bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dikkopf-1 as a Novel Serologic and Prognostic Biomarker for Lung and Esophageal Carcinomas
Authors: Yamabuki Takumi , Takano Atsushi , Hayama Satoshi , Ishikawa Nobuhisa , Kato Tatsuya , Miyamoto Masaki , Ito Tomoo , Ito Hiroyuki , Miyagi Yohei , Nakayama Haruhiko , Fujita Masahiro , Hosokawa Masao , Tsuchiya Eiju , Kohno Nobuoki , Kondo Satoshi , Nakamura Yusuke , Daigo Yataro 
Published: March 2007

Abstract
Gene expression profile analysis of lung and esophageal carcinomas revealed that Dikkopf-1 (DKK1) was highly transactivated in the great majority of lung cancers and esophageal squamous cell carcinomas (ESCC). Immunohistochemical staining using tumor tissue microarrays consisting of 279 archived non–small cell lung cancers (NSCLC) and 280 ESCC specimens showed that a high level of DKK1 expression was associated with poor prognosis of patients with NSCLC as well as ESCC, and multivariate analysis confirmed its independent prognostic value for NSCLC. In addition, we identified that exogenous expression of DKK1 increased the migratory activity of mammalian cells, suggesting that DKK1 may play a significant role in progression of human cancer. We established an ELISA system to measure serum levels of DKK1 and found that serum DKK1 levels were significantly higher in lung and esophageal cancer patients than in healthy controls. The proportion of the DKK1-positive cases was 126 of 180 (70.0%) NSCLC, 59 of 85 (69.4%) SCLC, and 51 of 81 (63.0%) ESCC patients, whereas only 10 of 207 (4.8%) healthy volunteers were falsely diagnosed as positive. A combined ELISA assays for both DKK1 and carcinoembryonic antigen increased sensitivity and classified 82.2% of the NSCLC patients as positive whereas only 7.7% of healthy volunteers were falsely diagnosed to be positive. The use of both DKK1 and ProGRP increased sensitivity to detect SCLCs up to 89.4%, whereas false-positive rate in healthy donors was only 6.3%. Our data imply that DKK1 should be useful as a novel diagnostic/prognostic biomarker in clinic and probably as a therapeutic target for lung and esophageal cancer. [Cancer Res 2007;67(6):2517–25]
p53-Independent Abrogation of a Postmitotic Checkpoint Contributes to Human PapillomavirusE6-Induced Polyploidy
Authors: Liu Yingwang , Heilman Susan A. , Illanes Diego , Sluder Greenfield , Chen Jason J. 
Published: March 2007

AbstractPolyploidy is often an early event during cervical carcinogenesis, and it predisposes cells to aneuploidy, which is thought to play a causal role in tumorigenesis. Cervical and anogenital cancers are induced by the high-risk types of human papillomavirus (HPV). The HPV E6 oncoprotein induces polyploidy in human keratinocytes, yet the mechanism is not known. It was believed that E6 induces polyploidy by abrogating the spindle checkpoint after mitotic stress. We have tested this hypothesis using human keratinocytes in which E6 expression induces a significant amount of polyploidy. We found that E6 expression does not affect the spindle checkpoint. Instead, we provide direct evidence that E6 is capable of abrogating the subsequent G1 arrest after adaptation of the mitotic stress. E6 targets p53 for degradation, and previous studies have shown an important role for p53 in modulation of the G1 arrest after mitotic stress. Importantly, we have discovered that E6 mutants defective in p53 degradation also induce polyploidy, although with lower efficiency. These results suggest that E6 is able to induce polyploidy via both p53-dependent and p53-independent mechanisms. Therefore, our studies highlight a novel function of HPV E6 that may contribute to HPV-induced carcinogenesis and improve our understanding of the onset of the disease. [Cancer Res 2007;67(6):2603–10]
Dasatinib Inhibits Migration and Invasion in Diverse Human Sarcoma Cell Lines and Induces Apoptosis in Bone Sarcoma Cells Dependent on Src Kinase for Survival
Authors: Shor Audrey C. , Keschman Elizabeth A. , Lee Francis Y. , Muro-Cacho Carlos , Letson G. Douglas , Trent Jonathan C. , Pledger W. Jack , Jove Richard 
Published: March 2007

