bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Therapeutic Combination Using PD 0332991 and Bortezomib: Study in the 5T33MM Myeloma Model
Authors: Menu Eline , Garcia Josefina , Huang Xiangao , Di Liberto Maurizio , Toogood Peter L. , Chen Isan , Vanderkerken Karin , Chen-Kiang Selina 
Published: July 2008

Abstract
Multiple myeloma (MM) remains incurable partly because no effective cell cycle–based therapy has been available to both control tumor cell proliferation and synergize with cytotoxic killing. PD 0332991 is an orally active small molecule that potently and specifically inhibits Cdk4 and Cdk6. It has been shown to induce rapid G1 cell cycle arrest in primary human myeloma cells and suppress tumor growth in xenograft models. To improve therapeutic targeting of myeloma progression, we combined tumor suppression by PD 0332991 with cytotoxic killing by bortezomib, a proteasome inhibitor widely used in myeloma treatment, in the immunocompetent 5T33MM myeloma model. We show that 5T33MM tumor cells proliferate aggressively in vivo due to expression of cyclin D2, elevation of Cdk4, and impaired p27Kip1 expression, despite inhibition of Cdk4/6 by p18INK4c and the maintenance of a normal plasma cell transcription program. PD 0332991 potently inhibits Cdk4/6-specific phosphorylation of Rb and cell cycle progression through G1 in aggressively proliferating primary 5T33MM cells, in vivo and ex vivo. This leads to tumor suppression and a significant improvement in survival. Moreover, induction of G1 arrest by PD 0332991 sensitizes 5T33MM tumor cells to killing by bortezomib. Inhibition of Cdk4/6 by PD 0332991, therefore, effectively controls myeloma tumor expansion and sensitizes tumor cells to bortezomib killing in the presence of an intact immune system, thereby representing a novel and promising cell cycle–based combination therapy. [Cancer Res 2008;68(14):5519–23]
Identification of Hypoxia-Inducible Factor-1α as a Novel Target for miR-17-92 MicroRNA Cluster
Authors: Taguchi Ayumu , Yanagisawa Kiyoshi , Tanaka Masaharu , Cao Ke , Matsuyama Yasushi , Goto Hidemi , Takahashi Takashi 
Published: July 2008

Abstract
MicroRNAs (miRNAs) are a distinct class of small noncoding RNAs that posttranscriptionally repress expression of target genes through imperfect base pairing with the 3′ untranslated region. We previously reported amplification and overexpression of the miR-17-92 miRNA cluster at 13q31.3 in lung cancers, as well as growth inhibition by treatment with antisense oligonucleotides against miR-17-5p and miR-20a, constituents of miR-17-92, specifically in miR-17-92–overexpressing lung cancer cell lines. Although these findings clearly suggested important roles of miR-17-92 overexpression in lung cancers, only a few targets for the miR-17-92 cluster have been identified thus far. In this study, we identified hypoxia-inducible factor (HIF)-1α as a novel direct target for miR-17-92 through global expression profiling by mass spectrometric analysis using an isobaric tagging reagent, iTRAQ, combined with bioinformatic target prediction. This is the first report to describe negative regulation of HIF-1α by miRNA, which seemed to occur without disrupting the induction of HIF-1α for cellular adaptation to hypoxia. In addition, overexpression of c-myc led to down-regulation of HIF-1α and induction of miR-17-92, the latter of which was previously reported to be a transcriptional activation activity, suggesting that the induction of miR-17-92 may play a role at least in part in c-myc–mediated repression of HIF-1α. Together with previous reports on the functional negative regulation of c-myc by HIF-1α, our findings suggest the possible existence of an intricate and finely tuned circuit involving c-myc, miR-17-92, and HIF-1α that may play a role in cancer cell proliferation under normoxia in a cellular context–dependent manner. [Cancer Res 2008;68(14):5540–5]
Recruitment and Activation of Natural Killer CellsIn vitroby a Human Dendritic Cell Vaccine
Authors: Gustafsson Karin , Ingelsten Madeleine , Bergqvist Linda , Nyström Jenny , Andersson Bengt , Karlsson-Parra Alex 
Published: July 2008

