bluuebunny/crossref_metadata_2025_split huggingface dataset:
Medullary Thyroid Carcinoma Arises in the Absence of Prolactin Signaling
Authors: Kedzia Cécile , Lacroix Ludovic , Ameur Nabahet , Ragot Thierry , Kelly Paul A. , Caillou Bernard , Binart Nadine 
Published: September 2005

Abstract
Prolactin, a pituitary hormone, exerts pleiotropic effects in various cells. These effects are mediated by a membrane receptor highly expressed in many tissues. To analyze prolactin effects on the thyroid gland, we first identified prolactin receptor (PRLR) mRNAs by in situ hybridization. To further evaluate the physiologic relevance of PRLR actions in the thyroid in vivo, we used PRLR knockout mice. Whereas the histologic structure of thyroid of PRLR-null mice was not disturbed, we show that T4 levels are lower in null animals (13.63 ± 2.98 versus 10.78 ± 2.25 pmol/L in null mice), confirming that prolactin participates in the control of thyroid metabolism. To further investigate thyroid effects in mice, we measured body temperature and thyroid-stimulating hormone in young and adult male and/or female PRLR-null mice and their normal siblings. Surprisingly, in null animals, we saw medullary thyroid carcinoma (MTC) arising from parafollicular C cells producing calcitonin. The incidence of these carcinomas attained 41% in PRLR-null mice, whereas this malignant tumor occurs sporadically or as a component of the familial cancer syndrome in humans. This finding suggests that PRLR-null mice could represent a valuable animal model for MTC, which could be compared with existing MTC models. These observations suggest a possible link between the appearance of this carcinoma and the absence of prolactin signaling.
Trastuzumab Therapy for Tamoxifen-Stimulated Endometrial Cancer
Authors: Osipo Clodia , Meeke Kathleen , Liu Hong , Cheng Dong , Lim Sherry , Weichel Alyssa , Jordan V. Craig 
Published: September 2005

Abstract
A novel in vivo model of tamoxifen-stimulated endometrial cancer was developed and the role of HER-2/neu investigated by using trastuzumab. Tamoxifen-stimulated tumors (ECC-1TAM) were growth stimulated by 17β-estradiol (E2), tamoxifen, or raloxifene. Trastuzumab inhibited growth of E2-stimulated ECC-1E2 tumors by 50% and tamoxifen-stimulated ECC-1TAM tumors by 100%. ECC-1 tumors expressed functional estrogen receptor α (ERα) as measured by induction of pS2 and c-myc mRNAs. E2 induced pS2 and c-myc mRNAs up to 40-fold in ECC-1E2 and ECC-1TAM. Tamoxifen induced pS2 and c-myc mRNAs up to 5-fold in ECC-1E2 tumors and up to 10-fold in ECC-TAM tumors. Trastuzumab blocked E2-induced pS2 mRNA (P &lt; 0.01) in ECC-1E2 by 50% and tamoxifen-induced c-myc mRNA (P &lt; 0.1) in ECC-1TAM tumors by 70%. Trastuzumab decreased phosphorylated and total HER-2/neu protein in ECC-1E2 and ECC-1TAM tumors. However, only phospho-ERK-1/2 and not phospho-Akt protein was decreased by trastuzumab in tamoxifen-treated ECC-1TAM tumors. The insulin-like growth factor (IGF-I) signaling pathway also activates extracellular signal-related kinase (ERK)-1/2 and could block the efficacy of trastuzumab in ECC-1E2 tumors. The results showed that IGF-I, IGF-IR mRNAs, and phospho-insulin receptor substrate-1 (IRS-1) protein were decreased in ECC-1TAM compared with ECC-1E2 tumors. The results show that trastuzumab is an effective therapy for both E2-stimulated and tamoxifen-stimulated endometrial cancer. The data suggest estrogenic activities of E2 and tamoxifen at ERα-regulated pS2 and c-myc genes are in part mediated by HER-2/neu. However, trastuzumab is a better growth inhibitor of ECC-1TAM tumors where there is diminished IGF-I signaling allowing for complete blockade of the downstream phospho-ERK-1/2 signal.
CY15, a Malignant Histiocytic Tumor That Is Phenotypically Similar to Immature Dendritic Cells
Authors: Kammertoens Thomas , Willebrand Ralf , Erdmann Bettina , Li Liangping , Li Yongping , Engels Boris , Uckert Wolfgang , Blankenstein Thomas 
Published: September 2005

