bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phosphoprotein Pathway Mapping: Akt/Mammalian Target of Rapamycin Activation Is Negatively Associated with Childhood Rhabdomyosarcoma Survival
Authors: Petricoin Emanuel F. , Espina Virginia , Araujo Robyn P. , Midura Brieanne , Yeung Choh , Wan Xiaolin , Eichler Gabriel S. , Johann Donald J. , Qualman Stephen , Tsokos Maria , Krishnan Kartik , Helman Lee J. , Liotta Lance A. 
Published: April 2007

Abstract
Mapping of protein signaling networks within tumors can identify new targets for therapy and provide a means to stratify patients for individualized therapy. Despite advances in combination chemotherapy, the overall survival for childhood rhabdomyosarcoma remains ∼60%. A critical goal is to identify functionally important protein signaling defects associated with treatment failure for the 40% nonresponder cohort. Here, we show, by phosphoproteomic network analysis of microdissected tumor cells, that interlinked components of the Akt/mammalian target of rapamycin (mTOR) pathway exhibited increased levels of phosphorylation for tumors of patients with short-term survival. Specimens (n = 59) were obtained from the Children's Oncology Group Intergroup Rhabdomyosarcoma Study (IRS) IV, D9502 and D9803, with 12-year follow-up. High phosphorylation levels were associated with poor overall and poor disease-free survival: Akt Ser473 (overall survival P &lt; 0.001, recurrence-free survival P &lt; 0.0009), 4EBP1 Thr37/46 (overall survival P &lt; 0.0110, recurrence-free survival P &lt; 0.0106), eIF4G Ser1108 (overall survival P &lt; 0.0017, recurrence-free survival P &lt; 0.0072), and p70S6 Thr389 (overall survival P &lt; 0.0085, recurrence-free survival P &lt; 0.0296). Moreover, the findings support an altered interrelationship between the insulin receptor substrate (IRS-1) and Akt/mTOR pathway proteins (P &lt; 0.0027) for tumors from patients with poor survival. The functional significance of this pathway was tested using CCI-779 in a mouse xenograft model. CCI-779 suppressed phosphorylation of mTOR downstream proteins and greatly reduced the growth of two different rhabdomyosarcoma (RD embryonal P = 0.00008; Rh30 alveolar P = 0.0002) cell lines compared with controls. These results suggest that phosphoprotein mapping of the Akt/mTOR pathway should be studied further as a means to select patients to receive mTOR/IRS pathway inhibitors before administration of chemotherapy. [Cancer Res 2007;67(7):3431–40]
CXCL10 Promotes Invasion-Related Properties in Human Colorectal Carcinoma Cells
Authors: Zipin-Roitman Adi , Meshel Tsipi , Sagi-Assif Orit , Shalmon Bruria , Avivi Camila , Pfeffer Raphael M. , Witz Isaac P. , Ben-Baruch Adit 
Published: April 2007

Abstract
CXCL10 was recently shown to exert antimalignancy functions by influencing the tumor microenvironment. Here, we have taken a different approach, investigating the effects of CXCL10 directly on tumor-promoting functions in colorectal carcinoma (CRC) cells. CXCL10 expression was detected in preferred metastatic sites of CRC (liver, lungs, and lymph nodes), and its CXCR3 receptor was expressed by eight CRC cell lines (detected: reverse transcription-PCR and/or flow cytometry). Detailed analysis was done on two cell lines derived from primary CRC tumors (SW480, KM12C) and their metastatic descendents (SW620 and KM12SM). The three known variants of CXCR3 (CXCR3-A, CXCR3-B, and CXCR3-alt) were detected in all four cell lines. CXCR3 expression was also observed on colorectal tumor cells in biopsies of CRC patients (immunohistochemistry). CXCL10 and CXCR3 expression were potently induced in CRC cells by Interferon γ and all four CRC cell lines responded to CXCL10 by extracellular signal-regulated kinase 1/2 dephosphorylation. The chemokine did not affect tumor cell growth or angiogenesis-related functions in the tumor cells, such as CXCL8 and vascular endothelial growth factor secretion. Importantly, CXCL10 significantly up-regulated invasion-related properties in CRC cells: It promoted matrix metalloproteinase 9 expression and induced CRC cell migration. Of note, CXCL10-induced migration was detected only in the two metastatic cells and not in their primary counterparts. Also, CXCL10 promoted the adhesion of metastatic cells to laminin. These results suggest that CXCL10 can be exploited by CRC cells toward their progression, thus possibly antagonizing the antimalignancy effects of the chemokine on the tumor microenvironment. Therefore, care should be taken when considering CXCL10 as a therapeutic antitumor modality for CRC treatment. [Cancer Res 2007;67(7):3396–405]
Aurora A and B Overexpression and Centrosome Amplification in Early Estrogen-Induced Tumor Foci in the Syrian Hamster Kidney: Implications for Chromosomal Instability, Aneuploidy, and Neoplasia
Authors: Hontz Adrianne E. , Li Sara Antonia , Lingle Wilma L. , Negron Vivian , Bruzek Amy , Salisbury Jeffrey L. , Li Jonathan J. 
Published: April 2007

