bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regression of Latent Endometrial Precancers by Progestin Infiltrated Intrauterine Device
Authors: Ørbo Anne , Rise Cecil E. , Mutter George L. 
Published: June 2006

Abstract
PTEN tumor suppressor inactivation is the earliest step in endometrial carcinogenesis, occurring in morphologically unremarkable endometrial glands in half of normal women. We test the hypothesis that sex hormones positively or negatively select for these “latent precancers” by examining their emergence, persistence, and regression rates under differing hormonal conditions. Perimenopausal and postmenopausal women had an intake endometrial biopsy and underwent hormonal therapy with progestin-impregnated intrauterine device (IUD; n = 21), cyclic oral progestins (n = 28), or surveillance only (n = 22) with follow-up biopsies. For comparison, premenopausal naturally cycling endometrial biopsies were studied as single time points in 87 patients and multiple surveillance time points in 34 patients. Biopsies in which any PTEN protein-null glands were found by immunohistochemistry were scored as containing a latent endometrial precancer. All groups had a similar proportion of latent precancers at intake but differed after therapy. Emergence rates were highest (21%) for the naturally cycling premenopausal group compared with just 9% for untreated perimenopausal women. The IUD group had the highest rate of regression, with a 62% pretherapy and 5% post-therapy rate of latent precancers. This contrasted to nonsignificant changes for the oral progestin and untreated control groups. Delivery of high doses of progestins locally to the endometrium by IUD leads to ablation of preexisting PTEN-inactivated endometrial latent precancers and is a possible mechanism for reduction of long-term endometrial cancer risk known to occur in response to this hormone. (Cancer Res 2006; 66(11): 5613-7)
Mutation of Tumor Suppressor Gene Men1 Acutely Enhances Proliferation of Pancreatic Islet Cells
Authors: Schnepp Robert W. , Chen Ya-Xiong , Wang Haoren , Cash Tim , Silva Albert , Diehl J. Alan , Brown Eric , Hua Xianxin 
Published: June 2006

Abstract
Multiple endocrine neoplasia type 1 (MEN1), an inherited tumor syndrome affecting endocrine organs including pancreatic islets, results from mutation of the tumor suppressor gene Men1 that encodes protein menin. Although menin is known to be involved in regulating cell proliferation in vitro, it is not clear how menin regulates cell cycle and whether mutation of Men1 acutely promotes pancreatic islet cell proliferation in vivo. Here we show that excision of the floxed Men1 in mouse embryonic fibroblasts (MEF) accelerates G0/G1 to S phase entry. This accelerated S-phase entry is accompanied by increased cyclin-dependent kinase 2 (CDK2) activity as well as decreased expression of CDK inhibitors p18Ink4c and p27Kip1. Moreover, Men1 excision results in decreased expression of p18Ink4c and p27Kip1 in the pancreas. Furthermore, complementation of menin-null cells with wild-type menin represses S-phase entry. To extend the role of menin in repressing cell cycle in cultured cells to in vivo pancreatic islets, we generated a system in which floxed Men1 alleles can be excised in a temporally controllable manner. As early as 7 days following Men1 excision, pancreatic islet cells display increased proliferation, leading to detectable enlargement of pancreatic islets 14 days after Men1 excision. These observations are consistent with the notion that an acute effect of Men1 mutation is accelerated S-phase entry and enhanced cell proliferation in pancreatic islets. Together, these results suggest a molecular mechanism whereby menin suppresses MEN1 tumorigenesis at least partly through repression of G0/G1 to S transition. (Cancer Res 2006; 66(10): 5707-15)
Emodin Inhibits Tumor Cell Adhesion through Disruption of the Membrane Lipid Raft-Associated Integrin Signaling Pathway
Authors: Huang Qing , Shen Han-Ming , Shui Guanghou , Wenk Markus R. , Ong Choon-Nam 
Published: June 2006

