bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of Functional Fas Ligand Enhances Intestinal Tumorigenesis in the Min Mouse Model
Authors: Fingleton Barbara , Carter Kathy J. , Matrisian Lynn M. 
Published: May 2007

AbstractFas ligand (FasL/CD95L), a member of the tumor necrosis factor family, interacts with a specific receptor Fas, ultimately leading to cell death. Tumor expression of FasL has been proposed to aid in immune evasion through a “Fas counterattack” mechanism but has also been described as a proinflammatory factor. Here, we tested the role of FasL in a mouse model of spontaneous tumor development. We used the Min mouse in which multiple benign polyps develop in the intestine due to a mutation in the Apc tumor suppressor gene. Mutant mice deficient in functional FasL, termed gld/gld, were crossed to Min mice to generate tumor-prone animals lacking functional FasL. Comparison of FasL-deficient versus proficient Min mice revealed a significant increase in polyp number in the gld/gld mice. We next assessed immune cell infiltration into adenomas. There was no difference in the number of either lymphocytes or macrophages; however, the number of tumor-infiltrating neutrophils was 3-fold lower in the gld/gld specimens compared with controls. Neutrophil migration in vitro was stimulated by wild-type but not mutant FasL. In a nontumor-bearing colitis model in vivo, neutrophil recruitment to the intestine was also reduced in gld/gld mice. Although the Fas counterattack hypothesis suggests that the absence of FasL would result in increased immune-mediated tumor elimination, the opposite is true in the Min model with lack of functional FasL associated with reduced neutrophil influx and increased tumor development. Thus, the proinflammatory rather than counterattack role of tumor FasL is more relevant. [Cancer Res 2007;67(10):4800–4806]
Extralymphatic Tumors Prepare Draining Lymph Nodes to Invasion via a T-Cell Cross-Tolerance Process
Authors: Preynat-Seauve Olivier , Contassot Emmanuel , Schuler Prisca , Piguet Vincent , French Lars E. , Huard Bertrand 
Published: May 2007

Abstract
Metastases often develop in lymphoid organs. However, the immunologic mechanism allowing such invasion is not known because these organs are considered to be hostile to tumor cells. Here, we analyzed the interactions between tumor cells and CD8+ T cells in such lymphoid organs. Tumor cells implanted into lymph nodes were able to induce tumor-specific cytotoxic CD8+ T-cell responses, conducting to tumor rejection, in contrast to primary extralymphatic tumors rapidly anergizing T cells in draining lymph nodes (DLN) via a cross-presentation process. This abortive CD8+ T-cell response to extralymphatic tumor is independent of the subcellular localization of antigen in tumor cells and is consistent with a lack of CD4+ T-cell help. Notably, this anergy was potent enough to allow successful DLN implantation of tumor cells. Such distant cross-tolerization of tumor-specific CD8+ T cells may be a determinant permissive event leading to invasion of DLN. In this situation, metastatic tumor cells do not need to down-regulate their immunogenicity to spread. [Cancer Res 2007;67(10):5009–16]
Ras Transformation of RIE-1 Cells Activates Cap-Independent Translation of Ornithine Decarboxylase: Regulation by the Raf/MEK/ERK and Phosphatidylinositol 3-Kinase Pathways
Authors: Origanti Sofia , Shantz Lisa M. 
Published: May 2007

AbstractOrnithine decarboxylase (ODC) is the first and generally rate-limiting enzyme in polyamine biosynthesis. Deregulation of ODC is critical for oncogenic growth, and ODC is a target of Ras. These experiments examine translational regulation of ODC in RIE-1 cells, comparing untransformed cells with those transformed by an activated Ras12V mutant. Analysis of the ODC 5′ untranslated region (5′UTR) revealed four splice variants with the presence or absence of two intronic sequences. All four 5′UTR species were found in both cell lines; however, variants containing intronic sequences were more abundant in Ras-transformed cells. All splice variants support internal ribosome entry site (IRES)–mediated translation, and IRES activity is markedly elevated in cells transformed by Ras. Inhibition of Ras effector targets indicated that the ODC IRES element is regulated by the phosphorylation status of the translation factor eIF4E. Dephosphorylation of eIF4E by inhibition of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) or the eIF4E kinase Mnk1/2 increases ODC IRES activity in both cell lines. When both the Raf/MEK/ERK and phosphatidylinositol 3-kinase/mammalian target of rapamycin pathways are inhibited in normal cells, ODC IRES activity is very low and cells arrest in G1. When these pathways are inhibited in Ras-transformed cells, cell cycle arrest does not occur and ODC IRES activity increases, helping to maintain high ODC activity. [Cancer Res 2007;67(10):4834–42]
Expression of Nicotinic Acetylcholine Receptor Subunit Genes in Non–Small-Cell Lung Cancer Reveals Differences between Smokers and Nonsmokers
Authors: Lam David Chi-leung , Girard Luc , Ramirez Ruben , Chau Wing-shun , Suen Wai-sing , Sheridan Shelley , Tin Vicky P.C. , Chung Lap-ping , Wong Maria P. , Shay Jerry W. , Gazdar Adi F. , Lam Wah-kit , Minna John D. 
Published: May 2007