Abstract
Estrogen-induced Syrian hamster tumors in the kidney represent a useful model to gain insight into the role of estrogens in oncogenic processes. We provided evidence that early tumor foci in the kidney arise from interstitial ectopic uterine-like germinal stem cells, and that early tumor foci and well-established tumors are highly aneuploid (92–94%). The molecular mechanisms whereby estrogens mediate this process are unclear. Here, we report that estrogen treatment induced significant increases in Aurora A protein expression (8.7-fold), activity (2.6-fold), mRNA (6.0-fold), and Aurora B protein expression (4.6-fold) in tumors, compared with age-matched cholesterol-treated kidneys. Immunohistochemistry revealed that this increase in Aurora A and B protein expression was essentially confined to cells within early and large tumor foci at 3.5 and 6 months of estrogen treatment, respectively. Upon estrogen withdrawal or coadministration of tamoxifen for 10 days, a 78% to 79% and 81% to 64% reduction in Aurora A and B expression, respectively, were observed in primary tumors compared with tumors continuously exposed to estrogens. These data indicate that overexpressed Aurora A and B in these tumors are under estrogen control via estrogen receptor α. Aurora A coenriched with the centrosome fraction isolated from tumors in the kidney. Centrosome amplification (number and area/cell) was detected in early tumor foci and large tumors but not in adjacent uninvolved or age-matched control kidneys. Taken together, these data indicate that persistent overexpression of Aurora A and B is under estrogen control, and is coincident with centrosome amplification, chromosomal instability, and aneuploidy, and represent an important mechanism driving tumorigenesis. [Cancer Res 2007;67(7):2957–63]
Dual Role of Inactivating Lef1 Mutations in Epidermis: Tumor Promotion and Specification of Tumor Type
Authors: Niemann Catherin , Owens David M. , Schettina Peter , Watt Fiona M. 
Published: April 2007

Abstract
The NH2 terminus of LEF1 is frequently mutated in human sebaceous tumors. To investigate how this contributes to cancer, we did two-stage chemical carcinogenesis on K14ΔNLef1 transgenic mice, which express NH2-terminally truncated Lef1 in the epidermal basal layer. Transgenic mice developed more tumors, more rapidly than littermate controls, even without exposure to tumor promoter. They developed sebaceous tumors, whereas controls developed squamous cell carcinomas. K14ΔNLef1 epidermis failed to up-regulate p53 and p21 proteins during tumorigenesis or in response to UV irradiation, and this correlated with impaired p14ARF induction. We propose that LEF1 NH2-terminal mutations play a dual role in skin cancer, specifying tumor type by inhibiting Wnt signaling and acting as a tumor promoter by preventing induction of p53. [Cancer Res 2007;67(7):2916–21]
A High-Throughput Study in Melanoma Identifies Epithelial-Mesenchymal Transition as a Major Determinant of Metastasis
Authors: Alonso Soledad R. , Tracey Lorraine , Ortiz Pablo , Pérez-Gómez Beatriz , Palacios José , Pollán Marina , Linares Juan , Serrano Salvio , Sáez-Castillo Ana I. , Sánchez Lydia , Pajares Raquel , Sánchez-Aguilera Abel , Artiga Maria J. , Piris Miguel A. , Rodríguez-Peralto José L. 
Published: April 2007

