibitors, inhibited retinoic acid repression of cyclin D1, but not cyclin D3 proteins. Notably, phospho-T286 cyclin D1 expression was inhibited by lithium chloride, implicating GSK3 in these effects. Expression of cyclin D1 and cyclin D3 was deregulated in retinoic acid–resistant HBE cells, directly implicating these species in retinoic acid response. D-type cyclins were independently targeted using small interfering RNAs. Repression of each D-type cyclin suppressed HBE growth. Repression of all D-type cyclins cooperatively suppressed HBE growth. Thus, retinoic acid repressed cyclin D1 and cyclin D3 through distinct mechanisms. GSK3 plays a key role in retinoid regulation of cyclin D1. Taken together, these findings highlight these cyclins as molecular pharmacologic targets for cancer chemoprevention.
2-Deoxyglucose as an Energy Restriction Mimetic Agent: Effects on Mammary Carcinogenesis and on Mammary Tumor Cell Growth In vitro
Authors: Zhu Zongjian , Jiang Weiqin , McGinley John N. , Thompson Henry J. 
Published: September 2005

Abstract
Dietary energy restriction (DER) is a potent inhibitor of carcinogenesis, but chronic DER in human populations is difficult to sustain. Consequently, interest exists in identifying energy restriction mimetic agents (ERMAs), agents that provide the health benefits of DER without reducing caloric intake. The selection of a candidate ERMAs for this study was based on evidence that DER inhibits carcinogenesis by limiting glucose availability. The study objective was to determine if 2-deoxyglucose (2-DG), a glucose analogue that blocks its metabolism, would inhibit mammary carcinogenesis. Pilot studies were done to establish a dietary concentration of 2-DG that would not affect growth. For the carcinogenesis study, ninety 21-day-old female Sprague-Dawley rats were injected i.p. with 50 mg of 1-methyl-1-nitrosourea per kilogram of body weight. Following injection, animals were ad libitum fed AIN-93G diet containing 0.00%, 0.02%, or 0.03% (w/w) 2-DG for 5 weeks. 2-DG decreased the incidence and multiplicity of mammary carcinomas and prolonged cancer latency (P &lt; 0.05). The 0.02% dose of 2-DG had no effect on circulating levels of glucose, insulin, insulin-like growth factor-I, IGF binding protein-3, leptin, or body weight gain. Using MCF-7 human breast cancer cells to investigate the signaling pathways perturbed by disruption of glucose metabolism, 2-DG reduced cell growth and intracellular ATP in a dose- and time-dependent manner (P &lt; 0.01). Treatment with 2-DG increased levels of phosphorylated AMP-activated protein kinase and Sirt-1 and reduced phosphorylated Akt (P &lt; 0.05). These studies support the hypothesis that DER inhibits carcinogenesis, in part, by limiting glucose availability and that energy metabolism is a target for the development of ERMA for chemoprevention.
A Robust Algorithm for Copy Number Detection Using High-Density Oligonucleotide Single Nucleotide Polymorphism Genotyping Arrays
Authors: Nannya Yasuhito , Sanada Masashi , Nakazaki Kumi , Hosoya Noriko , Wang Lili , Hangaishi Akira , Kurokawa Mineo , Chiba Shigeru , Bailey Dione K. , Kennedy Giulia C. , Ogawa Seishi 
Published: September 2005

Abstract
We have developed a robust algorithm for copy number analysis of the human genome using high-density oligonucleotide microarrays containing 116,204 single-nucleotide polymorphisms. The advantages of this algorithm include the improvement of signal-to-noise (S/N) ratios and the use of an optimized reference. The raw S/N ratios were improved by accounting for the length and GC content of the PCR products using quadratic regressions. The use of constitutional DNA, when available, gives the lowest SD values (0.16 ± 0.03) and also enables allele-based copy number detection in cancer genomes, which can unmask otherwise concealed allelic imbalances. In the absence of constitutional DNA, optimized selection of multiple normal references with the highest S/N ratios, in combination with the data regressions, dramatically improves SD values from 0.67 ± 0.12 to 0.18 ± 0.03. These improvements allow for highly reliable comparison of data across different experimental conditions, detection of allele-based copy number changes, and more accurate estimations of the range and magnitude of copy number aberrations. This algorithm has been implemented in a software package called Copy Number Analyzer for Affymetrix GeneChip Mapping 100K arrays (CNAG). Overall, these enhancements make CNAG a useful tool for high-resolution detection of copy number alterations which can help in the understanding of the pathogenesis of cancers and other diseases as well as in exploring the complexities of the human genome.
Amplification and Overexpression of the KIT Gene Is Associated with Progression in the Seminoma Subtype of Testicular Germ Cell Tumors of Adolescents and Adults
Authors: McIntyre Alan , Summersgill Brenda , Grygalewicz Beata , Gillis Ad J.M. , Stoop J. , van Gurp Ruud J.H.L.M. , Dennis Nening , Fisher Cyril , Huddart Robert , Cooper Colin , Clark Jeremy , Oosterhuis J. Wolter , Looijenga Leendert H.J. , Shipley Janet 
Published: September 2005

