bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mimp, a Mitochondrial Carrier Homologue, Inhibits Met-HGF/SF-Induced Scattering and Tumorigenicity by Altering Met-HGF/SF Signaling Pathways
Authors: Leibowitz-Amit Raya , Tsarfaty Galia , Abargil Yamit , Yerushalmi Gil M. , Horev Judith , Tsarfaty Ilan 
Published: September 2006

Abstract
We have recently shown that Mimp, a mitochondrial carrier protein homologue, is induced by Met-hepatocyte growth factor/scatter factor (HGF/SF) signaling and decreases the mitochondrial membrane potential in DA3 mammary adenocarcinoma cells. We show here that induction of Mimp leads to growth arrest in response to HGF/SF by arresting cells at the S phase of the cell cycle. Induction of Mimp or its transient expression does not lead to apoptosis. Mimp also attenuates HGF/SF-induced cellular scattering in vitro and tumor growth in vivo. The exogenous induction of Mimp at levels similar to its endogenous induction by HGF/SF increases the level of the Met protein and its phosphorylation by HGF/SF but reduces the levels of Shc and prevents the HGF/SF-induced tyrosine phosphorylation of Grb2 and Shc. In contrast, the level of phosphatidylinositol 3-kinase (PI3K) increases following Mimp induction and the level of phosphorylated PI3K in response to HGF/SF is unaffected by the exogenous induction of Mimp. Moreover, exogenous Mimp prevents the HGF/SF-induced transcription of the serum response element-luciferase reporter gene. Our results show that Mimp expression reduces Met-HGF/SF-induced proliferation and scattering by attenuating and altering the downstream signaling of Met. These data show a new link between a tyrosine kinase growth factor receptor and a mitochondrial carrier homologue that regulates cellular growth, motility, and tumorigenicity. (Cancer Res 2006; 66(17): 8687-97)
The Extent and Severity of Vascular Leakage as Evidence of Tumor Aggressiveness in High-Grade Gliomas
Authors: Cao Yue , Nagesh Vijaya , Hamstra Daniel , Tsien Christina I. , Ross Brian D. , Chenevert Thomas L. , Junck Larry , Lawrence Theodore S. 
Published: September 2006

Abstract
Magnetic resonance imaging reveals heterogeneous regions within high-grade gliomas, such as a contrast-enhanced rim, a necrotic core, and non–contrast-enhanced abnormalities. It is unclear which of these regions best describes tumor aggressiveness. We hypothesized that the vascular leakage volume, reflecting disorganized angiogenesis typical of glioblastoma, would be a strong predictor of clinical outcome. The FLAIR tumor volume, post-gadolinium T1 tumor volume, tumor vascular leakage volume determined by dynamic contrast-enhanced imaging, and volume of the contrast-enhanced rim seen on post-gadolinium T1-weighted images were defined for 20 patients about to undergo treatment for newly diagnosed high-grade gliomas. The potential for imaging characteristics to improve prediction of survival and time to progression over clinical variables was tested by using Cox regression analysis. Single-variable Cox regression analysis of each of the four tumor subvolumes revealed that the vascular leakage volume was the only significant predictor of survival. When the joint effect of clinical variables and the vascular leakage volume were tested for prediction of survival, only the age and the vascular leakage volume were selected as significant predictors. However, when time to progression was tested as a dependent variable, both the vascular leakage volume and the vascular permeability were selected as copredictors, along with surgical status. Our findings suggest that for patients with high-grade glioma, time to progression after radiation therapy is influenced by both underlying biological aggressiveness (vascularity) and volume of aggressive tumor. In contrast, survival depends chiefly on the volume of aggressive tumor at the time of presentation. (Cancer Res 2006; 66(17): 8912-7)
Mechanism of Increased Coxsackie and Adenovirus Receptor Gene Expression and Adenovirus Uptake by Phytoestrogen and Histone Deacetylase Inhibitor in Human Bladder Cancer Cells and the Potential Clinical Application
Authors: Pong Rey-Chen , Roark Ryan , Ou Jiun-Yih , Fan Jianhai , Stanfield Jennifer , Frenkel Eugene , Sagalowsky Arthur , Hsieh Jer-Tsong 
Published: September 2006