Abstract
Metastatic disease is the primary cause of death in cutaneous malignant melanoma (CMM) patients. To understand the mechanisms of CMM metastasis and identify potential predictive markers, we analyzed gene-expression profiles of 34 vertical growth phase melanoma cases using cDNA microarrays. All patients had a minimum follow-up of 36 months. Twenty-one cases developed nodal metastatic disease and 13 did not. Comparison of gene expression profiling of metastatic and nonmetastatic melanoma cases identified 243 genes with a &gt;2-fold differential expression ratio and a false discovery rate of &lt;0.2 (206 up-regulated and 37 down-regulated). This set of genes included molecules involved in cell cycle and apoptosis regulation, epithelial-mesenchymal transition (EMT), signal transduction, nucleic acid binding and transcription, protein synthesis and degradation, metabolism, and a specific group of melanoma- and neural-related proteins. Validation of these expression data in an independent series of melanomas using tissue microarrays confirmed that the expression of a set of proteins included in the EMT group (N-cadherin, osteopontin, and SPARC/osteonectin) were significantly associated with metastasis development. Our results suggest that EMT-related genes contribute to the promotion of the metastatic phenotype in primary CMM by supporting specific adhesive, invasive, and migratory properties. These data give a better understanding of the biology of this aggressive tumor and may provide new prognostic and patient stratification markers in addition to potential therapeutic targets. [Cancer Res 2007;67(7):3450–60]
Systemic Targeting Inhibitor of κB Kinase Inhibits Melanoma Tumor Growth
Authors: Yang Jinming , Pan Wei-Hua , Clawson Gary A. , Richmond Ann 
Published: April 2007

Abstract
Constitutive activation of nuclear factor-κB (NF-κB) has been directly implicated in tumorigenesis of various cancer types, including melanoma. Inhibitor of κB kinase (IKK) functions as a major mediator of NF-κB activation. Thus, development of an IKK-specific inhibitor has been a high priority, although it remains unclear whether systemic inhibition of IKK will provide therapeutic benefit. In this study, we show that inhibition of NF-κB activity in melanocytes that are persistently expressing an active H-RasV12 gene and are deficient in the tumor suppressors inhibitor A of cyclin-dependent kinase 4/alternative reading frame results in reduction of melanoma tumor growth in vivo. This effect is, at least in part, via regulation of NF-κB nuclear activation and RelA phosphorylation. Based on this result, we developed a double hammerhead ribozyme long-term expression system to silence either IKKα or IKKβ. The ribozymes were placed in an EBV construct and delivered i.v. to nude mice bearing melanoma lesions, which developed after i.v. injection of H-Ras–transformed melanoma cells. Our in vivo data show that knockdown of endogenous IKKβ significantly reduces the growth of the melanoma lesions and knockdown of either IKKα or IKKβ prolongs the life span of immunocompetent mice. [Cancer Res 2007;67(7):3127–34]
Tumor Suppression by IFN Regulatory Factor-1 Is Mediated by Transcriptional Down-regulation of Cyclin D1
Authors: Kröger Andrea , Stirnweiss Anja , Pulverer Julia Elisabeth , Klages Katjana , Grashoff Martina , Reimann Jörg , Hauser Hansjörg 
Published: April 2007

AbstractIFNs have been ascribed to mediate antitumor effects. IFN regulatory factor-1 (IRF-1) is a major target gene of IFNs. It inhibits cell proliferation and oncogenic transformation. Here, we show that 60% of all mRNAs deregulated by oncogenic transformation mediated by c-myc and H-ras are reverted to the expression levels of nontransformed cells by IRF-1. These include cell cycle–regulating genes. An indirect target is cyclin D1. Activation of IRF-1 decreased cyclin D1 expression and cyclin-dependent kinase 4 kinase activity concomitant with change in the levels of hyperphosphorylated retinoblastoma protein. These effects are mediated by inhibition of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway and a transcriptional repression of cyclin D1. As shown by in vitro assays and tumor growth in nude mice, IRF-1–mediated effects on cell cycle progression were found to be overridden by ectopic expression of cyclin D1. Conversely, decrease of cyclin D1 by RNA interference experiments prevents transformation and tumor growth. The data show that cyclin D1 is a key target for IRF-1–mediated tumor-suppressive effects. [Cancer Res 2007;67(7):2972–81]
The Aryl Propionic AcidR-Flurbiprofen Selectively Induces p75NTR-Dependent Decreased Survival of Prostate Tumor Cells
Authors: Quann Emily J. , Khwaja Fatima , Zavitz Kenton H. , Djakiew Daniel 
Published: April 2007