Abstract
Sarcomas are rare malignant mesenchymal tumors for which there are limited treatment options. One potential molecular target for sarcoma treatment is the Src tyrosine kinase. Dasatinib (BMS-354825), a small-molecule inhibitor of Src kinase activity, is a promising cancer therapeutic agent with p.o. bioavailability. Dasatinib exhibits antitumor effects in cultured human cell lines derived from epithelial tumors, including prostate and lung carcinomas. However, the action of dasatinib in mesenchymally derived tumors has yet to be shown. Based on our previous findings of Src activation in human sarcomas, we evaluated the effects of dasatinib in 12 cultured human sarcoma cell lines derived from bone and soft tissue sarcomas. Dasatinib inhibited Src kinase activity at nanomolar concentrations in these sarcoma cell lines. Downstream components of Src signaling, including focal adhesion kinase and Crk-associated substrate (p130CAS), were also inhibited at similar concentrations. This inhibition of Src signaling was accompanied by blockade of cell migration and invasion. Moreover, apoptosis was induced in the osteosarcoma and Ewing's subset of bone sarcomas at nanomolar concentrations of dasatinib. Inhibition of Src protein expression by small interfering RNA also induced apoptosis, indicating that these bone sarcoma cell lines are dependent on Src activity for survival. These results show that dasatinib inhibits migration and invasion of diverse sarcoma cell types and selectively blocks the survival of bone sarcoma cells. Therefore, dasatinib may provide therapeutic benefit by preventing the growth and metastasis of sarcomas in patients. [Cancer Res 2007;67(6):2800–8]
Histone H2AX Is a Mediator of Gastrointestinal Stromal Tumor Cell Apoptosis following Treatment with Imatinib Mesylate
Authors: Liu Ying , Tseng Michelle , Perdreau Sophie A. , Rossi Ferdinand , Antonescu Cristina , Besmer Peter , Fletcher Jonathan A. , Duensing Stefan , Duensing Anette 
Published: March 2007

Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and are caused by activating mutations of the KIT or platelet-derived growth factor receptor α (PDGFRA) tyrosine kinases. GISTs can be successfully treated with imatinib mesylate, a selective small-molecule protein kinase inhibitor that was first clinically approved to target the oncogenic BCR-ABL fusion protein kinase in chronic myelogenous leukemia, but which also potently inhibits KIT and PDGFR family members. The mechanistic events by which KIT/PDGFRA kinase inhibition leads to clinical responses in GIST patients are not known in detail. We report here that imatinib triggers GIST cell apoptosis in part through the up-regulation of soluble histone H2AX, a core histone H2A variant. We found that untreated GIST cells down-regulate H2AX in a pathway that involves KIT, phosphoinositide-3-kinase, and the ubiquitin/proteasome machinery, and that the imatinib-mediated H2AX up-regulation correlates with imatinib sensitivity. Depletion of H2AX attenuated the apoptotic response of GIST cells to imatinib. Soluble H2AX was found to sensitize GIST cells to apoptosis by aberrant chromatin aggregation and a transcriptional block. Our results underscore the importance of H2AX as a human tumor suppressor protein, provide mechanistic insights into imatinib-induced tumor cell apoptosis and establish H2AX as a novel target in cancer therapy. [Cancer Res 2007;67(6):2685–92]
Genome-Wide, High-Resolution Detection of Copy Number, Loss of Heterozygosity, and Genotypes from Formalin-Fixed, Paraffin-Embedded Tumor Tissue Using Microarrays
Authors: Jacobs Sharoni , Thompson Ella R. , Nannya Yasuhito , Yamamoto Go , Pillai Raji , Ogawa Seishi , Bailey Dione K. , Campbell Ian G. 
Published: March 2007

Abstract
Formalin-fixed, paraffin-embedded (FFPE) material tends to yield degraded DNA and is thus suboptimal for use in many downstream applications. We describe an integrated analysis of genotype, loss of heterozygosity (LOH), and copy number for DNA derived from FFPE tissues using oligonucleotide microarrays containing over 500K single nucleotide polymorphisms. A prequalifying PCR test predicted the performance of FFPE DNA on the microarrays better than age of FFPE sample. Although genotyping efficiency and reliability were reduced for FFPE DNA when compared with fresh samples, closer examination revealed methods to improve performance at the expense of variable reduction in resolution. Important steps were also identified that enable equivalent copy number and LOH profiles from paired FFPE and fresh frozen tumor samples. In conclusion, we have shown that the Mapping 500K arrays can be used with FFPE-derived samples to produce genotype, copy number, and LOH predictions, and we provide guidelines and suggestions for application of these samples to this integrated system. [Cancer Res 2007;67(6):2544–51]
Angiotensin-(1-7) Inhibits Growth of Human Lung Adenocarcinoma Xenografts in Nude Mice through a Reduction in Cyclooxygenase-2
Authors: Menon Jyotsana , Soto-Pantoja David R. , Callahan Michael F. , Cline J. Mark , Ferrario Carlos M. , Tallant E. Ann , Gallagher Patricia E. 
Published: March 2007

