bluuebunny/crossref_metadata_2025_split huggingface dataset:
Membrane-Type 4 Matrix Metalloproteinase Promotes Breast Cancer Growth and Metastases
Authors: Chabottaux Vincent , Sounni Nor Eddine , Pennington Caroline J. , English William R. , van den Brûle Frédéric , Blacher Silvia , Gilles Christine , Munaut Carine , Maquoi Erik , Lopez-Otin Carlos , Murphy Gillian , Edwards Dylan R. , Foidart Jean-Michel , Noël Agnès 
Published: May 2006

Abstract
Membrane-type matrix metalloproteinases (MT-MMP) constitute a subfamily of six distinct membrane-associated MMPs. Although the contribution of MT1-MMP during different steps of cancer progression has been well documented, the significance of other MT-MMPs is rather unknown. We have investigated the involvement of MT4-MMP, a glycosylphosphatidylinositol–anchored protease, in breast cancer progression. Interestingly, immunohistochemical analysis shows that MT4-MMP production at protein level is strongly increased in epithelial cancer cells of human breast carcinomas compared with normal epithelial cells. Positive staining for MT4-MMP is also detected in lymph node metastases. In contrast, quantitative reverse transcription-PCR analysis reveals similar MT4-MMP mRNA levels in human breast adenocarcinomas and normal breast tissues. Stable transfection of MT4-MMP cDNA in human breast adenocarcinoma MDA-MB-231 cells does not affect in vitro cell proliferation or invasion but strongly promotes primary tumor growth and associated metastases in RAG-1 immunodeficient mice. We provide for the first time evidence that MT4-MMP overproduction accelerates in vivo tumor growth, induces enlargement of i.t. blood vessels, and is associated with increased lung metastases. These results identify MT4-MMP as a new putative target to design anticancer strategies. (Cancer Res 2006; 66(10): 5165-72)
Keratoepithelin Suppresses the Progression of Experimental Human Neuroblastomas
Authors: Becker Jürgen , Erdlenbruch Bernhard , Noskova Ievgeniia , Schramm Alexander , Aumailley Monique , Schorderet Daniel F. , Schweigerer Lothar 
Published: May 2006

Abstract
Neuroblastoma is the most common extracranial childhood tumor. High expression of activin A is associated with a favorable prognosis, but the contributing mechanisms have remained unclear. Our previous demonstration of the activin A–mediated up-regulation of keratoepithelin led to the consideration that keratoepithelin could modulate neuroblastoma growth and/or progression. We report here that enhanced keratoepithelin expression in human neuroblastoma cells suppresses neuroblastoma cell cohesion and adhesion to various extracellular matrix proteins and that it inhibits neuroblastoma cell proliferation and invasion in vitro and in vivo. Using microarray analysis, we identified several keratoepithelin-regulated genes that may contribute to these biological changes. Together with the observation that keratoepithelin is expressed in human neuroblastomas in vivo, our data suggest that keratoepithelin could play a beneficial role in neuroblastoma development and/or progression. (Cancer Res 2006; 66(10): 5314-21)
Resistance to Imatinib of Bcr/Abl P190 Lymphoblastic Leukemia Cells
Authors: Mishra Suparna , Zhang Bin , Cunnick Jess M. , Heisterkamp Nora , Groffen John 
Published: May 2006

Abstract
Around 20% of patients with acute lymphoblastic leukemia are Philadelphia chromosome positive (Ph-positive acute lymphoblastic leukemia) and express the Bcr/Abl tyrosine kinase. Treatment with the tyrosine kinase inhibitor Imatinib is currently standard for chronic myelogenous leukemia, which is also caused by Bcr/Abl. However, Imatinib has shown limited efficacy for treating Ph-positive acute lymphoblastic leukemia. In our study, we have investigated the effect of Imatinib therapy on murine P190 Bcr/Abl lymphoblastic leukemia cells. Three of four cultures were very sensitive to treatment with 5 μmol/L Imatinib. Significant cell death also initially occurred when the same cultures were treated in the presence of stromal support. However, after 6 days, remaining cells started to proliferate vigorously. The Bcr/Abl tyrosine kinase present in the cells that were now able to multiply in the presence of 5 μmol/L Imatinib was still inhibited by the drug. In concordance with this, the Abl ATP-binding pocket domain of Bcr/Abl in the resistant cells did not contain point mutations which would make the protein Imatinib resistant. The effect of stroma in selecting Imatinib-resistant lymphoblasts did not require direct cell-cell contact. SDF-1α could substitute for the presence of stromal cells. Our results show that stroma selects Imatinib-resistant Bcr/Abl P190 lymphoblasts that are less dependent on Bcr/Abl tyrosine kinase activity. Therefore, therapy for Ph-positive acute lymphoblastic leukemia, aimed at interfering with the protective effect of stroma in combination with Imatinib, could be of benefit for the eradication of the leukemic cells. (Cancer Res 2006; 66(10): 5387-93)
DNA Fusion Vaccines Induce Epitope-Specific Cytotoxic CD8+ T Cells against Human Leukemia-Associated Minor Histocompatibility Antigens
Authors: Rice Jason , Dunn Stuart , Piper Karen , Buchan Sarah L. , Moss Paul A. , Stevenson Freda K. 
Published: May 2006