AbstractEpidemiologic studies show that patients chronically consuming nonsteroidal anti-inflammatory drugs (NSAID) for arthritis exhibit a reduced incidence of prostate cancer. In addition, some NSAIDs show anticancer activity in vitro. NSAIDs exert their anti-inflammatory effects by inhibiting cyclooxygenase (COX) activity; however, evidence suggests that COX-independent mechanisms mediate decreased prostate cancer cell survival. Hence, we examined the effect of selected aryl propionic acid NSAIDs and structurally related compounds on the decreased survival of prostate cancer cell lines PC-3, DU-145, and LNCaP by induction of the p75NTR protein. p75NTR has been shown to function as a tumor suppressor in the prostate by virtue of its intracellular death domain that can initiate apoptosis and inhibit growth. The most efficacious compounds for induction of p75NTR and decreased survival, in rank-order, were R-flurbiprofen, ibuprofen, oxaprozin, fenoprofen, naproxen, and ketoprofen. Because R-flurbiprofen and ibuprofen exhibited the greatest efficacy, we examined their dose-dependent specificity of induction for p75NTR relative to other members of the death receptor family. Whereas treatment with R-flurbiprofen or ibuprofen resulted in a massive induction of p75NTR protein levels, the expression of Fas, p55TNFR, DR3, DR4, DR5, and DR6 remained largely unchanged. Moreover, transfection of either cell line before R-flurbiprofen or ibuprofen treatment with a dominant negative form of p75NTR to antagonize p75NTR activity or p75NTR small interfering RNA to prevent p75NTR protein expression rescued both cell lines from decreased survival. Hence, R-flurbiprofen and ibuprofen selectively induce p75NTR-dependent decreased survival of prostate cancer cells independently of COX inhibition. [Cancer Res 2007;67(7):3254–62]
Regulation of Vascular Endothelial Growth Factor Receptor-1 Expression by Specificity Proteins 1, 3, and 4 in Pancreatic Cancer Cells
Authors: Abdelrahim Maen , Baker Cheryl H. , Abbruzzese James L. , Sheikh-Hamad David , Liu Shengxi , Cho Sung Dae , Yoon Kyungsil , Safe Stephen 
Published: April 2007

Abstract
Vascular endothelial growth factor receptor-1 (VEGFR1) is expressed in cancer cell lines and tumors and, in pancreatic and colon cancer cells, activation of VEGFR1 is linked to increased tumor migration and invasiveness. Tolfenamic acid, a nonsteroidal anti-inflammatory drug, decreases Sp protein expression in Panc-1 and L3.6pl pancreatic cancer cells, and this was accompanied by decreased VEGFR1 protein and mRNA and decreased luciferase activity on cells transfected with constructs (pVEGFR1) containing VEGFR1 promoter inserts. Comparable results were obtained in pancreatic cancer cells transfected with small inhibitory RNAs for Sp1, Sp3, and Sp4 and all three proteins bound to GC-rich elements in the VEGFR1 promoter. These results show that VEGFR1 is regulated by Sp proteins and that treatment with tolfenamic acid decreases expression of this critical angiogenic factor. Moreover, in vitro studies in Panc-1 cells show that activation of VEGFR1 by VEGFB to increase mitogen-activated protein kinase 1/2 phosphorylation and cell migration on collagen-coated plates is also inhibited by tolfenamic acid. Thus, targeted degradation of Sp proteins is highly effective for inhibiting VEGFR1 and associated angiogenic responses in pancreatic cancer. [Cancer Res 2007;67(7):3286–94]
Isogenic Normal Basal and Luminal Mammary Epithelial Isolated by a Novel Method Show a Differential Response to Ionizing Radiation
Authors: Huper Gudrun , Marks Jeffrey R. 
Published: April 2007

Abstract
Epithelial cells within the normal breast duct seem to be the primary target for neoplastic transformation events that eventually produce breast cancer. Normal epithelial cells are easily isolated and propagated using standard techniques. However, these techniques almost invariably result in populations of cells that are largely basal in character. Because only ∼20% of human breast cancers exhibit a basal phenotype, our understanding of the disease may be skewed by using these cells as the primary comparator to cancer. Further, because germ line mutations in BRCA1 yield breast cancers that are most often of the basal type, a comparison of normal basal and luminal cells could yield insight into the tissue and cell type specificity of this hereditary cancer susceptibility gene. In this report, we describe a simplified and efficient method for isolating basal and luminal cells from normal human breast tissue. These isogenic cells can be independently propagated and maintain phenotypic markers consistent with their respective lineages. Using these cultured cells, we show that basal and luminal cells exhibit distinct responses to ionizing radiation. Basal cells undergo a rapid but labile cell cycle arrest, whereas luminal cells show a much more durable arrest, primarily at the G2-M boundary. Molecular markers, including p53 protein accumulation, p53-activated genes, and BRCA1 nuclear focus formation all correlate with the respective cell cycle responses. Further, we show that short-term cultures of human breast tissue fragments treated with ionizing radiation show a similar phenomenon as indicated by the biphasic accumulation of p53 protein in the basal versus luminal layer. Together, these results indicate that normal basal cells have a transitory cell cycle arrest after DNA damage that may underlie their increased susceptibility to transformation after the loss of functional BRCA1. [Cancer Res 2007;67(7):2990–3001]
Tumor-Specific Cooperation of Retinoblastoma Protein Family and Snf5 Inactivation
Authors: Chai Jingjing , Lu Xiangdong , Godfrey Virginia , Fletcher Christopher , Roberts Charles W.M. , Van Dyke Terry , Weissman Bernard E. 
Published: April 2007