AbstractAngiotensin-(1-7) [Ang-(1-7)] is an endogenous peptide of the renin-angiotensin system with vasodilator and antiproliferative properties. Our previous studies showed that Ang-(1-7) reduced serum-stimulated growth of human lung cancer cells in vitro through activation of a unique AT(1-7) receptor. The current study investigates the effect of Ang-(1-7) on lung tumor growth in vivo, using a human lung tumor xenograft model. Athymic mice with tumors resulting from injection of A549 human lung cancer cells were treated for 28 days with either i.v. saline or Ang-(1-7), delivered by implanted osmotic mini-pumps. Treatment with Ang-(1-7) reduced tumor volume by 30% compared with the size before treatment; in contrast, tumor size in the saline-treated animals increased 2.5-fold. These results correlate with a reduction in the proliferation marker Ki67 in the Ang-(1-7)–infused tumors when compared with the saline-infused tumor tissues. Treatment with Ang-(1-7) significantly reduced cyclooxygenase-2 (COX-2) mRNA and protein in tumors of Ang-(1-7)–infused mice when compared with mice treated with saline as well as in the parent A549 human lung cancer cells in tissue culture. These results suggest that Ang-(1-7) may decrease COX-2 activity and proinflammatory prostaglandins to inhibit lung tumor growth. In contrast, the heptapeptide had no effect on COX-1 mRNA in xenograft tumors or A549 cells. Because Ang-(1-7), a peptide with antithrombotic properties, reduces growth through activation of a selective AT(1-7) receptor, our results suggest that the heptapeptide represents a novel treatment for lung cancer by reducing COX-2. [Cancer Res 2007;67(6):2809–15]
Betulinic Acid Inhibits Prostate Cancer Growth through Inhibition of Specificity Protein Transcription Factors
Authors: Chintharlapalli Sudhakar , Papineni Sabitha , Ramaiah Shashi K. , Safe Stephen 
Published: March 2007

Abstract
Betulinic acid is a pentacyclic triterpene natural product initially identified as a melanoma-specific cytotoxic agent that exhibits low toxicity in animal models. Subsequent studies show that betulinic acid induces apoptosis and antiangiogenic responses in tumors derived from multiple tissues; however, the underlying mechanism of action is unknown. Using LNCaP prostate cancer cells as a model, we now show that betulinic acid decreases expression of vascular endothelial growth (VEGF) and the antiapoptotic protein survivin. The mechanism of these betulinic acid–induced antiangiogenic and proapoptotic responses in both LNCaP cells and in tumors is due to activation of selective proteasome-dependent degradation of the transcription factors specificity protein 1 (Sp1), Sp3, and Sp4, which regulate VEGF and survivin expression. Thus, betulinic acid acts as a novel anticancer agent through targeted degradation of Sp proteins that are highly overexpressed in tumors. [Cancer Res 2007;67(6):2816–23]
Identification of a Fibroblast Growth Factor Receptor 1 Splice Variant That Inhibits Pancreatic Cancer Cell Growth
Authors: Liu Zhanbing , Neiss Nicola , Zhou Shaoxia , Henne-Bruns Doris , Korc Murray , Bachem Max , Kornmann Marko 
Published: March 2007

Abstract
Fibroblast growth factor receptors (FGFR) play important roles in many biological processes. Nothing is presently known about possible roles of the human FGFR1-IIIb mRNA splice variant. In this study, we characterized for the first time the effects of FGFR1-IIIb expression on the transformed phenotype of human pancreatic cancer cells. The full-length FGFR1-IIIb cDNA was generated and stably expressed in PANC-1 and MIA PaCa-2 pancreatic cancer and TAKA-1 pancreatic ductal cells. FGFR1-IIIb–expressing cells synthesized a glycosylated 110-kDa protein enhancing tyrosine phosphorylation of FGFR substrate-2 on FGF-1 stimulation. The basal anchorage-dependent and anchorage-independent cell growth was significantly inhibited. These effects were associated with a marked reduction of p44/42 mitogen-activated protein kinase (MAPK) phosphorylation in combination with enhanced activity of p38 MAPK and c-Jun NH2-terminal kinase. FGFR1-IIIb expression inhibited single-cell movement and in vitro invasion as determined by time-lapse microscopy and Boyden chamber assay as well as in vivo tumor formation and growth in nude mice. Microscopic analysis of the xenograft tumors revealed a reduced Ki-67 labeling and a lower amount of tumor necrosis in FGFR1-IIIb–expressing tumors. Our results show that FGFR1-IIIb is a functional FGFR that inhibits the transformed phenotype of human pancreatic cancer cells. [Cancer Res 2007;67(6):2712–9]
Sensitization of Mesothelioma Cells to Tumor Necrosis Factor–Related Apoptosis–Inducing Ligand–Induced Apoptosis by Heat Stress via the Inhibition of the 3-Phosphoinositide-Dependent Kinase 1/Akt Pathway
Authors: Pespeni Melissa H. , Hodnett Maki , Abayasiriwardana Keith S. , Roux Jérémie , Howard Marybeth , Broaddus V. Courtney , Pittet Jean-François 
Published: March 2007