AbstractNicotine and its derivatives, by binding to nicotinic acetylcholine receptors (nAChR) on bronchial epithelial cells, can regulate cellular proliferation and apoptosis via activating the Akt pathway. Delineation of nAChR subtypes in non–small-cell lung cancers (NSCLC) may provide information for prevention or therapeutic targeting. Expression of nAChR subunit genes in 66 resected primary NSCLCs, 7 histologically non-involved lung tissues, 13 NSCLC cell lines, and 6 human bronchial epithelial cell lines (HBEC) was analyzed with quantitative PCR and microarray analysis. Five nonmalignant HBECs were exposed to nicotine in vitro to study the variation of nAChR subunit gene expression with nicotine exposure and removal. NSCLCs from nonsmokers showed higher expression of nAChR α6 (P &lt; 0.001) and β3 (P = 0.007) subunit genes than those from smokers, adjusted for gender. In addition, nAChR α4 (P &lt; 0.001) and β4 (P = 0.029) subunit gene expression showed significant difference between NSCLCs and normal lung. Using Affymetrix GeneChip U133 Sets, 65 differentially expressed genes associated with NSCLC nonsmoking nAChR α6β3 phenotype were identified, which gave high sensitivity and specificity of prediction. nAChR α1, α5, and α7 showed significant reversible changes in expression levels in HBECs upon nicotine exposure. We conclude that between NSCLCs from smokers and nonsmokers, different nAChR subunit gene expression patterns were found, and a 65-gene expression signature was associated with nonsmoking nAChR α6β3 expression. Finally, nicotine exposure in HBECs resulted in reversible differences in nAChR subunit gene expression. These results further implicate nicotine in bronchial carcinogenesis and suggest targeting nAChRs for prevention and therapy in lung cancer. [Cancer Res 2007;67(10):4638–47]
Dominant-Negative but not Gain-of-Function Effects of a p53.R270H Mutation in Mouse Epithelium Tissue after DNA Damage
Authors: Wijnhoven Susan W.P. , Speksnijder Ewoud N. , Liu Xiaoling , Zwart Edwin , vanOostrom Conny Th. M. , Beems Rudolf B. , Hoogervorst Esther M. , Schaap Mirjam M. , Attardi Laura D. , Jacks Tyler , van Steeg Harry , Jonkers Jos , de Vries Annemieke 
Published: May 2007

Abstract
p53 alterations in human tumors often involve missense mutations that may confer dominant-negative or gain-of-function properties. Dominant-negative effects result in inactivation of wild-type p53 protein in heterozygous mutant cells and as such in a p53 null phenotype. Gain-of-function effects can directly promote tumor development or metastasis through antiapoptotic mechanisms or transcriptional activation of (onco)genes. Here, we show, using conditional mouse technology, that epithelium-specific heterozygous expression of mutant p53 (i.e., the p53.R270H mutation that is equivalent to the human hotspot R273H) results in an increased incidence of spontaneous and UVB-induced skin tumors. Expression of p53.R270H exerted dominant-negative effects on latency, multiplicity, and progression status of UVB-induced but not spontaneous tumors. Surprisingly, gain-of-function properties of p53.R270H were not detected in skin epithelium. Apparently, dominant-negative and gain-of-function effects of mutant p53 are highly tissue specific and become most manifest upon stabilization of p53 after DNA damage. [Cancer Res 2007;67(10):4648–56]
Immune Mechanisms in Non–Hodgkin Lymphoma: Joint Effects of the TNF G308A and IL10 T3575A Polymorphisms with Non–Hodgkin Lymphoma Risk Factors
Authors: Wang Sophia S. , Cozen Wendy , Cerhan James R. , Colt Joanne S. , Morton Lindsay M. , Engels Eric A. , Davis Scott , Severson Richard K. , Rothman Nathaniel , Chanock Stephen J. , Hartge Patricia 
Published: May 2007