Abstract
We have previously identified amplification at 4q12 in testicular germ cell tumors of adolescents and adults centered around the KIT gene encoding a tyrosine kinase transmembrane receptor. Analysis of primary testicular germ cell tumors totaling 190 cases revealed 21% of the seminoma subtype with an increased copy number of KIT whereas this change was rarely found in the nonseminomas. In most cases, gain of KIT did not include the immediately flanking noncoding DNA or the flanking genes KDR and PDGFRA. Increased copy number of KIT was not found in the putative precursor lesion, carcinoma in situ (CIS), adjacent to tumor with this change. KIT overexpression was found independent of gain and KIT immunostaining was stronger in selected cases with gain of KIT compared to those without. Taken together with activating mutations of KIT in exon 17 identified in 13% of seminomas, this suggests that the KIT gene product plays a role in the progression of CIS towards seminoma, the further understanding of which may lead to novel less toxic therapeutic approaches.
Targeting Medulloblastoma: Small-Molecule Inhibitors of the Sonic Hedgehog Pathway as Potential Cancer Therapeutics
Authors: Romer Justyna , Curran Tom 
Published: September 2005

Abstract
Medulloblastoma is the most common malignant pediatric brain tumor for which no satisfactory treatments exist. The Sonic Hedgehog signaling pathway seems to play an important role in the pathology of this disease. Here we review our recent demonstration that a small-molecule inhibitor of this pathway can regress tumors that arise in a transgenic mouse model of medulloblastoma. These and other findings suggest that inhibitors of Sonic Hedgehog signaling may offer an effective way to target some malignancies.
Meeting Report: The International Conference on Tumor Progression and Therapeutic Resistance
Authors: El-Deiry Wafik S. 
Published: September 2005

Abstract
A multidisciplinary conference was held November 7 to 9, 2004 in Philadelphia, PA to focus on the problem of drug resistance in cancer. A great deal of knowledge is beginning to unravel the complex molecular and cellular changes associated with malignant tumor progression. With this comes many opportunities for therapeutic development. Featuring the latest tools, models, and research findings, this conference which included over 250 members of both academia and industry was a great opportunity to learn and develop new approaches and collaborations. The Keynote speaker was Dr. Robert Horvitz (Massachusetts Institute of Technology), who won the 2002 Nobel Prize in Medicine for his pioneering work on the cell death pathway in Caenorhabditis elegans. Speakers covered various aspects of tumor progression and therapy from simple models to clinical trials.
Isolation and In vitro Propagation of Tumorigenic Breast Cancer Cells with Stem/Progenitor Cell Properties
Authors: Ponti Dario , Costa Aurora , Zaffaroni Nadia , Pratesi Graziella , Petrangolini Giovanna , Coradini Danila , Pilotti Silvana , Pierotti Marco A. , Daidone Maria Grazia 
Published: September 2005

Abstract
Breast cancer–initiating cells have been recently identified in breast carcinoma as CD44+/CD24−/low cells, which exclusively retain tumorigenic activity and display stem cell–like properties. However, at present, direct evidence that breast cancer–initiating cells can be propagated in vitro is still lacking. We report here the isolation and in vitro propagation of breast cancer–initiating cells from three breast cancer lesions and from an established breast carcinoma cell line. Our breast carcinoma–derived cultures encompassed undifferentiated cells capable of self-renewal, extensive proliferation as clonal nonadherent spherical clusters, and differentiation along different mammary epithelial lineages (ductal and myoepithelial). Interestingly, cultured cells were CD44+/CD24− and Cx43−, overexpressed neoangiogenic and cytoprotective factors, expressed the putative stem cell marker Oct-4, and gave rise to new tumors when as few as 103 cells were injected into the mammary fat pad of SCID mice. Long-term cultures of breast tumorigenic cells with stem/progenitor cell properties represent a suitable in vitro model to study breast cancer–initiating cells and to develop therapeutic strategies aimed at eradicating the tumorigenic subpopulation within breast cancer.
Gefitinib Reverses Chemotherapy Resistance in Gefitinib-Insensitive Multidrug Resistant Cancer Cells Expressing ATP-Binding Cassette Family Protein
Authors: Yang Chih-Hsin , Huang Ching-Ju , Yang Chao-Shun , Chu Yu-Chuan , Cheng Ann-Lii , Whang-Peng Jacqueline , Yang Pan-Chyr 
Published: September 2005