Abstract
Malignant rhabdoid tumors (MRT) are rare aggressive cancers that occur in young children. Seventy-five percent of sporadic MRTs harbor inactivating SNF5 mutations, and mice heterozygous for an Snf5-null allele develop MRTs with partial penetrance. The diagnosis of choroid plexus carcinomas (CPC) in addition to MRTs in families with a single mutant SNF5 allele prompted us to assess the role of SNF5 loss in CPC in genetically engineered mice. With high frequency, TgT121 mice develop CPCs that are initiated by inactivation of retinoblastoma protein (pRb) and related proteins p107 and p130. However, CPC penetrance and latency were not significantly affected by Snf5 heterozygosity, consistent with recent evidence that CPCs in SNF5 families were, in many cases, misdiagnosed MRTs. Surprisingly, although the CPC phenotype was unaffected, TgT121;Snf5+/− mice developed MRTs with increased penetrance and decreased latency compared with TgT121;Snf5+/+ littermates. MRTs expressed the T121 protein with a concomitant increase in mitotic activity. The predominant appearance of TgT121;Snf5+/− MRTs in the spinal cord led to the discovery that these tumors likely arose from a subset of spinal cord neural progenitor cells expressing T121 rather than from transdifferentiation of CPC. Significantly, the target cell type(s) for MRT is unknown. Hence, this study not only shows that pRbf and SNF5 inactivation cooperate to induce MRTs but also provides new insight into the MRT target population. [Cancer Res 2007;67(7):3002–9]
Improvement of Antitumor Activity by Gene Amplification with a Replicating but Nondisseminating Adenovirus
Authors: Bourbeau Denis , Lau Cara Jean , Jaime Jairo , Koty Zafiro , Zehntner Simone P. , Lavoie Geneviève , Mes-Masson Anne-Marie , Nalbantoglu Josephine , Massie Bernard 
Published: April 2007

Abstract
Gene therapy is a promising approach for cancer treatment; however, efficacy of current vectors remains insufficient. To improve the success of suicide gene therapy, we constructed a replication-competent adenoviral vector that has its protease gene deleted and expresses bacterial cytosine deaminase fused with bacterial uracil phosphoribosyltransferase (CU). The prodrug, 5-fluorocytosine, is transformed into the highly toxic and tissue-diffusible 5-fluorouracil by CU in infected cells. This vector is incapable of producing infectious particles but is able to undergo a single round of replication, thereby increasing transgene copy number and expression. In the presence of 5-FC, compared with the first-generation vector (AdCU), the replication-competent vector, Ad(dPS)CU-IRES-E1A, was significantly more efficacious for in vitro tumor cell killing and in bystander assays, whereas 25-fold fewer viral particles were required in a three-dimensional spheroid model. For in vivo experiments, in which virus was injected into preestablished intracranial glioma xenografts, followed by 5-FC treatment, mice receiving Ad(dPS)CU-IRES-E1A had significantly smaller tumors at 35 days postinjection as well as significantly longer median survival than mice treated with the replication-deficient, protease-deleted vector [Ad(dPS)CU]. In an immunocompetent syngeneic model, Ad(dPS)CU + 5-FC–treated mice had a median survival of only 23 days, whereas Ad(dPS)CU-IRES-E1A + 5-FC–treated animals had a survival of 57.1% at 365 days. In conclusion, Ad(dPS)CU-IRES-E1A in the presence of 5-FC produces more potent tumoricidal effects than its replication-deficient counterparts. [Cancer Res 2007;67(7):3387–95]