AbstractThe graft-versus-leukemia effect of allogeneic stem-cell transplantation is believed to be mediated by T-cell recognition of minor histocompatibility antigens on recipient cells. For minor histocompatibility antigens HA-1 and HA-2, normal cell expression is restricted to hemopoietic cells, and boosting the immune response to these antigens may potentiate graft-versus-leukemia effect without accompanying graft-versus-host disease. To increase efficacy, expansion of HA-1- or HA-2-specific CTL before transplantation is desirable. However, primary HA-1- or HA-2-specific CTL expanded in vitro are often of low avidity. An alternative approach is to prime specific CTL responses in vivo by vaccination. Clearly, donor vaccination must be safe and specific. We have developed DNA fusion vaccines able to induce high levels of epitope-specific CTL using linked CD4+ T-cell help. The vaccines incorporate a domain of tetanus toxin (DOM) fused to a sequence encoding a candidate MHC class I binding peptide. This design generates antitumor CD8+ T-cell responses and protective immunity in preclinical models. For clinical application, we constructed vaccines encoding HLA-A*0201-restricted peptides from human HA-1 and HA-2, which were fused to DOM, and tested their performance in HLA-A*0201-transgenic mice. Priming induced epitope-specific, IFNγ-producing CD8+ T cells with cytotoxic function boosted to high levels with electroporation. Strikingly, these mouse T cells efficiently killed human lymphoblastoid cell lines expressing endogenous HA-1 or HA-2. High avidity is indicated by the independence of cytolysis from CD8/MHC class I interaction. These safe epitope-specific vaccines offer a potential strategy to prime HA-1- or HA-2-specific CTL in transplant donors before adoptive transfer. (Cancer Res 2006; 66(10): 5436-42)
BRCA1 Promotes Induction of ssDNA by Ionizing Radiation
Authors: Schlegel Brian P. , Jodelka Francine M. , Nunez Rafael 
Published: May 2006

Abstract
The BRCA1 tumor suppressor contributes to the repair of DNA double-strand breaks (DSB) through homologous recombination, but the mechanism is unknown. The rapid accumulation of BRCA1 into nuclear foci in response to induction of DNA breaks suggests that BRCA1 may function in an early step in the repair pathway. We examined the role of BRCA1 in one such early step, the resection of DSBs to generate ssDNA. The appearance of ssDNA in response to ionizing radiation is similar to that of BRCA1 foci formation, suggesting that the two processes are related. Furthermore, BRCA1 colocalizes to ssDNA sites induced by ionizing radiation. Overexpression of BRCA1 causes an increase in cells exhibiting ssDNA induced by ionizing radiation. Mutant BRCA1 that lacks the COOH-terminal BRCT domain also promotes ssDNA but fails to form nuclear foci. Knockdown of BRCA1 expression reduces ssDNA and Rad51 foci formation in response to ionizing radiation. These results indicate that BRCA1 promotes induction of ssDNA in response to ionizing radiation and accumulates at sites of ssDNA. (Cancer Res 2006; 66(10): 5181-9)
Identification of Candidate Alkylator-Induced Cancer Susceptibility Genes by Whole Genome Scanning in Mice
Authors: Fenske Timothy S. , McMahon Christine , Edwin Deepa , Jarvis Joseph C. , Cheverud James M. , Minn Matthew , Mathews Vikram , Bogue Molly A. , Province Michael A. , McLeod Howard L. , Graubert Timothy A. 
Published: May 2006