Abstract
Gefitinib inhibits the ATP-binding site of the tyrosine kinase associated with the epidermal growth factor receptor. It is conceivable that gefitinib may inhibit functions of ATP-binding cassette (ABC) transporters by binding at their ATP-binding sites. The aim of this study is to systematically explore the combined effect of gefitinib and chemotherapeutic agents in gefitinib-insensitive multidrug resistant (MDR) cells that overexpress ABC transporters. MCF7 breast carcinoma cells and CL1 lung adenocarcinoma cells were both insensitive to gefitinib. MDR cancer cells were developed by stepwise escalating concentrations of each chemotherapeutic agent in culture media. Cells that overexpress P-glycoprotein (MCF7/Adr and CL1/Pac), breast cancer–resistant protein (MCF7/TPT and CL1/Tpt), and MDR-associated protein 1 (MCF7/Vp) were used in this study. All resistant mutants were insensitive to gefitinib. Gefitinib (0.3-3 μmol/L) added to culture media had no effect on IC50 values of paclitaxel, topotecan, doxorubicin, or etoposide in wild-type MCF7 or CL1 cells. In contrast, these concentrations of gefitinib caused a dose-dependent reversal of resistance to paclitaxel in CL1/Pac cells, to doxorubicin in MCF7/ADR cells, and to topotecan in CL1/Tpt and MCF7/TPT cells. Gefitinib had no influence on sensitivity to etoposide in MDR-associated protein1 overexpressing MCF7/VP cells. Topotecan efflux was inhibited and accumulation was partially restored in CL1/Tpt and MCF7/TPT cells when cells were incubated simultaneously with gefitinib. Our results suggest that the interaction of gefitinib and chemotherapeutic agents does occur in cells expressing one of these two proteins.
Immunostimulatory Effects of Low-Dose Cyclophosphamide Are Controlled by Inducible Nitric Oxide Synthase
Authors: Loeffler Markus , Krüger Jörg A. , Reisfeld Ralph A. 
Published: September 2005

AbstractCyclophosphamide is a widely used chemotherapeutic drug that was recently applied as either an antiangiogenic/antivasculogenic or an immunostimulatory agent in combination with cancer immunotherapies. It has been previously shown that cyclophosphamide augments the efficacy of antitumor immune responses by depleting CD4+CD25+ T regulatory cells and increasing both T-lymphocyte proliferation and T memory cells. Furthermore, cyclophosphamide was shown to mediate killing of circulating endothelial progenitors. However, the molecular basis for these observations has not yet been elucidated. We show here that the cyclophosphamide-mediated inhibition of inducible nitric oxide synthase is directly linked to its immunostimulatory but not to its antivasculogenic effects. Moreover, combined application of cyclophosphamide with a novel, oral DNA vaccine targeting platelet-derived growth factor B (PDGF-B), overexpressed by proliferating endothelial cells in the tumor vasculature, not only completely inhibited the growth of different tumor types but also led to tumor rejections in mice. These findings provide a new rationale at the molecular level for the combination of chemotherapy and immunotherapy in cancer treatment.
Nitric Oxide Sensitizes Tumor Cells to Dendritic Cell–Mediated Apoptosis, Uptake, and Cross-Presentation
Authors: Huang Jian , Tatsumi Tomohide , Pizzoferrato Eva , Vujanovic Nikola , Storkus Walter J. 
Published: September 2005

AbstractDendritic cells are professional antigen-presenting cells associated with efficient antigen processing and presentation to T cells. However, recent evidence also suggests that dendritic cells may mediate direct tumoricidal functions. In this study, we investigated the mechanism by which murine dendritic cells mediate the apoptotic death of murine lymphoma cell lines, and whether dendritic cell effector function could be enhanced by preconditioning tumor cells with the protein phosphatase inhibitor nitric oxide (NO) by altering the balance of proapoptotic/antiapoptotic proteins in the treated cells. We observed that NO donor compound sensitized lymphomas to dendritic cell–mediated cytotoxicity in vitro. Both immature and spontaneously matured bone marrow–derived dendritic cells (SM-DC) were capable of inducing tumor cell apoptosis, with SM-DCs serving as comparatively better killers. Fas ligand (FasL)-Fas engagement proved important in this activity because elevated expression of membrane-bound FasL was detected on SM-DCs, and dendritic cells derived from FasL-deficient mice were less capable of killing NO-sensitized tumor cells than wild-type dendritic cells. As FasL-deficient dendritic cells were still capable of mediating a residual degree of tumor killing, this suggests that FasL-independent mechanisms of apoptosis are also involved in dendritic cell–mediated tumor killing. Because NO-treated tumor cells displayed a preferential loss of survivin protein expression via a proteasome-dependent pathway, enhanced tumor sensitivity to dendritic cell–mediated killing may be associated with the accelerated turnover of this critical antiapoptotic gene product. Importantly, NO-treated tumor cells were also engulfed more readily than control tumor cells and this resulted in enhanced cross-presentation of tumor-associated antigens to specific T cells in vitro.