Abstract
The origin and pathogenesis of histiocytic malignancies and the biology of the tumor cells are poorly understood. We have isolated a murine histiocytic tumor cell line (CY15) from a BALB/c IFNγ−/− mouse and characterized it in terms of phenotype and function. The morphology, as judged by electron microscopy, and the surface marker phenotype suggests that CY15 cells are similar to immature dendritic cells (CD11c low, MHC II low, CD11b+, B7.1+, B7.2+, and CD40+). The cells form tumors in BALB/c mice and metastasize to spleen, liver, lung, kidney, and to a lesser extend to lymph nodes and bone marrow, as judged by the growth of green fluorescent protein transfected tumor cells in mice. CY15 cells are capable of actively taking up antigen (FITC-ovalbumin) and can stimulate T lymphocytes in an allogenic mixed lymphocyte reaction but less effectively than their normal counterparts (immature dendritic cells). They respond to interleukin 4 (IL-4) with up-regulation of CD11c. If stimulated with IFNγ the cells up-regulate MHC II, CD40 B7.1, and B7.2. Lipopolysaccharide induces the cells to up-regulate B7.1 and B7.2 and to secrete tumor necrosis factor α and IL-12. Based on these data, CY15 is a dendritic cell–like tumor cell line and may serve as a transplantable tumor model for histiocytosis in humans.
Targeted Delivery of IFNγ to Tumor Vessels Uncouples Antitumor from Counterregulatory Mechanisms
Authors: Curnis Flavio , Gasparri Anna , Sacchi Angelina , Cattaneo Angela , Magni Fulvio , Corti Angelo 
Published: September 2005

AbstractBecause of its immunomodulatory and anticancer activities, IFNγ has been used as an anticancer drug in several clinical studies, unfortunately with modest results. Attempts to increase the response by increasing the dose or by repeated continuous injection often resulted in lower efficacy, likely due to counterregulatory effects. We show here that targeted delivery of low doses of IFNγ to CD13, a marker of angiogenic vessels, can overcome major counterregulatory mechanisms and delay tumor growth in two murine models that respond poorly to IFNγ. Tumor vascular targeting was achieved by coupling IFNγ to GCNGRC, a CD13 ligand, by genetic engineering technology. The dose-response curve was bell-shaped. Maximal effects were induced with a dose of 0.005 μg/kg, about 500-fold lower than the dose used in patients. Nontargeted IFNγ induced little or no effects over a range of 0.003 to 250 μg/kg. Studies on the mechanism of action showed that low doses of targeted IFNγ could activate tumor necrosis factor (TNF)-dependent antitumor mechanisms, whereas high doses of either targeted or nontargeted IFNγ induced soluble TNF-receptor shedding in circulation, a known counterregulatory mechanism of TNF activity. These findings suggest that antitumor activity and counterregulatory mechanisms could be uncoupled by tumor vascular targeting with extremely low doses of IFNγ.
EMP3, a Myelin-Related Gene Located in the Critical 19q13.3 Region, Is Epigenetically Silenced and Exhibits Features of a Candidate Tumor Suppressor in Glioma and Neuroblastoma
Authors: Alaminos Miguel , Dávalos Verónica , Ropero Santiago , Setién Fernando , Paz Maria F. , Herranz Michel , Fraga Mario F. , Mora Jaume , Cheung Nai-Kong V. , Gerald William L. , Esteller Manel 
Published: September 2005

Abstract
The presence of common genomic deletions in the 19q13 chromosomal region in neuroblastomas and gliomas strongly suggests the presence of a putative tumor suppressor gene for these neoplasms in this region that, despite much effort, has not yet been identified. In an attempt to address this issue, we compared the expression profile of 89 neuroblastoma tumors with that of benign ganglioneuromas by microarray analysis. Probe sets (637 of 62,839) were significantly down-regulated in neuroblastoma tumors, including, most importantly, a gene located at 19q13.3: the epithelial membrane protein 3 (EMP3), a myelin-related gene involved in cell proliferation and cell-cell interactions. We found that EMP3 undergoes hypermethylation-mediated transcriptional silencing in neuroblastoma and glioma cancer cell lines, whereas the use of the demethylating agent 5-aza-2-deoxycytidine restores EMP3 gene expression. Furthermore, the reintroduction of EMP3 into neuroblastoma cell lines displaying methylation-dependent silencing of EMP3 induces tumor suppressor–like features, such as reduced colony formation density and tumor growth in nude mouse xenograft models. Screening a large collection of human primary neuroblastomas (n = 116) and gliomas (n = 41), we observed that EMP3 CpG island hypermethylation was present in 24% and 39% of these tumor types, respectively. Furthermore, the detection of EMP3 hypermethylation in neuroblastoma could be clinically relevant because it was associated with poor survival after the first 2 years of onset of the disease (Kaplan-Meier; P = 0.03) and death of disease (Kendall τ, P = 0.03; r = 0.19). Thus, EMP3 is a good candidate for being the long-sought tumor suppressor gene located at 19q13 in gliomas and neuroblastomas.
A Survivin Gene Signature Predicts Aggressive Tumor Behavior
Authors: Salz Whitney , Eisenberg Dan , Plescia Janet , Garlick David S. , Weiss Robert M. , Wu Xue-Ru , Sun Tung-Tien , Altieri Dario C. 
Published: September 2005