Abstract
Two common single nucleotide polymorphisms in immunoregulatory genes (TNF G308A, rs1800629 and IL10 T3575A, rs1800890) have been recently reported as risk factors for non–Hodgkin lymphoma (NHL) in a large pooled analysis. We systematically investigated the effects of other established NHL risk factors in relation to the tumor necrosis factor (TNF) G308A or interleukin 10 (IL10) T3575A genotypes. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) from 1,172 cases and 982 population-based controls in a U.S. multicenter study. We investigated NHL overall and two common subtypes [diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma]. NHL risks were increased among those with both an autoimmune condition and the TNF G308A GA/AA (ORNHL, 2.1; 95% CI, 1.0–4.2) or the IL10 T3575A TA/AA genotype (ORNHL, 1.6; 95% CI, 0.9–2.6) compared with individuals without an autoimmune condition and with the common TNF G308A GG or IL10 T3575A TT genotype, respectively; results were similar for DLBCL and follicular lymphoma. We found that elevated DLBCL risk associated with last-born status was more pronounced among those with TNF G308A GA/AA (ORDLBCL, 2.7; 95% CI, 1.1–6.4) or IL10 T3575A TA/AA (ORDLBCL, 2.9; 95% CI, 1.6–5.2). Similarly, elevated DLBCL risk associated with obesity (body mass index, ≥35 versus &lt;25 kg/m2) was observed only among those with TNF G308A GA/AA (ORDLBCL, 2.5; 95% CI, 1.1–5.7) or IL10 T3575A TA/AA genotypes (ORDLBCL, 2.0; 95% CI, 1.1–3.5). These exploratory results require replication but provide evidence that autoimmune conditions, late birth order, and obesity act partly through a common inflammatory pathway, posing a greater risk to individuals with variant TNF and IL10 genotypes than those with wild-type alleles. [Cancer Res 2007;67(10):5042–54]
Survivin, a Member of the Inhibitor of Apoptosis Family, Is Induced by Photodynamic Therapy and Is a Target for Improving Treatment Response
Authors: Ferrario Angela , Rucker Natalie , Wong Sam , Luna Marian , Gomer Charles J. 
Published: May 2007

Abstract
We observed that photodynamic therapy (PDT) induces the expression and phosphorylation of the inhibitor of apoptosis (IAP) protein survivin in murine and human cancer cells and tumors. Survivin inhibits caspase-9, blocks apoptosis, and is associated with resistance to chemotherapy and radiation. Survivin is a client protein for the 90-kDa heat shock protein (Hsp-90), and the binding of survivin to Hsp-90 assists in the maturation, proper folding, assembly, and transport of this IAP protein. A derivative of the antibiotic geldanamycin, 17-allylamino-17-demethoxygeldanamycin (17-AAG), interferes with proper binding of client proteins, such as survivin, to Hsp-90 and leads to misfolding of client proteins, ubiquination, and proteasome degradation. We hypothesized that PDT efficacy may be reduced by treatment-mediated expression and phosphorylation of survivin, and therefore, targeting the survivin pathway could increase PDT responsiveness. To address this hypothesis, we examined cellular and molecular responses following exposure to PDT, 17-AAG, and the combination of PDT plus 17-AAG in human BT-474 breast cancer cells using Photofrin and NPe6 as photosensitizers. Cells treated with the combination of PDT and 17-AAG exhibited decreased expression of the Hsp-90 client proteins phosphorylated survivin, phosphorylated Akt, and Bcl-2. The decreased expression of these client proteins was accompanied by higher apoptotic indexes and increased cytotoxicity. To confirm a specific role for survivin in modulating PDT, we used a human melanoma cell line, YUSAC2/T34A-C4, stably transfected with an inducible dominant-negative survivin gene under the control of a tetracycline-regulated (tet-off) promoter. PDT treatment of melanoma cells expressing the dominant-negative survivin resulted in increased cleavage of the caspase substrate poly(ADP-ribose) polymerase, apoptosis, and cytotoxicity when compared with results following PDT of the same melanoma cell line expressing wild-type survivin. These results show for the first time that targeting survivin and possibly other Hsp-90 client proteins improves in vitro PDT responsiveness and suggest that manipulation of the antiapoptotic pathway maintained by survivin may enhance PDT-mediated cancer therapy. [Cancer Res 2007;67(10):4989–95]
EGFR-T790M Is a Rare Lung Cancer Susceptibility Allele with Enhanced Kinase Activity
Authors: Vikis Haris , Sato Mitsuo , James Michael , Wang Daolong , Wang Yian , Wang Min , Jia Dongmei , Liu Yan , Bailey-Wilson Joan E. , Amos Christopher I. , Pinney Susan M. , Petersen Gloria M. , de Andrade Mariza , Yang Ping , Wiest Jonathan S. , Fain Pamela R. , Schwartz Ann G. , Gazdar Adi , Gaba Colette , Rothschild Henry , Mandal Diptasri , Kupert Elena , Seminara Daniela , Viswanathan Avinash , Govindan Ramaswamy , Minna John , Anderson Marshall W. , You Ming 
Published: May 2007