AbstractRecruitment of circulating natural killer (NK) cells into inflamed lymph nodes is known to provide a potent, IFN-γ–dependent boost for Th1-polarized immune responses in mouse models. Such NK cell recruitment into draining lymph nodes is induced by certain s.c. injected adjuvants, including mature vaccine dendritic cells (DC), and is mediated by a CXCR3-dependent pathway. Here, we show that monocyte-derived immature human DCs stimulated with polyinosinic acid:polycytidylic acid, IFN-α, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IFN-γ, α-type 1–polarized DC (αDC1), secrete profuse amounts of the CXCR3 ligand CXCL9/MIG and substantial amounts of CXCL10/IP-10 and CXCL11/I-TAC after withdrawal of maturation stimuli. In sharp contrast, no measurable production of these chemokines was found in DCs after maturation with the current gold standard maturation cocktail for human DC-based cancer vaccines consisting of TNF-α, IL-1β, IL-6, and prostaglandin-E2 (PGE2-DC). PGE2-DCs preferentially produced the Th2 and regulatory T-cell–attracting chemokines CCL17/TARC and CCL22/MDC, whereas only marginal levels of these chemokines were produced by αDC1s. Functional studies in vitro showed that supernatants from mature αDC1s actively recruited CD3−CD56+ NK cells and that adding anti-CXCL9/MIG antibodies to the αDC1 supernatant substantially reduced this recruitment. Finally, αDC1s were able to induce IFN-γ production when cocultured with resting autologous NK cells, but only if concurrent CD40 ligation was provided. These novel findings indicate that injected human αDC1-based vaccines have the potential to recruit and activate NK cells during their arrival to draining lymph nodes and that this feature may be of relevance for efficient priming of Th1 cells and CTLs. [Cancer Res 2008;68(14):5965–71]
Overexpression of Vascular Endothelial Growth Factor and the Development of Post-Transplantation Cancer
Authors: Basu Aninda , Contreras Alan G. , Datta Dipak , Flynn Evelyn , Zeng Liling , Cohen Herbert T. , Briscoe David M. , Pal Soumitro 
Published: July 2008

Abstract
Cancer is an increasing and major problem after solid organ transplantation. In part, the increased cancer risk is associated with the use of immunosuppressive agents, especially calcineurin inhibitors. We propose that the effect of calcineurin inhibitors on the expression of vascular endothelial growth factor (VEGF) leads to an angiogenic milieu that favors tumor growth. Here, we used 786-0 human renal cancer cells to investigate the effect of cyclosporine (CsA) on VEGF expression. Using a full-length VEGF promoter-luciferase construct, we found that CsA markedly induced VEGF transcriptional activation through the protein kinase C (PKC) signaling pathway, specifically involving PKCζ and PKCδ isoforms. Moreover, CsA promoted the association of PKCζ and PKCδ with the transcription factor Sp1 as observed by immunoprecipitation assays. Using promoter deletion constructs, we found that CsA-mediated VEGF transcription was primarily Sp1 dependent. Furthermore, CsA-induced and PKC-Sp1–mediated VEGF transcriptional activation was partially inhibited by von Hippel-Lindau protein. CsA also promoted the progression of human renal tumors in vivo, wherein VEGF is overexpressed. Finally, to evaluate the in vivo significance of CsA-induced VEGF overexpression in terms of post-transplantation tumor development, we injected CT26 murine carcinoma cells (known to form angiogenic tumors) into mice with fully MHC mismatched cardiac transplants. We observed that therapeutic doses of CsA increased tumor size and VEGF mRNA expression and also enhanced tumor angiogenesis. However, coadministration of a blocking anti-VEGF antibody inhibited this CsA-mediated tumor growth. Collectively, these findings define PKC-mediated VEGF transcriptional activation as a key component in the progression of CsA-induced post-transplantation cancer. [Cancer Res 2008;68(14):5689–98]
Modulation of CD59 Expression by Restrictive Silencer Factor–Derived Peptides in Cancer Immunotherapy for Neuroblastoma
Authors: Donev Rossen M. , Gray Lisa C. , Sivasankar Baalasubramanian , Hughes Timothy R. , van den Berg Carmen W. , Morgan B. Paul 
Published: July 2008