Abstract
Coxsackie and adenovirus receptor (CAR) is known as a principal receptor for adenovirus commonly used as a gene delivery vector. Down-regulation of CAR is often detected in several cancer types. Epigenetic modifiers such as histone deacetylase inhibitor FK228 (depsipeptide) have been shown to increase CAR expression as well as the uptake of adenovirus in bladder cancer in vivo and in vitro, indicating that altered transcriptional regulation of CAR is the key mechanism responsible for the decreased CAR levels in this cancer. In this study, we screened agents that could induce CAR expression in bladder cancer cells. Fifty-eight drugs with various chemical properties were tested. Ipriflavone and plant isoflavones were found to exhibit the ability to induce CAR gene expression in combination with FK228. Genistein, the natural isoflavone found in soybean, when combined with FK228, exerts a synergistic effect on CAR gene and protein expression in bladder cancer cells. Chromatin immunoprecipitation results showed an increased histone acetylation in the CAR promoter gene, which is due to the suppression of histone deacetylase activity by both agents. Also, our data indicated that combination treatment is a potent chemotherapeutic regimen for bladder cancer cells and the subsequent administration of recombinant adenovirus could further eliminate the remaining cells. Taken together, our results provide a strong rationale for combining chemotherapeutic and gene therapeutic agents to enhance the therapeutic efficacy in bladder cancer. (Cancer Res 2006; 66(17): 8822-8)
Susceptibility to Induced and Spontaneous Carcinogenesis Is Increased in Fatless A-ZIP/F-1 but not in Obese ob/ob Mice
Authors: Ablamunits Vitaly , Cohen Yehuda , Brazee Irina B. , Gaetz Harold P. , Vinson Charles , Klebanov Simon 
Published: September 2006

Abstract
Obesity is typically associated with increased tumor susceptibility, whereas caloric restriction, a regimen resulting in leanness, inhibits carcinogenesis. The link between adiposity and malignancies suggests that adipose tissue may influence carcinogenesis. An adipose tissue hormone, leptin, could be procarcinogenic because it stimulates proliferation in various tissues and tumor cell lines. Leptin may contribute to the correlation between adiposity and malignancies as its levels are usually increased in obese subjects and reduced by caloric restriction. We hypothesized that leptin deficiency, despite obesity, would inhibit carcinogenesis in leptin-null ob/ob mice and tested this hypothesis in two models: (a) two-stage skin carcinogenesis initiated by 7,12-dimethylbenz(a)anthracene and promoted by phorbol 12-myristate 13-acetate (PMA) and (b) p53 deficiency. Contrary to a typical association between obesity and enhanced carcinogenesis, obese ob/ob mice developed induced skin papillomas and spontaneous p53-deficient malignancies, mostly lymphomas, similarly to their lean littermates. Surprisingly, lipodystrophic (ZIP) mice that had very little both adipose tissue and leptin were highly susceptible to carcinogenesis. Hyperphagia, hyperinsulinemia, and hyperglycemia are unlikely to have contributed significantly to the enhancement of carcinogenesis in ZIP mice because similarly hyperphagic, hyperinsulinemic, and hyperglycemic ob/ob mice had normal susceptibility to carcinogenesis. Our data suggest that, in contrast to a well-known correlation between obesity and cancer, the direct effect of adipose tissue may rather be protective. (Cancer Res 2006; 66(17): 8897-902)
Telomere Maintenance Mechanisms in Liposarcomas: Association with Histologic Subtypes and Disease Progression
Authors: Costa Aurora , Daidone Maria Grazia , Daprai Laura , Villa Raffaella , Cantù Sabrina , Pilotti Silvana , Mariani Luigi , Gronchi Alessandro , Henson Jeremy D. , Reddel Roger R. , Zaffaroni Nadia 
Published: September 2006