Abstract
The use of tyrosine kinase inhibitors (TKI) has yielded great success in treatment of lung adenocarcinomas. However, patients who develop resistance to TKI treatment often acquire a somatic resistance mutation (T790M) located in the catalytic cleft of the epidermal growth factor receptor (EGFR) enzyme. Recently, a report describing EGFR-T790M as a germ-line mutation suggested that this mutation may be associated with inherited susceptibility to lung cancer. Contrary to previous reports, our analysis indicates that the T790M mutation confers increased Y992 and Y1068 phosphorylation levels. In a human bronchial epithelial cell line, overexpression of EGFR-T790M displayed a growth advantage over wild-type (WT) EGFR. We also screened 237 lung cancer family probands, in addition to 45 bronchoalveolar tumors, and found that none of them contained the EGFR-T790M mutation. Our observations show that EGFR-T790M provides a proliferative advantage with respect to WT EGFR and suggest that the enhanced kinase activity of this mutant is the basis for rare cases of inherited susceptibility to lung cancer. [Cancer Res 2007;67(10):4665–70]
The Antibody-Mediated Targeted Delivery of Interleukin-15 and GM-CSF to the Tumor Neovasculature Inhibits Tumor Growth and Metastasis
Authors: Kaspar Manuela , Trachsel Eveline , Neri Dario 
Published: May 2007

AbstractTumor-targeting immunocytokines represent a new class of anticancer pharmaceutical agents, which often display a superior therapeutic index compared with the corresponding unconjugated cytokines. In this article, we have studied the anticancer properties of interleukin-15 (IL-15) and granulocyte macrophage colony-stimulating factor (GM-CSF), fused to the human antibody fragment scFv(L19), specific to the EDB domain of fibronectin, a marker of angiogenesis. The immunocytokines L19-IL-15 and L19-GM-CSF were expressed in mammalian cells and purified to homogeneity, revealing no loss of cytokine activity in in vitro assays. Furthermore, the ability of the two immunocytokines to selectively localize to tumors in vivo was confirmed by biodistribution analysis with radioiodinated protein preparations. L19-IL-15 and L19-GM-CSF displayed a potent antitumor activity both in s.c. and in metastatic F9 and C51 murine models of cancer in immunocompetent mice. This therapeutic action was superior compared with IL-15–based and GM-CSF–based fusion proteins, containing antibodies of irrelevant specificity in the mouse, which were used as non–tumor-targeting controls. For both L19-IL-15 and L19-GM-CSF immunocytokines, CD8+ T cells seemed to mostly contribute to the therapeutic action as shown by in vivo cell depletion experiments. The results presented in this article are of clinical significance, considering the fact that the sequence of EDB is identical in mouse and man and that the tumor-targeting ability of the L19 antibody has been extensively shown in clinical trials in patients with cancer. [Cancer Res 2007;67(10):4940–8]
MMP-9 Short Interfering RNA Induced Senescence Resulting in Inhibition of Medulloblastoma Growth via p16INK4a and Mitogen-Activated Protein Kinase Pathway
Authors: Rao Jasti S. , Bhoopathi Praveen , Chetty Chandramu , Gujrati Meena , Lakka Sajani S. 
Published: May 2007

Abstract
The involvement of matrix metalloproteinases (MMP) has been suggested in cellular mechanisms leading to medulloblastoma, the most common malignant brain tumor in children. A significant association of the expression levels of MMP-9 with survival and M stage suggests that patients with medulloblastoma metastatic disease at diagnosis may benefit from the anti-MMP therapy. Here, we have evaluated the tumorigenicity of medulloblastoma cells after infection with an adenovirus containing a 21-bp short interfering RNA sequence of the human MMP-9 gene (Ad-MMP-9). Infection of Daoy medulloblastoma cells with Ad-MMP-9 reduced MMP-9 activity and protein levels compared with parental and Ad-SV controls. Ad-MMP-9 decreased the number of viable Daoy cells in a concentration-dependent manner. Fluorescence-activated cell sorting analysis indicated that Ad-MMP-9 infection caused a dose-dependent cell cycle arrest in the G0-G1 phase. Ad-MMP-9–induced cell cycle arrest seems to be mediated by the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway and the cell cycle inhibitor p16INK4a and is phenotypically indistinguishable from senescence. Ad-MMP-9 treatment inhibited medulloblastoma tumor growth in an intracranial model and was mediated by up-regulation of p16 expression. These studies validate the usefulness of targeting MMP-9 and provide a novel perspective in the treatment of medulloblastoma. [Cancer Res 2007;67(10):4956–64]
Synergistic Activation of the Tumor Suppressor, HLJ1, by the Transcription Factors YY1 and Activator Protein 1
Authors: Wang Chi-Chung , Tsai Meng-Feng , Dai Ting-Hao , Hong Tse-Ming , Chan Wing-Kai , Chen Jeremy J.W. , Yang Pan-Chyr 
Published: May 2007