Abstract
Cell adhesion and spreading is a crucial step in the metastatic cascade of cancer cells, and interruption of this step is considered to be a logical strategy for prevention and treatment of tumor metastasis. Emodin is the major active component of the rhizome of Rheum palmatum L., with known anticancer activities. Here, we first found that emodin significantly inhibited cell adhesion of various human cancer cells. This inhibition was achieved through suppressing the recruitment of focal adhesion kinase (FAK) to integrin β1 as well as the phosphorylation of FAK followed by the decreased formation of focal adhesion complex (FAC). In understanding the underlying mechanisms, we found that emodin inhibited the lipid raft clustering and subsequent colocalization of integrin β1 and FAC proteins within lipid rafts. Lipid profile analysis revealed significant decrease of cholesterol and sphingolipids in raft fraction after emodin treatment. Cholesterol replenishment abolished the adverse effect of emodin on the translocation of integrin β1 and FAC proteins into the lipid raft fraction and cell adhesion. Therefore, data from this study provide novel evidence that emodin inhibits cell adhesion and spreading through disruption of the membrane lipid raft-associated integrin signaling pathway. (Cancer Res 2006; 66(11): 5807-15)
Generation of Antitumor Responses by Genetic Modification of Primary Human T Cells with a Chimeric NKG2D Receptor
Authors: Zhang Tong , Barber Amorette , Sentman Charles L. 
Published: June 2006

AbstractTo create more effective T cells against human tumors, we have designed a strategy to allow T cells to recognize tumor cells using natural killer (NK) cell receptors but retain the effector responses of T lymphocytes. NKG2D is an activating cell surface receptor expressed on NK cells and on some T-cell subsets. Its ligands are primarily expressed on tumor cells. We have shown that by linking mouse NKG2D to the CD3ζ chain, it was possible to generate a chimeric NKG2D (chNKG2D) receptor that allowed activation of murine T cells on engagement with NKG2D ligand-positive tumor cells leading to antitumor responses in mice. In this study, a human version of the chNKG2D receptor was expressed on primary human T cells, and antitumor responses were determined. Human peripheral blood mononuclear cell–derived T cells were retrovirally transduced with a human chNKG2D receptor gene. These chNKG2D-bearing human T cells responded to NKG2D ligand-positive tumor cells by producing T-helper 1 cytokines, proinflammatory chemokines, and significant cellular cytotoxicity. This response could be blocked by anti-NKG2D antibodies, and it was dependent on NKG2D ligand expression on the target cells but not on expression of MHC molecules. In addition, the activity of chNKG2D-bearing T cells remained unimpaired after exposure to a soluble NKG2D ligand, soluble MICA, at concentrations as high as 1.5 μg/mL. These data indicate the feasibility of using chNKG2D receptors in primary human T cells and suggest that this approach may be a promising means for cancer immunotherapy. (Cancer Res 2006; 66(11): 5927-33)
Identification of Specific Gene Copy Number Changes in Asbestos-Related Lung Cancer
Authors: Nymark Penny , Wikman Harriet , Ruosaari Salla , Hollmén Jaakko , Vanhala Esa , Karjalainen Antti , Anttila Sisko , Knuutila Sakari 
Published: June 2006

Abstract
Asbestos is a well-known lung cancer-causing mineral fiber. In vitro and in vivo experiments have shown that asbestos can cause chromosomal damage and aberrations. Lung tumors, in general, have several recurrently amplified and deleted chromosomal regions. To investigate whether a distinct chromosomal aberration profile could be detected in the lung tumors of heavily asbestos-exposed patients, we analyzed the copy number profiles of 14 lung tumors from highly asbestos-exposed patients and 14 matched tumors from nonexposed patients using classic comparative genomic hybridization (CGH). A specific profile could lead to identification of the underlying genes that may act as mediators of tumor formation and progression. In addition, array CGH analyses on cDNA microarrays (13,000 clones) were carried out on 20 of the same patients. Classic CGH showed, on average, more aberrations in asbestos-exposed than in nonexposed patients, and an altered region in chromosome 2 seemed to occur more frequently in the asbestos-exposed patients. Array CGH revealed aberrations in 18 regions that were significantly associated with either of the two groups. The most significant regions were 2p21-p16.3, 5q35.3, 9q33.3-q34.11, 9q34.13-q34.3, 11p15.5, 14q11.2, and 19p13.1-p13.3 (P &lt; 0.005). Furthermore, 11 fragile sites coincided with the 18 asbestos-associated regions (P = 0.08), which may imply preferentially caused DNA damage at these sites. Our findings are the first evidence, indicating that asbestos exposure may produce a specific DNA damage profile. (Cancer Res 2006; 66(11): 5737-43)
Specific Recruitment of CC Chemokine Receptor 4–Positive Regulatory T Cells in Hodgkin Lymphoma Fosters Immune Privilege
Authors: Ishida Takashi , Ishii Toshihiko , Inagaki Atsushi , Yano Hiroki , Komatsu Hirokazu , Iida Shinsuke , Inagaki Hiroshi , Ueda Ryuzo 
Published: June 2006