Abstract
Secondary malignancies are a serious adverse consequence of alkylator chemotherapy. The risk of developing an alkylator-associated malignancy is influenced by genetic background, although the relevant genetic factors are poorly understood. To screen for novel susceptibility factors, we established a mouse model of alkylator-induced malignancy. We exposed mice from 20 inbred strains to the prototypical alkylating agent, N-nitroso-N-ethylurea (ENU). ENU was a potent carcinogen in many of the strains tested, inducing 140 tumors in 240 ENU-treated mice (66% incidence of at least one tumor in evaluable mice), compared with a background incidence of 8% spontaneous tumors in 240 strain-, age-, and sex-matched control mice (relative risk, 8.4; P &lt; 0.0001). A wide variety of tumor histologies were noted, including epithelial carcinomas, soft tissue sarcomas, and hematopoietic tumors. Cancer susceptibility was a heritable trait for the most common tumor types, lung adenocarcinoma (H2 = 0.25), T cell lymphoma (H2 = 0.19), and myeloid malignancies (H2 = 0.10). Quantitative trait locus mapping identified regions on chromosomes 3, 6, 9, and 15 containing candidate genes associated with lung adenoma, lung carcinoma, and lymphoma susceptibility. This novel mouse model recapitulates many features of human alkylator-associated cancer and supports the hypothesis that susceptibility to this syndrome is influenced by inherited polymorphisms that could be used to make informed clinical treatment decisions. (Cancer Res 2006; 66(10): 5029-38)
Intratumor CD4 T-Cell Accumulation Requires Stronger Priming than for Expansion and Lymphokine Secretion
Authors: Joncker Nathalie T. , Helft Julie , Jacquet Alexandra , Premel Virginie , Lantz Olivier 
Published: May 2006

AbstractT cells need to migrate to and accumulate inside tumors before mediating rejection of the tumor. The number of specific T cells inside tumors may depend on the efficiency of priming in the draining lymph node (DLN), intratumor deletion, suppressive phenomena, or both. We used monoclonal anti-male antigen CD4 (Marilyn) T cells and tumor cell lines expressing or not the corresponding antigen (Dby) to analyze CD4 T-cell accumulation in tumors. Priming by MHC II+ or MHC II− male splenocytes or Dby+ tumor cells induced similar Marilyn T-cell expansion in the DLN and recirculation in other lymph nodes and capacity to produce IFN-γ. However, intratumor accumulation was different for each priming condition. In mice with Dby− tumors, MHC II+ male splenocyte priming induced greater, although not statistically significant, Marilyn T-cell accumulation in the tumors than MHC II− male splenocyte priming. In mice with Dby+ tumors, priming in the tumor DLN induced less Marilyn T-cell intratumor accumulation than priming by MHC II+ male splenocytes. We saw comparable differences for Marilyn T-cell accumulation in gut lamina propria, suggesting that priming affects effector T-cell accumulation in inflamed tissues. Mature dendritic cells were loaded with graded doses of Dby peptide to control for antigen-presenting cell characteristics during priming. We observed similar proliferation, with higher concentrations inducing higher intratumor accumulation. Thus, intratumor accumulation requires stronger stimulation than for proliferation or the capacity to secrete lymphokines. In this system, priming intensity alone can explain the number of intratumor T cells without having to call for intratumor deletion or suppression phenomena. (Cancer Res 2006; 66(10): 5443-51)
Lack of Rb and p53 Delays Cerebellar Development and Predisposes to Large Cell Anaplastic Medulloblastoma through Amplification of N-Myc and Ptch2
Authors: Shakhova Olga , Leung Carly , van Montfort Erwin , Berns Anton , Marino Silvia 
Published: May 2006

Abstract
Medulloblastomas are among the most common malignant brain tumors in childhood. They typically arise from neoplastic transformation of granule cell precursors in the cerebellum via deregulation of molecular pathways involved in normal cerebellar development. In a mouse model, we show here that impairment of the balance between proliferation and differentiation of granule cell precursors in the external granular layer of the developing cerebellum predisposes but is not sufficient to induce neoplastic transformation of these progenitor cells. Using array-based chromosomal comparative genomic hybridization, we show that genetic instability resulting from inactivation of the p53 pathway together with deregulation of proliferation induced by Rb loss eventually leads to neoplastic transformation of these cells by acquiring additional genetic mutations, mainly affecting N-Myc and Ptch2 genes. Moreover, we show that p53 loss influences molecular mechanisms that cannot be mimicked by the loss of either p19ARF, p21, or ATM. (Cancer Res 2006; 66(10): 5190-200)
Activator Protein-2 Overexpression Accounts for Increased Insulin Receptor Expression in Human Breast Cancer
Authors: Paonessa Francesco , Foti Daniela , Costa Vanessa , Chiefari Eusebio , Brunetti Giuseppe , Leone Francesco , Luciano Francesco , Wu Frank , Lee Amy S. , Gulletta Elio , Fusco Alfredo , Brunetti Antonio 
Published: May 2006