AbstractTumor cells escape clearance by complement by abundantly expressing CD59 and other membrane complement regulators. Existing strategies for blocking/knocking down these regulators can contribute to tumor immunoclearance in vitro; however, there are numerous difficulties restricting their use in vivo. Here, we report a new strategy for suppression of CD59 expression in neuroblastoma using peptides that target regulators of CD59 expression. We identified the neural-restrictive silencer factor (REST) as a target for modulation of CD59 expression in neuroblastoma. We next designed plasmids that encoded peptides comprising different DNA-binding domains of REST and transfected them into neuroblastoma cell lines. These peptides suppressed CD59 expression, sensitizing neuroblastoma to complement-mediated killing triggered by anti-GD2 therapeutic monoclonal antibody. These CD59-modulating peptides might be effective therapeutic adjuvants to therapeutic monoclonal antibodies used for treatment of neuroblastoma and other cancer types sharing the same mechanism for regulation of CD59 expression. [Cancer Res 2008;68(14):5979–87]
An In vitro Multistep Carcinogenesis Model for Human Cervical Cancer
Authors: Narisawa-Saito Mako , Yoshimatsu Yuki , Ohno Shin-ichi , Yugawa Takashi , Egawa Nagayasu , Fujita Masatoshi , Hirohashi Setsuo , Kiyono Tohru 
Published: July 2008

Abstract
Human papillomaviruses (HPV) are believed to be the primary causal agents for development of cervical cancer, and deregulated expression of two viral oncogenes E6 and E7 in basal cells, mostly by integration, is considered to be a critical event for disease progression. However, lines of evidence suggest that, besides expression of E6 and E7 genes, additional host genetic alterations are required for cancer development. To directly test this hypothesis, we first transduced HPV16 E6 and E7 with or without hTERT into several lines of normal human cervical keratinocytes (HCK) from independent donors and then searched for additional alterations required for carcinogenesis. Oncogenic HrasG12V (Hras) provided marked tumor forming ability in nude mice and ErbB2 or c-Myc (Myc) endowed weaker but significant tumor forming ability. Combined transduction of Myc and Hras to HCKs expressing E6 and E7 resulted in the creation of highly potent tumor-initiating cells. These results show that only one or two genetic changes occurring after deregulated expression of high-risk HPV oncogenes might be sufficient for development of cervical cancer. [Cancer Res 2008;68(14):5699–705]
Temozolomide Preferentially Depletes Cancer Stem Cells in Glioblastoma
Authors: Beier Dagmar , Röhrl Stefanie , Pillai Deepu R. , Schwarz Stefanie , Kunz-Schughart Leoni A. , Leukel Petra , Proescholdt Martin , Brawanski Alexander , Bogdahn Ulrich , Trampe-Kieslich Ariane , Giebel Bernd , Wischhusen Jörg , Reifenberger Guido , Hau Peter , Beier Christoph P. 
Published: July 2008