AbstractHodgkin lymphoma (HL) is characterized by the presence of a small number of tumor cells in a rich background of inflammatory cells, but the contribution of the abundant nontumor cells to HL pathogenesis is poorly understood. We showed that migratory CD4+ cells induced by HL cells were hyporesponsive to T-cell receptor stimulation and suppressed the activation/proliferation of the effector CD4+ T cells in an autologous setting. We further showed that HL cells in the affected lymph nodes were surrounded by a large number of lymphocytes expressing both CC chemokine receptor 4 (CCR4) and FOXP3. These findings indicate that the migratory cells induced by HL cells function as regulatory T (Treg) cells so that these cells create a favorable environment for the tumor cells to escape from host immune system. In addition, we showed that a chimeric anti-CCR4 monoclonal antibody (mAb) could deplete CCR4+ T cells and inhibit the migration of CD4+CD25+ T cells in vitro. Recognition of the importance of CCR4+ Treg cells in the pathogenesis of HL will allow rational design of more effective treatments, such as use of an anti-CCR4 mAb, to overcome the suppressive effect of CCR4+ Treg cells on the host immune response to tumor cells. (Cancer Res 2006; 66(11): 5716-22)
Identification of Interleukin-13 Receptor α2 Peptide Analogues Capable of Inducing Improved Antiglioma CTL Responses
Authors: Eguchi Junichi , Hatano Manabu , Nishimura Fumihiko , Zhu Xinmei , Dusak Jill E. , Sato Hidemitsu , Pollack Ian F. , Storkus Walter J. , Okada Hideho 
Published: June 2006

AbstractRestricted and high-level expression of interleukin-13 receptor α2 (IL-13Rα2) in a majority of human malignant gliomas makes this protein an attractive vaccine target. We have previously described the identification of the IL-13Rα2345-353 peptide as a human leukocyte antigen-A2 (HLA-A2)–restricted CTL epitope. However, as it remains unclear how efficiently peptide-based vaccines can induce specific CTLs in patients with malignant gliomas, we have examined whether analogue epitopes could elicit heteroclitic antitumor T-cell responses versus wild-type peptides. We have created three IL-13Rα2 analogue peptides by substitutions of the COOH-terminal isoleucine (I) for valine (V) and the NH2-terminal tryptophan (W) for either alanine (A), glutamic acid (E), or nonsubstituted (W; designated as 1A9V, 1E9V, and 9V, respectively). In comparison with the native IL-13Rα2 epitope, the analogue peptides 9V and 1A9V displayed higher levels of binding affinity and stability in HLA-A2 complexes and yielded an improved stimulatory index for patient-derived, specific CTLs against the native epitope expressed by HLA-A2+ glioma cells. In HLA-A2-transgenic HHD mice, immunization with the peptides 9V and 1A9V induced enhanced levels of CTL reactivity and protective immunity against an intracranial challenge with IL13Rα2-expressing syngeneic tumors when compared with vaccines containing the native IL-13Rα2 epitope. These findings indicate highly immunogenic IL-13Rα2 peptide analogues may be useful for the development of vaccines capable of effectively expanding IL-13Rα2-specific, tumor-reactive CTLs in glioma patients. (Cancer Res 2006; 66(11): 5883-91)
Developmental Exposure to Estradiol and Bisphenol A Increases Susceptibility to Prostate Carcinogenesis and Epigenetically Regulates Phosphodiesterase Type 4 Variant 4
Authors: Ho Shuk-Mei , Tang Wan-Yee , Belmonte de Frausto Jessica , Prins Gail S. 
Published: June 2006