Abstract
Heat stress may enhance the effect of apoptosis-inducing agents in resistant tumor cells. One such agent is the tumor necrosis factor–related apoptosis–inducing ligand (TRAIL), which has attracted intense interest for its ability to induce apoptosis in tumors without affecting nonmalignant cells. We therefore tested whether heat stress potentiates TRAIL-induced apoptosis in mesothelioma cells, its cell type being resistant to TRAIL alone. We found that heat stress enhanced the apoptosis caused by TRAIL but not by chemotherapy. To explain this potentiation, we found that heat stress decreased Akt phosphorylation via the dissociation of heat shock protein 90 (Hsp90) from its client protein 3-phosphoinositide-dependent kinase 1 (PDK-1), a major Akt kinase. The role of Hsp90 and the Akt pathway was confirmed by showing that inhibitors of Hsp90 and the phosphatidyilinositol-3 kinase/Akt pathway reproduced the effect of heat stress on TRAIL-induced apoptosis and that the effect of inhibiting Hsp90 on TRAIL-induced apoptosis could be overcome by activating the Akt pathway with a constitutively active construct of the Akt kinase PDK-1. The effect of heat stress involved multiple steps of the apoptotic machinery. Heat stress potentiated the death receptor pathway, as shown by an increase in TRAIL-induced caspase 8 cleavage. Nonetheless, knockdown of Bid, the main intermediary molecule from the death receptor pathway to the mitochondria, inhibited the effect of heat stress, showing that mitochondrial amplification was required for potentiation by heat stress. In summary, these results support the novel concept that heat stress inhibits the Akt pathway by dissociating PDK-1 from its chaperone Hsp90, leading to potentiation of TRAIL-induced apoptosis in resistant malignant cells. [Cancer Res 2007;67(6):2865–71]
Oncolytic Immunovirotherapy for Melanoma Using Vesicular Stomatitis Virus
Authors: Diaz Rosa Maria , Galivo Feorillo , Kottke Timothy , Wongthida Phonphimon , Qiao Jian , Thompson Jill , Valdes Mikael , Barber Glen , Vile Richard G. 
Published: March 2007

AbstractRelatively little attention has been paid to the role of virotherapy in promoting antitumor immune responses. Here, we show that CD8+ T cells are critical for the efficacy of intratumoral vesicular stomatitis virus virotherapy and are induced against both virally encoded and tumor-associated immunodominant epitopes. We tested three separate immune interventions to increase the frequency/activity of activated antitumoral T cells. Depletion of Treg had a negative therapeutic effect because it relieved suppression of the antiviral immune response, leading to early viral clearance. In contrast, increasing the circulating levels of tumor antigen–specific T cells using adoptive T cell transfer therapy, in combination with intratumoral virotherapy, generated significantly improved therapy over either adoptive therapy or virotherapy alone. Moreover, the incorporation of a tumor-associated antigen within the oncolytic vesicular stomatitis virus increased the levels of activation of naïve T cells against the antigen, which translated into increased antitumor therapy. Therefore, our results show that strategies which enhance immune activation against tumor-associated antigens can also be used to enhance the efficacy of virotherapy. [Cancer Res 2007;67(6):2840–7]
Large-Scale CpG Methylation Analysis Identifies Novel Candidate Genes and Reveals Methylation Hotspots in Acute Lymphoblastic Leukemia
Authors: Taylor Kristen H. , Pena-Hernandez Keila E. , Davis J. Wade , Arthur Gerald L. , Duff Deiter J. , Shi Huidong , Rahmatpanah Farah B. , Sjahputera Ozy , Caldwell Charles W. 
Published: March 2007