Abstract
The prognosis of patients suffering from glioblastoma (GBM) is dismal despite multimodal therapy. Although chemotherapy with temozolomide may contain tumor growth for some months, invariable tumor recurrence suggests that cancer stem cells (CSC) maintaining these tumors persist. We have therefore investigated the effect of temozolomide on CD133+ and CD133− GBM CSC lines. Although differentiated tumor cells constituting the bulk of all tumor cells were resistant to the cytotoxic effects of the substance, temozolomide induced a dose- and time-dependent decline of the stem cell subpopulation. Incubation with sublethal concentrations of temozolomide for 2 days completely depleted clonogenic tumor cells in vitro and substantially reduced tumorigenicity in vivo. In O6-methylguanine-DNA-methyltransferase (MGMT)–expressing CSC lines, this effect occurred at 10-fold higher doses compared with MGMT-negative CSC lines. Thus, temozolomide concentrations that are reached in patients were only sufficient to completely eliminate CSC in vitro from MGMT-negative but not from MGMT-positive tumors. Accordingly, our data strongly suggest that optimized temozolomide-based chemotherapeutic protocols might substantially improve the elimination of GBM stem cells and consequently prolong the survival of patients. [Cancer Res 2008;68(14):5706–15]
Jagged-1 and Notch3 Juxtacrine Loop Regulates Ovarian Tumor Growth and Adhesion
Authors: Choi Jung-Hye , Park Joon T. , Davidson Ben , Morin Patrice J. , Shih Ie-Ming , Wang Tian-Li 
Published: July 2008

Abstract
Notch3 gene amplification and pathway activation have been reported in ovarian serous carcinoma. However, the primary Notch3 ligand that initiates signal transduction in ovarian cancer remains unclear. In this report, we identify Jagged-1 as the highest expressed Notch ligand in ovarian tumor cells as well as in peritoneal mesothelial cells that are in direct contact with disseminated ovarian cancer cells. Cell-cell adhesion and cellular proliferation were reduced in Notch3-expressing ovarian cancer cells that were cocultured with Jagged-1 knockdown mesothelial and tumor feeder cells. Interaction of Notch3-expressing ovarian cancer cells with Jagged-1–expressing feeder cells activated the promoter activity of candidate Notch3 target genes, and this activity was attenuated by Notch3 siRNA. Constitutive expression of the Notch3 intracellular domain significantly suppressed the Jagged-1 shRNA–mediated growth inhibitory effect. In Notch3-expressing ovarian cancer cells, Jagged-1–stimulating peptides enhanced cellular proliferation, which was suppressed by γ-secretase inhibitor and Notch3 siRNA. Taken together, our results show that Jagged-1 is the primary Notch3 ligand in ovarian carcinoma and Jagged-1/Notch3 interaction constitutes a juxtacrine loop promoting proliferation and dissemination of ovarian cancer cells within the intraperitoneal cavity. [Cancer Res 2008;68(14):5716–23]
PIK3IP1, a Negative Regulator of PI3K, Suppresses the Development of Hepatocellular Carcinoma
Authors: He Xin , Zhu Zhenqi , Johnson Carla , Stoops John , Eaker Amanda E. , Bowen William , DeFrances Marie C. 
Published: July 2008