Abstract
HLJ1 is a novel tumor and invasion suppressor that inhibits tumorigenesis and cancer metastasis. However, the mechanism of HLJ1 activation is currently unclear. Here, we identify an enhancer segment in the HLJ1 gene at −2,125 to −1,039 bp upstream of the transcription start site. A 50-bp element between −1,492 and −1,443 bp is the minimal enhancer segment, which includes the activator protein 1 (AP-1) site (−1,457 to −1,451 bp), an essential regulatory domain that binds the transcriptional factors FosB, JunB, and JunD. Chromatin immunoprecipitation assays confirm that these AP-1 family members bind to a specific site in the HLJ1 enhancer segment in vivo. Overexpression of either YY1 at promoter or AP-1 at enhancer results in a 3-fold increase in the transcriptional activity of HLJ1. We propose a novel mechanism whereby expression of the tumor suppressor, HLJ1, is up-regulated via enhancer AP-1 binding to promoter YY1 and the coactivator, p300, through DNA bending and multiprotein complex formation. The combined expression of AP-1 and YY1 enhances HLJ1 expression by more than five times and inhibits in vitro cancer cell invasion. Elucidation of the regulatory mechanism of HLJ1 expression may facilitate the development of personalized therapy by inhibiting cancer cell proliferation, angiogenesis, and metastasis. [Cancer Res 2007;67(10):4816–26]
UGT1A1 Polymorphism Can Predict Hematologic Toxicity in Patients Treated with Irinotecan
Authors: Côté Jean-François , Kirzin Sylvain , Kramar Andrew , Mosnier Jean-François , Diebold Marie-Danièle , Soubeyran Isabelle , Thirouard Anne-Sophie , Selves Janick , Laurent-Puig Pierre , Ychou Marc 
Published: May 2007

Abstract
Purpose: Irinotecan (CPT-11) is approved in metastatic colorectal cancer treatment and can cause severe toxicity. The main purpose of our study was to assess the role of different polymorphisms on the occurrence of hematologic toxicities and disease-free survival in high-risk stage III colon cancer patients receiving 5-fluorouracil (5FU) and CPT-11 adjuvant chemotherapy regimen in a prospective randomized trial.
Experimental Design: Four hundred patients were randomized in a phase III trial comparing LV5FU2 to LV5FU2 + CPT-11. DNA from 184 patients was extracted and genotyped to detect nucleotide polymorphism: 3435C&gt;T for ABCB1, 6986A&gt;G for CYP3A5, UGT1A1*28 and −3156G&gt;A for UGT1A1.
Results: Genotype frequencies were similar in both treatment arms. In the test arm, no significant difference was observed in toxicity or disease-free survival for ABCB1 and CYP3A5 polymorphisms. UGT1A1*28 homozygous patients showed more frequent severe hematologic toxicity (50%) than UGT1A1*1 homozygous patients (16.2%), P = 0.06. Moreover, patients homozygous for the mutant allele of −3156G&gt;A UGT1A1 polymorphism showed more frequent severe hematologic toxicity (50%) than patients homozygous for wild-type allele (12.5%), P = 0.01. This toxicity occurred significantly earlier in homozygous mutant than wild-type homozygous patients (P = 0.043). In a Cox model, the hazard ratio for severe hematologic toxicity is significantly higher for patients with the A/A compared with the G/G genotype [hazard ratio, 8.4; 95% confidence interval, 1.9–37.2; P = 0.005].
Conclusions: This study supports the clinical utility of identification of UGT1A1 promoter polymorphisms before LV5FU2 + CPT-11 treatment to predict early hematologic toxicity. The −3156G&gt;A polymorphism seems to be a better predictor than the UGT1A1 (TA)6TAA&gt;(TA)7TAA polymorphism.