AbstractThis study examined DNA methylation associated with acute lymphoblastic leukemia (ALL) and showed that selected molecular targets can be pharmacologically modulated to reverse gene silencing. A CpG island (CGI) microarray containing more than 3,400 unique clones that span all human chromosomes was used for large-scale discovery experiments and led to 262 unique CGI loci being statistically identified as methylated in ALL lymphoblasts. The methylation status of 10 clones encompassing 11 genes (DCC, DLC-1, DDX51, KCNK2, LRP1B, NKX6-1, NOPE, PCDHGA12, RPIB9, ABCB1, and SLC2A14) identified as differentially methylated between ALL patients and controls was independently verified. Consequently, the methylation status of DDX51 was found to differentiate patients with B- and T-ALL subtypes (P = 0.011, Fisher's exact test). Next, the relationship between methylation and expression of these genes was examined in ALL cell lines (NALM-6 and Jurkat) before and after treatments with 5-aza-2-deoxycytidine and trichostatin A. More than a 10-fold increase in mRNA expression was observed for two previously identified tumor suppressor genes (DLC-1 and DCC) and also for RPIB9 and PCDHGA12. Although the mechanisms that lead to the CGI methylation of these genes are unknown, bisulfite sequencing of the promoter of RPIB9 suggests that expression is inhibited by methylation within SP1 and AP2 transcription factor binding motifs. Finally, specific chromosomal methylation hotspots were found to be associated with ALL. This study sets the stage for acquiring a better biological understanding of ALL and for the identification of epigenetic biomarkers useful for differential diagnosis, therapeutic monitoring, and the detection of leukemic relapse. [Cancer Res 2007;67(6):2617–25]
Caveolin-1–Deficient Mice Have Increased Tumor Microvascular Permeability, Angiogenesis, and Growth
Authors: Lin Michelle I. , Yu Jun , Murata Takahisa , Sessa William C. 
Published: March 2007

Abstract
Caveolin-1 (Cav-1) is a major structural protein that is essential to the formation of the organelle, caveolae. Cav-1 knockout (KO) mice were observed to be completely devoid of caveolae yet they exhibit a hyperpermeable vasculature. Given the nature of the hyperpermeable Cav-1 KO endothelium, we sought to investigate if tumors grown in Cav-1 KO mice would be leaky and grow faster. Indeed, Lewis lung carcinoma cells implanted into Cav-1 KO mice had increased tumor vascular permeability, measured by Evans blue extravasation and fibrinogen deposition compared with tumors implanted into wild-type (WT) mice. Cav-1 KO mice also had significantly higher tumor growth rates, attributable to increased tumor angiogenesis and decreased tumor cell death. Furthermore, administration of an antipermeability peptide, cavtratin, was able to correct the tumor hyperpermeability as well as attenuate the increased tumor growth. Mechanistically, endothelial cells isolated from Cav-1 KO mice exhibited increased tyrosine phosphorylation on vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) and decreased association with the adherens junction protein, VE-cadherin. Thus, the loss of Cav-1 increases tumor permeability and growth and that may relate to enhanced VEGF signaling due to lack of Cav-1 inhibition of VEGFR-2 or decreased VE-cadherin mediated VEGFR-2 phosphorylation. [Cancer Res 2007;67(6):2849–56]
Effect of Vascular Normalization by Antiangiogenic Therapy on Interstitial Hypertension, Peritumor Edema, and Lymphatic Metastasis: Insights from a Mathematical Model
Authors: Jain Rakesh K. , Tong Ricky T. , Munn Lance L. 
Published: March 2007

AbstractPreclinical and clinical evidence shows that antiangiogenic agents can decrease tumor vessel permeability and interstitial fluid pressure (IFP) in a process of vessel “normalization.” The resulting normalized vasculature has more efficient perfusion, but little is known about how tumor IFP and interstitial fluid velocity (IFV) are affected by changes in transport properties of the vessels and interstitium that are associated with antiangiogenic therapy. By using a mathematical model to simulate IFP and IFV profiles in tumors, we show here that antiangiogenic therapy can decrease IFP by decreasing the tumor size, vascular hydraulic permeability, and/or the surface area per unit tissue volume of tumor vessels. Within a certain window of antiangiogenic effects, interstitial convection within the tumor can increase dramatically, whereas fluid convection out of the tumor margin decreases. This would result in increased drug convection within the tumor and decreased convection of drugs, growth factors, or metastatic cancer cells from the tumor margin into the peritumor fluid or tissue. Decreased convection of growth factors, such as vascular endothelial growth factor-C (VEGF-C), would limit peritumor hyperplasia, and decreased VEGF-A would limit angiogenesis in sentinel lymph nodes. Both of these effects would reduce the probability of lymphatic metastasis. Finally, decreased fluid convection into the peritumor tissue would decrease peritumor edema associated with brain tumors and ascites accumulation in the peritoneal or pleural cavity, a major complication with a number of malignancies. [Cancer Res 2007;67(6):2729–35]