Abstract
Early developmental perturbations have been linked to adult-onset prostate pathology, including excessive exposure to estrogenic compounds; however, the molecular basis for this imprinting event is not known. An important and controversial health concern is whether low-dose exposures to hormonally active environmental estrogens, such as bisphenol A, can promote human diseases, including prostate cancer. Here, we show that transient developmental exposure of rats to low, environmentally relevant doses of bisphenol A or estradiol increases prostate gland susceptibility to adult-onset precancerous lesions and hormonal carcinogenesis. We found permanent alterations in the DNA methylation patterns of multiple cell signaling genes, suggesting an epigenetic basis for estrogen imprinting. For phosphodiesterase type 4 variant 4 (PDE4D4), an enzyme responsible for cyclic AMP breakdown, a specific methylation cluster was identified in the 5′-flanking CpG island that was gradually hypermethylated with aging in normal prostates, resulting in loss of gene expression. Early and prolonged hypomethylation at this site following neonatal estradiol or bisphenol A exposure resulted in continued, elevated PDE4D4 expression. Cell line studies confirmed that site-specific methylation is involved in transcriptional silencing of the PDE4D4 gene and showed hypomethylation of this gene in prostate cancer cells. Importantly, the PDE4D4 alterations in the estrogen-exposed prostates were distinguishable before histopathologic changes of the gland, making PDE4D4 a candidate molecular marker for prostate cancer risk assessment as a result of endocrine disruptors. In total, these findings indicate that low-dose exposures to ubiquitous environmental estrogens affect the prostate epigenome during development and, in so doing, promote prostate disease with aging. (Cancer Res 2006; 66(11): 5624-32)
Mechanistic Investigation and Implications of Photodynamic Therapy Induction of Vascular Endothelial Growth Factor in Prostate Cancer
Authors: Solban Nicolas , Pål Selbo K. , Alok Sinha K. , Sung Chang K. , Hasan Tayyaba 
Published: June 2006

AbstractPhotodynamic therapy (PDT) is now an approved therapeutic modality, and induction of vascular endothelial growth factor (VEGF) following subcurative PDT is of concern as VEGF may provide a survival stimulus to tumors. The processes that limit the efficacy of PDT warrant investigation so that mechanism-based interventions may be developed. This study investigates VEGF increase following subcurative PDT using the photosensitizer benzoporphyrin derivative (BPD) both in an in vitro and in an orthotopic model of prostate cancer using the human prostate cancer cell line LNCaP. The two subcurative doses used, 0.25 and 0.5 J/cm2, mimicked subcurative PDT and elicited a 1.6- and 2.1-fold increase, respectively, in secreted VEGF 24 hours following PDT. Intracellular VEGF protein measurement and VEGF mRNA showed a 1.4- and 1.6-fold increase only at 0.5 J/cm2. In vivo subcurative PDT showed an increase in VEGF by both immunohistochemistry and ELISA. In vitro analysis showed no activation of hypoxia-inducible factor-1α (HIF-1α) or cyclooxygenase-2 (COX-2) following subcurative PDT; furthermore, small interfering RNA inhibition of HIF-1α and COX-2 inhibitor treatment had no effect on PDT induction of VEGF. PDT in the presence of phosphatidylinositol 3-kinase/AKT inhibitor or mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase inhibitor still induced VEGF. However, subcurative PDT increased phosphorylated p38 and stress-activated protein kinase/c-Jun NH2-terminal kinase. The p38 MAPK inhibitor abolished PDT induction of VEGF. The results establish the importance of VEGF in subcurative BPD-PDT of prostate cancer and suggest possible molecular pathways for its induction. These findings should provide the basis for the development of molecular-based interventions for enhancing PDT and merit further studies. (Cancer Res 2006; 66(11):5633-40)
Activation of Abl Tyrosine Kinases Promotes Invasion of Aggressive Breast Cancer Cells
Authors: Srinivasan Divyamani , Plattner Rina 
Published: June 2006

Abstract
The Abl family of nonreceptor tyrosine kinases consists of two related proteins, c-Abl and Abl-related gene (Arg). Activated forms of the Abl kinases (BCR-Abl, Tel-Abl, and Tel-Arg) induce the development of human leukemia; it is not known, however, whether Abl kinases are activated in solid tumors or whether they contribute to tumor development or progression. Previously, we showed that Abl kinases are activated downstream of growth factor receptors, Src family kinases, and phospholipase Cγ1 (PLCγ1) in fibroblasts and influence growth factor–mediated proliferation, membrane ruffling, and migration. Growth factor receptors, Src kinases, and PLCγ1 are deregulated in many solid tumors and drive tumor invasion and metastasis. In this study, we found that Abl kinases are constitutively activated, in highly invasive breast cancer cell lines, downstream of deregulated ErbB receptors and Src kinases. Furthermore, activation of Abl kinases promotes breast cancer cell invasion, as treatment of cells with the Abl kinase inhibitor, STI571, or silencing c-Abl and Arg expression with RNA interference dramatically inhibits Matrigel invasion. This is the first evidence that (a) Abl kinases are deregulated and activated in a nonhematopoietic cancer, (b) activation of Abl kinases in breast cancer cells occurs via a novel mechanism, and (c) constitutive activation of Abl kinases promotes invasion of breast cancer cells. These data suggest that pharmacologic inhibitors targeted against Abl kinases could potentially be useful in preventing breast cancer progression in tumors harboring activated Abl kinases. (Cancer Res 2006; 66(11): 5648-55)
Insulin-Like Growth Factor I Receptor Pathway Inhibition by ADW742, Alone or in Combination with Imatinib, Doxorubicin, or Vincristine, Is a Novel Therapeutic Approach in Ewing Tumor
Authors: Martins Ana S. , Mackintosh Carlos , Martín David Herrero , Campos Maria , Hernández Teresa , Ordóñez Jose-Luis , de Alava Enrique 
Published: June 2006