AbstractHuman cancer cells maintain telomeres by telomerase activity (TA) or by alternative lengthening of telomeres (ALT). We proposed to define the prevalence of the two telomere maintenance mechanisms (TMM), to assess their association with histology, and to compare their prognostic relevance in a series of 93 patients with liposarcoma. ALT was detected by assaying ALT-associated promyelocytic leukemia nuclear bodies and TA was assayed using the telomeric repeat amplification protocol. ALT or TA was found in 25.9% or 26.6% of 139 tested liposarcoma lesions, respectively. Three lesions were ALT+/TA+ whereas ∼50% of lesions did not show any known TMM. TMM phenotype was consistent during disease progression. ALT was prevalent in dedifferentiated and in grade 3 liposarcomas whereas TA prevailed in most round-cell myxoid and in grade 2 liposarcomas. ALT and TA incidence was similar in primary and recurrent lesions whereas metastases were more frequently TA+ than ALT+ (59% versus 18%; P = 0.04). TMM presence negatively affected patient prognosis (P = 0.001): increased mortality was associated with positivity for TA (P = 0.038) or ALT (P &lt; 0.0001) compared with TMM absence. ALT proved to be a stronger prognostic discriminant of increased mortality than TA even when adjusted for tumor location, grade, and histology (hazard ratio for cause-specific death, 3.58 versus 1.15). Our results indicate that ALT can support fully malignant liposarcomas and is associated with unfavorable disease outcome. (Cancer Res 2006; 66(17): 8918-24)
AAL881, a Novel Small Molecule Inhibitor of RAF and Vascular Endothelial Growth Factor Receptor Activities, Blocks the Growth of Malignant Glioma
Authors: Sathornsumetee Sith , Hjelmeland Anita B. , Keir Stephen T. , McLendon Roger E. , Batt David , Ramsey Timothy , Yusuff Naeem , Rasheed B.K. Ahmed , Kieran Mark W. , Laforme Andrea , Bigner Darell D. , Friedman Henry S. , Rich Jeremy N. 
Published: September 2006

Abstract
Malignant gliomas are highly proliferative and angiogenic cancers resistant to conventional therapies. Although RAS and RAF mutations are uncommon in gliomas, RAS activity is increased in gliomas. Additionally, vascular endothelial growth factor and its cognate receptors are highly expressed in gliomas. We now report that AAL881, a novel low–molecular weight inhibitor of the kinase activities associated with B-RAF, C-RAF (RAF-1), and VEGF receptor-2 (VEGFR2), showed activity against glioma cell lines and xenografts. In culture, AAL881 inhibited the downstream effectors of RAF in a concentration-dependent manner, with inhibition of proliferation associated with a G1 cell cycle arrest, induction of apoptosis, and decreased colony formation. AAL881 decreased the proliferation of bovine aortic endothelial cells as well as the tumor cell secretion of vascular endothelial growth factor and inhibited the invasion of glioma cells through an artificial extracellular matrix. Orally administered AAL881 was well tolerated with minimal weight loss in non–tumor-bearing mice. Established s.c. human malignant glioma xenografts grown in immunocompromised mice treated with a 10-day course of oral AAL881 exhibited growth delays relative to control tumors, frequently resulting in long-term complete regressions. AAL881 treatment extended the survival of immunocompromised mice bearing orthotopic glioma xenografts compared with placebo controls. The intraparenchymal portions of orthotopic AAL881-treated tumors underwent widespread necrosis consistent with vascular disruption compared with the subarachnoid elements. These effects are distinct from our prior experience with VEGFR2 inhibitors, suggesting that targeting RAF itself or in combination with VEGFR2 induces profound tumor responses in gliomas and may serve as a novel therapeutic approach in patients with malignant gliomas. (Cancer Res 2006; 66(17): 8722-30)
A1 Adenosine Receptors in Microglia Control Glioblastoma-Host Interaction
Authors: Synowitz Michael , Glass Rainer , Färber Katrin , Markovic Darko , Kronenberg Golo , Herrmann Ken , Schnermann Juergen , Nolte Christiane , van Rooijen Nico , Kiwit Juergen , Kettenmann Helmut 
Published: September 2006