Abstract
Gene signatures that predict aggressive tumor behavior at the earliest stages of disease, ideally before overt tissue abnormalities, are urgently needed. To search for such genes, we generated a transgenic model of survivin, an essential regulator of cell division and apoptosis overexpressed in cancer. Transgenic expression of survivin in the urinary bladder did not cause histologic abnormalities of the urothelium. However, microarray analysis revealed that survivin-expressing bladders exhibited profound changes in gene expression profile affecting extracellular matrix and inflammatory genes. Following exposure to a bladder carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (OH-BBN), survivin transgenic animals exhibited accelerated tumor progression, preferential incidence of tumors as compared with premalignant lesions, and dramatically abbreviated survival. Conversely, transgenic expression of a survivin Thr34→Ala dominant-negative mutant did not cause changes in gene expression or accelerated tumor progression after OH-BBN treatment. Therefore, survivin expression induces global transcriptional changes in the tissue microenvironment that may promote tumorigenesis. Detection of survivin or its associated gene signature may provide an early biomarker of aggressive tumor behavior before the appearance of tissue abnormalities.
β1A Integrin Expression Is Required for Type 1 Insulin-Like Growth Factor Receptor Mitogenic and Transforming Activities and Localization to Focal Contacts
Authors: Goel Hira Lal , Breen Michael , Zhang Jianzhong , Das Ishita , Aznavoorian-Cheshire Sadie , Greenberg Norman M. , Elgavish Ada , Languino Lucia R. 
Published: September 2005

Abstract
The cells' ability to proliferate in response to growth factor stimulation is significantly altered during cancer progression. To investigate the mechanisms underlying these alterations in prostate cancer, the role and expression of β1A integrin and type 1 insulin-like growth factor receptor (IGF-IR), known to contribute to cell proliferation and transformation, were analyzed. Using small interfering RNA oligonucleotides to down-regulate β1A, we show that β1A expression is required for IGF-IR–mediated prostate cancer cell proliferation and anchorage-independent growth. In vivo, using age-matched transgenic adenocarcinoma of mouse prostate (TRAMP) mice at different stages of prostate cancer [prostatic intraepithelial neoplasia, PIN; well-differentiated adenocarcinoma, WD; and poorly differentiated adenocarcinoma, PD], the expression of β1A and of IGF-IR was studied. β1A and IGF-IR expression levels were concurrently up-regulated in high PIN and WD, whereas their expression did not correlate in late-stage PD. In contrast to the up-regulated expression of β1A, the levels of β1C, a β1 cytoplasmic variant that inhibits cell proliferation, were down-regulated in all stages of prostate cancer. A similar expression pattern was observed for a β1C downstream effector, Grb2-associated binder-1 (Gab1) which is known to inhibit IGF-IR phosphorylation. To analyze in vitro the mechanistic implications of β1A, β1C, and Gab1 deregulation in prostate cancer, we investigated whether expression of either β1 variant in β1-null cells affected IGF-IR localization. We found that IGF-IR and β1A were colocalized in highly specialized integrin signaling compartments, designated focal contacts. However, in the presence of β1C, IGF-IR remained diffuse on the cell surface and did not localize to focal contacts. The findings that β1 integrins and IGF-IR are concurrently deregulated and that expression of β1 integrins is necessary to achieve appropriate IGF-IR intracellular distribution point to the important role that the cross-talk between these receptors may have during prostate cancer progression and will be helpful in formulating new therapeutic strategies.
Inability of Transforming Growth Factor-β to Cause SnoN Degradation Leads to Resistance to Transforming Growth Factor-β–Induced Growth Arrest in Esophageal Cancer Cells
Authors: Edmiston Jeffery S. , Yeudall W. Andrew , Chung Theodore D. , Lebman Deborah A. 
Published: September 2005