Abstract
Various studies have shown that the insulin receptor (IR) is increased in most human breast cancers, and both ligand-dependent malignant transformation and increased cell growth occur in cultured breast cells overexpressing the IR. However, although numerous in vivo and in vitro observations have indicated an important contributory role for the IR in breast cancer cell biology, the molecular mechanisms accounting for increased IR expression in breast tumors have not previously been elucidated. Herein, we did immunoblot analyses of nuclear protein from cultured breast cancer cells and normal and tumoral tissues from breast cancer patients combined with promoter studies by using a series of human wild-type and mutant IR promoter constructs. We provide evidence that IR overexpression in breast cancer is dependent on the assembly of a transcriptionally active multiprotein-DNA complex, which includes the high-mobility group A1 (HMGA1) protein, the developmentally regulated activator protein-2 (AP-2) transcription factor and the ubiquitously expressed transcription factor Sp1. In cultured breast cancer cells and human breast cancer specimens, the expression of AP-2 was significantly higher than that observed in cells and tissues derived from normal breast, and this overexpression paralleled the increase in IR expression. However, AP-2 DNA-binding activity was undetectable with the IR gene promoter, suggesting that transactivation of this gene by AP-2 might occur indirectly through physical and functional cooperation with HMGA1 and Sp1. Our findings support this hypothesis and suggest that in affected individuals, hyperactivation of the AP-2 gene through the overexpression of IR may play a key role in breast carcinogenesis. (Cancer Res 2006; 66(10): 5085-93)
PTEN/Akt Signaling through Epidermal Growth Factor Receptor Is Prerequisite for Angiogenesis by Hepatocellular Carcinoma Cells That Is Susceptible to Inhibition by Gefitinib
Authors: Ueda Shu-ichi , Basaki Yuji , Yoshie Masumi , Ogawa Katsuhiro , Sakisaka Shotaro , Kuwano Michihiko , Ono Mayumi 
Published: May 2006

Abstract
Hepatocellular carcinoma (HCC) is one of the most common tumor-related causes of death worldwide for which there is still no satisfactory treatment. We previously reported the antiangiogenic effect of gefitinib, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been used successfully to treat lung cancer. In this study, we investigated the effects of gefitinib on tumor-induced angiogenesis by using HCC cell lines (HCC3, CBO12C3, and AD3) in vitro as well as in vivo. Oral administration of gefitinib inhibited angiogenesis induced by HCC3 and CBO12C3, but not by AD3 in the mouse dorsal air sac model. Production of both vascular endothelial growth factor (VEGF) and chemokine C-X-C motif ligand 1 (CXCL1) by EGF-stimulated HCC was more markedly inhibited by gefitinib in HCC3 and CBO12C3 cells than in AD3 cells. EGF stimulated the phosphorylation of EGFR, Akt, and extracellular signal-regulated kinase 1/2 (ERK1/2) in HCC3 and CBO12C3 cells, whereas EGF stimulated phosphorylation of EGFR and ERK1/2, but not Akt in AD3 cells. In fact, Akt was constitutively activated in the absence of EGF in AD3 cells. Gefitinib inhibited Akt phosphorylation in all three cell lines, but it was about five times less effective in AD3 cells. The concentration of PTEN in AD3 cells was about a half that in HCC3 and CBO12C3 cells. Transfection of HCC3 cells with PTEN small interfering RNA reduced their sensitivity to gefitinib in terms of its inhibitory effect on both Akt phosphorylation and the production of VEGF and CXCL1. In conclusion, effect of gefitinib on HCC-induced angiogenesis depends on its inhibition of the production of angiogenic factors, probably involving a PTEN/Akt signaling pathway. (Cancer Res 2006; 66(10): 5346-53)
Differentially Active Origins of DNA Replication in Tumor versus Normal Cells
Authors: Di Paola Domenic , Price Gerald B. , Zannis-Hadjopoulos Maria 
Published: May 2006

Abstract
Previously, a degenerate 36 bp human consensus sequence was identified as a determinant of autonomous replication in eukaryotic cells. Random mutagenesis analyses further identified an internal 20 bp of the 36 bp consensus sequence as sufficient for acting as a core origin element. Here, we have located six versions of the 20 bp consensus sequence (20mer) on human chromosome 19q13 over a region spanning ∼211 kb and tested them for ectopic and in situ replication activity by transient episomal replication assays and nascent DNA strand abundance analyses, respectively. The six versions of the 20mer alone were capable of supporting autonomous replication of their respective plasmids, unlike random genomic sequence of the same length. Furthermore, comparative analyses of the endogenous replication activity of these 20mers at their respective chromosomal sites, in five tumor/transformed and two normal cell lines, done by in situ chromosomal DNA replication assays, involving preparation of nascent DNA by the λ exonuclease method and quantification by real-time PCR, showed that these sites coincided with chromosomal origins of DNA replication in all cell lines. Moreover, a 2- to 3-fold higher origin activity in the tumor/transformed cells by comparison to the normal cells was observed, suggesting a higher activation of these origins in tumor/transformed cell lines. (Cancer Res 2006; 66(10): 5094-103)
Doxorubicin plus Interleukin-2 Chemoimmunotherapy against Breast Cancer in Mice
Authors: Ewens Andrew , Luo Liqun , Berleth Erica , Alderfer James , Wollman Robert , Hafeez Bilal Bin , Kanter Peter , Mihich Enrico , Ehrke M. Jane 
Published: May 2006