AbstractWe report that experimental glioblastoma grow more vigorously in A1 adenosine receptor (A1AR)–deficient mice associated with a strong accumulation of microglial cells at and around the tumors. A1ARs were prominently expressed in microglia associated with tumor cells as revealed with immunocytochemistry but low in microglia in the unaffected brain tissue. The A1AR could also be detected on microglia from human glioblastoma resections. To study functional interactions between tumor and host cells, we studied glioblastoma growth in organotypical brain slice cultures. A1AR agonists suppressed tumor growth. When, however, microglial cells were depleted from the slices, the agonists even stimulated tumor growth. Thus, adenosine attenuates glioblastoma growth acting via A1AR in microglia. (Cancer Res 2006; 66(17): 8550-7)
Flavopiridol Induces Cellular FLICE-Inhibitory Protein Degradation by the Proteasome and Promotes TRAIL–Induced Early Signaling and Apoptosis in Breast Tumor Cells
Authors: Palacios Carmen , Yerbes Rosario , López-Rivas Abelardo 
Published: September 2006

Abstract
The cyclin-dependent kinase inhibitor flavopiridol is undergoing clinical trials as an antitumor drug. We show here that pretreatment of different human breast cancer cell lines with flavopiridol facilitates tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–induced apoptosis. In breast tumor cells, apoptosis induction by TRAIL is blocked at the level of apical caspase-8 activation. Flavopiridol treatment enhances TRAIL-induced formation of death-inducing signaling complex and early processing of procaspase-8. Subsequently, a TRAIL-induced, mitochondria-operated pathway of apoptosis is activated in cells treated with flavopiridol. Down-regulation of cellular FLICE-inhibitory proteins (c-FLIP; c-FLIPL and c-FLIPS) is observed on flavopiridol treatment. c-FLIP loss and apoptosis sensitization by flavopiridol are both prevented in cells treated with an inhibitor of the ubiquitin-proteasome system. Furthermore, targeting c-FLIP directly with small interfering RNA oligonucleotides also sensitizes various human breast tumor cell lines to TRAIL-induced apoptosis. Our results indicate that flavopiridol sensitizes breast cancer cells to TRAIL-induced apoptosis by facilitating early events in the apoptotic pathway, and this combination treatment could be regarded as a potential therapeutic tool against breast tumors. (Cancer Res 2006; 66(17): 8858-69)
Redistribution of Nucleoside Transporters to the Cell Membrane Provides a Novel Approach for Imaging Thymidylate Synthase Inhibition by Positron Emission Tomography
Authors: Perumal Meg , Pillai Radhakrishna G. , Barthel Henryk , Leyton Julius , Latigo John R. , Forster Martin , Mitchell Fraser , Jackman Ann L. , Aboagye Eric O. 
Published: September 2006

Abstract
Thymidylate synthase (EC 2.1.1.45) is a key enzyme for the de novo synthesis of DNA and as such a target for anticancer drug development. There is a need to develop noninvasive methods for assessing thymidylate synthase inhibition in tumors. The aim of this study was to assess the potential of 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) positron emission tomography (PET) for early measurement of thymidylate synthase inhibition and to elucidate the cellular mechanisms involved. Radiation-induced fibrosarcoma-1 tumor-bearing mice were injected with a single i.p. dose of the thymidylate synthase inhibitor 5-fluorouracil (5-FU; 165 mg/kg) and imaged by [18F]FLT-PET at 1 to 2 hours after treatment. Deoxyuridine, thymidine kinase 1 (cytoplasmic thymidine kinase; EC2.7.1.21), and ATP levels in excised tumors were measured. Cellular assays for membrane transport were also done. There was a 1.8-fold increase in the 60-minute [18F]FLT tumor/heart radioactivity ratio in drug-treated mice compared with vehicle controls (P = 0.0016). Plasma and tumor deoxyuridine levels increased significantly but thymidine kinase and ATP levels were unchanged. Whole-cell assays implicated a (low level) functional role for the type-1 equilibrative nucleoside transporter (ENT). There was an increase in type-1 ENT-binding sites per cell from 49,110 in untreated cells to 73,142 (P = 0.03) in cells treated with 10 μg/mL 5-FU for 2 hours, without a change in transporter affinity (P = 0.41). We conclude that [18F]FLT-PET can be used to measure thymidylate synthase inhibition as early as 1 to 2 hours after treatment with 5-FU by a mechanism involving redistribution of nucleoside transporters to the plasma membrane. (Cancer Res 2006; 66(17): 8558-64)
Valproic Acid Enhances the Efficacy of Chemotherapy in EBV-Positive Tumors by Increasing Lytic Viral Gene Expression
Authors: Feng Wen-hai , Kenney Shannon C. 
Published: September 2006