Abstract
It is well established that loss of a growth inhibitory response to transforming growth factor-β (TGF-β) is a common feature of epithelial cancers including esophageal cancer. However, the molecular basis for the abrogation of this key homeostatic mechanism is poorly understood. In esophageal cancer cell lines that are resistant to TGF-β–induced growth inhibition, TGF-β also fails to decrease transcription of c-myc despite the presence of functional signaling components. Consequently, to gain a better understanding of the mechanisms leading to resistance to TGF-β–induced growth arrest, the basis for the inability to decrease c-myc transcription was investigated. Regardless of sensitivity to TGF-β–induced growth arrest, TGF-β enhanced the ability of Smad3-protein complexes to bind c-myc regulatory elements. However, in a growth inhibition–resistant esophageal cancer cell line, the Smad3-protein complexes contained the SnoN oncoprotein. Furthermore, in esophageal cancer cell lines that are resistant to TGF-β–induced growth arrest, TGF-β does not cause degradation of SnoN. Analyses of the effect of modulating SnoN expression in both growth inhibition–sensitive and growth inhibition–resistant cell lines showed that degradation of SnoN is a prerequisite for both TGF-β–induced repression of c-myc transcription and growth arrest. The data indicate that SnoN-Smad3 complexes do not cause repression of c-myc transcription but rather prevent functionality of active repressor complexes. Thus, these studies reveal a novel mechanism for resistance to TGF-β–induced growth inhibition in esophageal cancer, namely the failure to degrade SnoN. In addition, they show that SnoN can block TGF-β repression of gene transcription.
Plexin D1 Expression Is Induced on Tumor Vasculature and Tumor Cells: A Novel Target for Diagnosis and Therapy?
Authors: Roodink Ilse , Raats Jos , van der Zwaag Bert , Verrijp Kiek , Kusters Benno , van Bokhoven Hans , Linkels Marianne , de Waal Robert M.W. , Leenders William P.J. 
Published: September 2005

Abstract
We previously reported that during mouse embryogenesis, plexin D1 (plxnD1) is expressed on neuronal and endothelial cells. Endothelial cells gradually loose plxnD1 expression during development. Here we describe, using in situ hybridization, that endothelial plxnD1 expression is regained during tumor angiogenesis in a mouse model of brain metastasis. Importantly, we found PLXND1 expression also in a number of human brain tumors, both of primary and metastatic origin. Apart from the tumor vasculature, abundant expression was also found on tumor cells. Via panning of a phage display library, we isolated two phages that carry single-domain antibodies with specific affinity towards a PLXND1-specific peptide. Immunohistochemistry with these single-domain antibodies on the same tumors that were used for in situ hybridization confirmed PLXND1 expression on the protein level. Furthermore, both these phages and the derived antibodies specifically homed to vessels in brain lesions of angiogenic melanoma in mice after i.v. injection. These results show that PLXND1 is a clinically relevant marker of tumor vasculature that can be targeted via i.v. injections.
NBS1 Knockdown by Small Interfering RNA Increases Ionizing Radiation Mutagenesis and Telomere Association in Human Cells
Authors: Zhang Ying , Lim Chang U.K. , Williams Eli S. , Zhou Junqing , Zhang Qinming , Fox Michael H. , Bailey Susan M. , Liber Howard L. 
Published: September 2005

Abstract
Hypomorphic mutations which lead to decreased function of the NBS1 gene are responsible for Nijmegen breakage syndrome, a rare autosomal recessive hereditary disorder that imparts an increased predisposition to development of malignancy. The NBS1 protein is a component of the MRE11/RAD50/NBS1 complex that plays a critical role in cellular responses to DNA damage and the maintenance of chromosomal integrity. Using small interfering RNA transfection, we have knocked down NBS1 protein levels and analyzed relevant phenotypes in two closely related human lymphoblastoid cell lines with different p53 status, namely wild-type TK6 and mutated WTK1. Both TK6 and WTK1 cells showed an increased level of ionizing radiation–induced mutation at the TK and HPRT loci, impaired phosphorylation of H2AX (γ-H2AX), and impaired activation of the cell cycle checkpoint regulating kinase, Chk2. In TK6 cells, ionizing radiation–induced accumulation of p53/p21 and apoptosis were reduced. There was a differential response to ionizing radiation–induced cell killing between TK6 and WTK1 cells after NBS1 knockdown; TK6 cells were more resistant to killing, whereas WTK1 cells were more sensitive. NBS1 deficiency also resulted in a significant increase in telomere association that was independent of radiation exposure and p53 status. Our results provide the first experimental evidence that NBS1 deficiency in human cells leads to hypermutability and telomere associations, phenotypes that may contribute to the cancer predisposition seen among patients with this disease.
Identification of Novel Small Molecule Inhibitors of Hypoxia-Inducible Factor-1 That Differentially Block Hypoxia-Inducible Factor-1 Activity and Hypoxia-Inducible Factor-1α Induction in Response to Hypoxic Stress and Growth Factors
Authors: Chau Noan-Minh , Rogers Paul , Aherne Wynne , Carroll Veronica , Collins Ian , McDonald Edward , Workman Paul , Ashcroft Margaret 
Published: September 2005