AbstractPurpose: Ewing tumor cell survival and proliferation depends on several autocrine loops. Targeting these loops is a promising therapeutic approach. We recently showed the cytostatic role of imatinib, an inhibitor of the SCF-KIT loop, on Ewing tumor cells, and in this study, we intend to analyze the inhibition of the insulin-like growth factor I receptor (IGF1R) loop.Experimental Design: We analyzed IGF1R blockade by ADW742, a small molecule specific for this receptor, alone and in combination with imatinib, vincristine, and doxorubicin on Ewing tumor cell lines. We studied the effect on proliferation, apoptosis, cell cycle, pathway phosphorylation, soft-agar growth, motility, and vascular endothelial growth factor expression levels.Results: Treatment with ADW742 induced down-regulation of IGF1R/AKT/mammalian target of rapamycin (mTOR) phosphorylation, which was deeper in cell lines having higher IGF1R activation levels. Treatment also induced dose-dependent inhibition of cell proliferation (IC50 = 0.55-1.4 μmol/L), inducing a G1 phase blockage and apoptosis. Addition of imatinib to ADW742 synergistically augmented these effects and was especially effective in inhibiting AKT/mTOR phosphorylation and reducing vascular endothelial growth factor expression in cell lines having high IGF1R activation levels. Combination with usual chemotherapeutic agents vincristine and doxorubicin showed synergistic interactions.Conclusions: Inhibition of Ewing tumor cell proliferation by ADW742 is mediated through blockade of IGF1R signaling. Combination of ADW742 with imatinib, vincristine, and doxorubicin induces a significant reduction of tumor cell growth, mainly by the increase in apoptosis with a pattern depending on IGF1R activation levels. This study supports a potential role for ADW742 in the treatment of Ewing tumor and AKT/mTOR as a possible surrogate marker of response to therapy.
Sulindac Sulfide and Exisulind Inhibit Expression of the Estrogen and Progesterone Receptors in Human Breast Cancer Cells
Authors: Lim Jin T.E. , Joe Andrew K. , Suzui Masumi , Shimizu Masahito , Masuda Muneyuki , Weinstein I. Bernard 
Published: June 2006

Abstract
In previous studies, we found that sulindac sulfide and exisulind (sulindac sulfone, Aptosyn) cause growth inhibition, arrest cells in the G1 phase of the cell cycle, and induce apoptosis in human breast cancer cell lines. These effects were associated with decreased expression of cyclin D1. The present study focuses on the effects of sulindac sulfide and exisulind on hormone signaling components in breast cancer cells. We found that estrogen receptor (ER)–positive and progesterone receptor (PR)–positive T47D breast cancer cells were somewhat more sensitive to growth inhibition by sulindac sulfide or exisulind than ER-negative PR-negative MB-MDA-468 breast cancer cells. Further studies indicated that sulindac sulfide and exisulind caused marked down-regulation of expression of the ER and PR-A and PR-B in T47D cells. However, neither compound caused a major change in expression of the retinoic acid receptor α (RARα), RARβ, or RARα in T47D cells. Sulindac sulfide and exisulind also caused a decrease in expression of the ER in estrogen-responsive MCF-7 breast cancer cells. Both compounds also markedly inhibited estrogen-stimulated activation of an estrogen-responsive promoter in transient transfection reporter assays. Treatment of T47D cells with specific protein kinase G (PKG) activators did not cause a decrease in ER or PR expression. Therefore, although sulindac sulfide and exisulind can cause activation of PKG, the inhibitory effects of these two compounds on ER and PR expression does not seem to be mediated by PKG. Our findings suggest that the growth inhibition by sulindac sulfide and exisulind in ER-positive and PR-positive human breast cancer cells may be mediated, in part, by inhibition of ER and PR signaling. Thus, these and related compounds may provide a novel approach to the prevention and treatment of human breast cancers, especially those that are ER positive.