Abstract
Phosphatidylinositol-3-kinase (PI3K) is a well-known regulator of cell division, motility, and survival in most cell types. Recently, we characterized a novel protein that we call PI3K Interacting Protein 1 (PIK3IP1), which binds to the p110 catalytic subunit of PI3K and reduces its activity in vitro. Little is known about the role of PIK3IP1 in normal and neoplastic growth in vivo. Proper liver function and development depend on intact PI3K signal transduction; when dysregulated, the PI3K pathway is linked to the development of liver cancer. To begin to dissect the contribution of PIK3IP1 to hepatic PI3K signaling in vivo and to liver tumorigenesis in particular, we formulated the following hypothesis: because PIK3IP1 down-regulates PI3K signaling and uncontrolled PI3K signaling is associated with liver cancer, then PIK3IP1-mediated down-regulation of the PI3K pathway should inhibit hepatocellular carcinoma (HCC) development. To test this idea, we generated transgenic mice overexpressing PIK3IP1 in hepatocytes in a mouse strain prone to develop HCC. Isolated PIK3IP1 transgenic mouse hepatocytes showed blunted PI3K signaling, DNA synthetic activity, motility, and survival compared with controls. In vivo, spontaneous liver tumorigenesis was significantly dampened in the transgenic animals. This was accompanied by decreased hepatic PI3K activity and reduced hepatocyte proliferation in the transgenics compared with controls. We also observed that human HCC expressed less PIK3IP1 protein than adjacent matched liver tissue. Our data show that PIK3IP1 is an important regulator of PI3K in vivo, and its dysregulation can contribute to liver carcinogenesis. [Cancer Res 2008;68(14):5591–8]
PAX8 Regulates Telomerase Reverse Transcriptase and Telomerase RNA Component in Glioma
Authors: Chen Yu-Jen , Campbell Hamish G. , Wiles Anna K. , Eccles Michael R. , Reddel Roger R. , Braithwaite Antony W. , Royds Janice A. 
Published: July 2008

Abstract
Paired box (PAX) developmental genes are frequently expressed in cancers and confer survival advantages on cancer cells. We have previously found that PAX genes are deregulated in glioma. We have now investigated the expression of PAX genes in glioma and their role in telomere maintenance. The mRNA level of PAX8 showed a positive correlation with telomerase activity in glioma biopsies (r2 = 0.75, P &lt; 0.001) and in established glioma cell lines (r2 = 0.97, P = 0.0025). We found that PAX8 is able to coordinately transactivate the promoter for both the telomerase catalytic subunit (hTERT) and the telomerase RNA component (hTR) genes. By electrophoretic mobility shift assay, quantitative PCR, and a telomerase activity assay, we show that PAX8 binds directly to the hTERT and hTR promoters, up-regulating hTERT and hTR mRNA, as well as telomerase activity. Additionally, PAX8 small interfering RNA down-regulated hTERT and hTR. Collectively, these results show that PAX8 may have a role in telomerase regulation. [Cancer Res 2008;68(14):5724–32]
Novel MEK1 Mutation Identified by Mutational Analysis of Epidermal Growth Factor Receptor Signaling Pathway Genes in Lung Adenocarcinoma
Authors: Marks Jenifer L. , Gong Yixuan , Chitale Dhananjay , Golas Ben , McLellan Michael D. , Kasai Yumi , Ding Li , Mardis Elaine R. , Wilson Richard K. , Solit David , Levine Ross , Michel Kathrin , Thomas Roman K. , Rusch Valerie W. , Ladanyi Marc , Pao William 
Published: July 2008

Abstract
Genetic lesions affecting a number of kinases and other elements within the epidermal growth factor receptor (EGFR) signaling pathway have been implicated in the pathogenesis of human non–small-cell lung cancer (NSCLC). We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this pathway that could contribute to lung tumorigenesis. We have identified in 2 of 207 primary lung tumors a somatic activating mutation in exon 2 of MEK1 (i.e., mitogen-activated protein kinase kinase 1 or MAP2K1) that substitutes asparagine for lysine at amino acid 57 (K57N) in the nonkinase portion of the kinase. Neither of these two tumors harbored known mutations in other genes encoding components of the EGFR signaling pathway (i.e., EGFR, HER2, KRAS, PIK3CA, and BRAF). Expression of mutant, but not wild-type, MEK1 leads to constitutive activity of extracellular signal–regulated kinase (ERK)-1/2 in human 293T cells and to growth factor–independent proliferation of murine Ba/F3 cells. A selective MEK inhibitor, AZD6244, inhibits mutant-induced ERK activity in 293T cells and growth of mutant-bearing Ba/F3 cells. We also screened 85 NSCLC cell lines for MEK1 exon 2 mutations; one line (NCI-H1437) harbors a Q56P substitution, a known transformation-competent allele of MEK1 originally identified in rat fibroblasts, and is sensitive to treatment with AZD6244. MEK1 mutants have not previously been reported in lung cancer and may provide a target for effective therapy in a small subset of patients with lung adenocarcinoma. [Cancer Res 2008;68(14):5524–8]
Identification of a Novel Subgroup of Melanomas with KIT/Cyclin-Dependent Kinase-4 Overexpression
Authors: Smalley Keiran S.M. , Contractor Rooha , Nguyen Thiennga K. , Xiao Min , Edwards Robin , Muthusamy Viswanathan , King Alastair J. , Flaherty Keith T. , Bosenberg Marcus , Herlyn Meenhard , Nathanson Katherine L. 
Published: July 2008