Abstract
As recently characterized, following s.c. implantation into syngeneic C57BL/6 mice, E0771 tumor invades locally into dermal layers and peritoneum, metastasizes to the lung, and induces a nonspecific immunosuppression in the host. Using this breast medullar adenocarcinoma model, a therapy consisting of a single moderate dose of doxorubicin followed by twice daily moderate doses of interleukin-2 for 30 days was examined for efficacy and mechanism of action when given to animals with established disease. This combination treatment, but not combinants alone, resulted in tumor-free long-term survival of 40% of the mice without significant toxicity and 83% of survivors had immune memory specific for E0771 cells. Treatment also decreased immune suppression induced by E0771 tumor. Full response to treatment required functional CD8+ T cells, whereas depletion of natural killer cells caused only a reduction in response rate. A serum “biomarker” profile that correlated with, and seemed predictive of, response to treatment was identified by nuclear magnetic resonance–based metabonomic analysis. The efficacy of this nontoxic treatment and the potential to be able to predict which individual is responding to treatment are characteristics that make this chemoimmunotherapy attractive for clinical testing. (Cancer Res 2006; 66(10): 5419-26)
Vaccination with Human HER-2/neu(435-443) CTL Peptide Induces Effective Antitumor Immunity against HER-2/neu-Expressing Tumor CellsIn vivo
Authors: Gritzapis Angelos D. , Mahaira Louisa G. , Perez Sonia A. , Cacoullos Nike T. , Papamichail Michael , Baxevanis Constantin N. 
Published: May 2006

AbstractHER-2/neu is a self-antigen expressed by tumors and nonmalignant epithelial tissues. The possibility of self-tolerance to HER-2/neu-derived epitopes has raised questions concerning their utility in antitumor immunotherapy. Altered HER-2/neu peptide ligands capable of eliciting enhanced immunity to tumor-associated HER-2/neu epitopes may circumvent this problem. The human CTL peptide HER-2/neu (435-443) [hHER-2(9435)] represents a xenogeneic altered peptide ligand of its mouse homologue, differing by one amino acid residue at position 4. In contrast to mHER-2(9435), vaccination of HLA-A*0201 transgenic (HHD) mice with hHER-2(9435) significantly increased the frequency of mHER-2(9435)-specific CTL and also induced strong protective and therapeutic immunity against the transplantable ALC tumor cell line transfected to coexpress HLA-A*0201 and hHER-2/neu or rHER-2/neu. Similar results were also obtained with wild-type C57BL/6 mice inoculated with HER-2/neu transfectants of ALC. Adoptive transfer of CD8+ CTL from mice immunized with hHER-2(9435) efficiently protected naive syngeneic mice inoculated with ALC tumors. In conclusion, our results show that HER-2(9435) serves as a tumor rejection molecule. They also propose a novel approach for generating enhanced immunity against a self-HER-2/neu CTL epitope by vaccinating with xenogeneic altered peptide ligands and provide useful insights for the design of improved peptide-based vaccines for the treatment of patients with HER-2/neu-overexpressing tumors. (Cancer Res 2006; 66(10): 5452-60)
Role of Macrophage Inhibitory Cytokine-1 in Tumorigenesis and Diagnosis of Cancer
Authors: Bauskin Asne R. , Brown David A. , Kuffner Tamara , Johnen Heiko , Luo X. Wei , Hunter Mark , Breit Samuel N. 
Published: May 2006

Abstract
Macrophage inhibitory cytokine-1 (MIC-1), a transforming growth factor-β superfamily cytokine, is involved in tumor pathogenesis, and its measurement can be used as a clinical tool for the diagnosis and management of a wide range of cancers. Although generally considered to be part of the cell's antitumorigenic repertoire, MIC-1 secretion, processing, and latent storage suggest a complex, dynamic variability in MIC-1 bioavailability in the tumor microenvironment, potentially modulating tumor progression and invasiveness. (Cancer Res 2006; 66(10): 4983-5)