Abstract
Hypoxia-inducible factor-1 (HIF-1) is a transcriptional complex that is activated in response to hypoxia and growth factors. HIF-1 plays a central role in tumor progression, invasion, and metastasis. Overexpression of the HIF-1α subunit has been observed in many human cancers and is associated with a poor prognostic outcome with conventional treatments. Targeting HIF-1 using novel small molecule inhibitors is, therefore, an attractive strategy for therapeutic development. We have generated U2OS human osteosarcoma cells stably expressing a luciferase reporter construct under the control of a hypoxia response element (U2OS-HRE-luc). The U2OS-HRE-luc cells were robustly and reproducibly sensitive to hypoxic stress in a HIF-1–dependent manner. We developed an automated U2OS-HRE-luc cell-based assay that was used in a high-throughput screen to identify compounds that inhibited HIF-1 activity induced by treatment with the hypoxia mimetic, deferoxamine mesylate. We performed a pilot screen of the National Cancer Institute Diversity Set of 2,000 compounds. We identified eight hit compounds, six of these were also identified by Rapisarda et al. in an independent hypoxia screen. However, there were two novel hit compounds, NSC-134754 and NSC-643735, that did not significantly inhibit constitutive luciferase activity in U2OS cells (U2OS-luc). We showed that both NSC-134754 and NSC-643735 significantly inhibited HIF-1 activity and HIF-1α protein induced by deferoxamine mesylate. Interestingly, NSC-134754 but not NCS-643735 inhibited HIF-1 activity and HIF-1α protein induced by hypoxia and significantly inhibited Glut-1 expression. Finally, we showed that both NCS-134754 and NCS-643735 inhibited HIF-1α protein induced by insulin-like growth factor-1. Our cell-based assay approach has successfully identified novel compounds that differentially target hypoxia and/or growth factor–mediated induction of HIF-1α.
ABCG2 Harboring the Gly482 Mutation Confers High-Level Resistance to Various Hydrophilic Antifolates
Authors: Shafran Assaf , Ifergan Ilan , Bram Eran , Jansen Gerrit , Kathmann Ietje , Peters Godefridus J. , Robey Robert W. , Bates Susan E. , Assaraf Yehuda G. 
Published: September 2005

Abstract
ABCG2 is an ATP-binding cassette transporter that confers resistance to various chemotherapeutic agents. Recent studies have established that an Arg (wild-type) to Gly mutation at amino acid 482 in ABCG2 alters substrate specificity. Here, we explored the role of this G482 mutation in antifolate resistance using a clinically relevant 4-hour drug exposure. Stable transfectants overexpressing the mutant G482 transporter displayed 120-, 1,000-, and &gt;6,250-fold resistance to the antifolates methotrexate, GW1843, and Tomudex, respectively, relative to parental human embryonic kidney cells. Moreover, although overexpressing equal transporter levels at the plasma membrane, G482-ABCG2 cells were 6-, 23-, and &gt;521-fold more resistant to methotrexate, GW1843, and Tomudex, respectively, than R482-ABCG2 cells. In contrast, upon a continuous (72-hour) drug exposure, both the G482- and R482-ABCG2 cells lost almost all their antifolate resistance; this result was consistent with the inability of ABCG2 to extrude long-chain antifolate polyglutamates. Ko143, a specific and potent ABCG2 inhibitor reversed methotrexate resistance in both G482- and R482-ABCG2 cells. Consistently, whereas the pool of free methotrexate in parental human embryonic kidney cells was prominent after 4 hours of transport with 1 μmol/L [3H]methotrexate, in R482- and G482-ABCG2 cells, it was minimal. Furthermore, G482-ABCG2 cells contained marked decreases in the di- and triglutamate species of [3H]methotrexate at 4 hours of incubation with methotrexate and in the tetra- and pentaglutamates at 24 hours. These changes were not associated with any significant decrease in folylypoly-γ-glutamate synthetase activity. These results provide the first evidence that the G482-ABCG2 mutation confers high-level resistance to various hydrophilic antifolates.