Abstract
Although many melanomas harbor either activating mutations in BRAF or NRAS, there remains a substantial, yet little known, group of tumors without either mutation. Here, we used a genomic strategy to define a novel group of melanoma cell lines with co-overexpression of cyclin-dependent kinase 4 (CDK4) and KIT. Although this subgroup lacked any known KIT mutations, they had high phospho-KIT receptor expression, indicating receptor activity. Quantitative PCR confirmed the existence of a similar KIT/CDK4 subgroup in human melanoma samples. Pharmacologic studies showed the KIT/CDK4-overexpressing subgroup to be resistant to BRAF inhibitors but sensitive to imatinib in both in vitro and in vivo melanoma models. Mechanistically, imatinib treatment led to increased apoptosis and G1 phase cell cycle arrest associated with the inhibition of phospho-ERK and increased expression of p27KIP. Other melanoma cell lines, which retained some KIT expression but lacked phospho-KIT, were not sensitive to imatinib, suggesting that KIT expression alone is not predictive of response. We suggest that co-overexpression of KIT/CDK4 is a potential mechanism of oncogenic transformation in some BRAF/NRAS wild-type melanomas. This group of melanomas may be a subpopulation for which imatinib or other KIT inhibitors may constitute optimal therapy. [Cancer Res 2008;68(14):5743–52]
Atypical Protein Kinase Cι Expression and Aurothiomalate Sensitivity in Human Lung Cancer Cells
Authors: Regala Roderick P. , Thompson E. Aubrey , Fields Alan P. 
Published: July 2008

Abstract
The antirheumatoid agent aurothiomalate (ATM) is a potent inhibitor of oncogenic PKCι. ATM inhibits non–small lung cancer (NSCLC) growth by binding PKCι and blocking activation of a PKCι-Par6-Rac1-Pak-Mek 1,2-Erk 1,2 signaling pathway. Here, we assessed the growth inhibitory activity of ATM in a panel of human cell lines representing major lung cancer subtypes. ATM inhibited anchorage-independent growth in all lines tested with IC50s ranging from ∼300 nmol/L to &gt;100 μmol/L. ATM sensitivity correlates positively with expression of PKCι and Par6, but not with the PKCι binding protein p62, or the proposed targets of ATM in rheumatoid arthritis (RA), thioredoxin reductase 1 or 2. PKCι expression profiling revealed that a significant subset of primary NSCLC tumors express PKCι at or above the level associated with ATM sensitivity. ATM sensitivity is not associated with general sensitivity to the cytotoxic agents cis-platin, placitaxel, and gemcitabine. ATM inhibits tumorigenicity of both sensitive and insensitive lung cell tumors in vivo at plasma drug concentrations achieved in RA patients undergoing ATM therapy. ATM inhibits Mek/Erk signaling and decreases proliferative index without effecting tumor apoptosis or vascularization in vivo. We conclude that ATM exhibits potent antitumor activity against major lung cancer subtypes, particularly tumor cells that express high levels of the ATM target PKCι and Par6. Our results indicate that PKCι expression profiling will be useful in identifying lung cancer patients most likely to respond to ATM therapy in an ongoing clinical trial. [Cancer Res 2008;68(14):5888–95]