Abstract
EBV infection in tumor cells is generally restricted to the latent forms of viral infection. Switching the latent form of viral infection into the lytic form may induce tumor cell death. We have previously reported that certain chemotherapy agents can increase the amount of lytic viral gene expression in EBV-positive tumor cells. In this report, we have explored the potential utility of valproic acid (VPA), an anti-seizure drug that also has strong histone deacetylase inhibitory activity, for activating lytic viral gene expression in EBV-positive tumors. Although VPA treatment alone induced only a modest increase in the level of lytic viral gene expression, it strongly enhanced the ability of chemotherapeutic agents to induce lytic EBV gene expression in EBV-positive epithelial and lymphoid cells in vitro. Furthermore, VPA enhanced cell killing in vitro by chemotherapeutic agents in lymphoblastoid cells and gastric cells (AGS) containing wild-type EBV. In contrast, VPA did not enhance the cytotoxicity of chemotherapy in lymphoblastoid cells containing a lytic-defective (BZLF1-knockout) form of EBV or in EBV-negative AGS cells. Finally, we found that the combination of VPA and chemotherapy was significantly more effective in inhibiting EBV-driven lymphoproliferative disease in severe combined immunodeficient mice than chemotherapy alone. These results suggest that VPA could potentiate the efficacy of chemotherapy for EBV-positive tumors in patients. (Cancer Res 2006; 66(17): 8762-9)
Low and High Dose UVB Regulation of Transcription Factor NF-E2-Related Factor 2
Authors: Kannan Sankaranarayanan , Jaiswal Anil K. 
Published: September 2006

Abstract
Transcription factor NF-E2-related factor 2 (Nrf2) regulates antioxidant response element (ARE)–mediated expression and coordinated induction of chemoprotective proteins in response to chemical stress. In this report, we investigated Nrf2 response to low and high dose UVB irradiation. Low dose (7.5 J/m2) UVB exposure of mouse hepatoma, mouse keratinocyte, and human skin fibroblast cells led to the nuclear accumulation of Nrf2 and up-regulation of ARE-mediated gene expression. On the contrary, and intriguingly, high dose (20 J/m2) UVB exposure of cells led to the nuclear exclusion of Nrf2 and down-regulation of chemoprotective gene expression with possible implications in UVB carcinogenesis. We investigated the mechanism by which high dose UVB induced the nuclear exclusion of Nrf2. Prior treatment with nuclear export inhibitor, leptomycin B, abrogated the UVB-induced nuclear exclusion of Nrf2, indicating that the decrease of Nrf2 in the nucleus was due to the nuclear export of Nrf2. High dose UVB increased the phosphorylation of Nrf2Y568 which stimulated the nuclear export of Nrf2. Mutation of Nrf2Y568 to phenylalanine and src kinase inhibitor PP2 abrogated/reduced the UVB-induced phosphorylation of Nrf2Y568 and nuclear exclusion of Nrf2. Transfection with src family member Fyn small interfering RNA resulted in the nuclear accumulation of Nrf2 and an increase in the expression and UVB induction of ARE-mediated gene expression. UVB exposure also induced the nuclear localization of Fyn. These results suggest that high dose UVB induced the activation/nuclear localization of Fyn which led to increased phosphorylation of Nrf2Y568 and enhanced nuclear export of Nrf2. This resulted in nuclear exclusion of Nrf2 and down-regulation of ARE-mediated chemoprotective gene expression. (Cancer Res 2006; 66(17): 8421-9)
Low-Calcium Serum-Free Defined Medium Selects for Growth of Normal Prostatic Epithelial Stem Cells
Authors: Litvinov Ivan V. , Vander Griend Donald J. , Xu Yi , Antony Lizamma , Dalrymple Susan L. , Isaacs John T. 
Published: September 2006

Abstract
Stage-specific differentiation markers were used to evaluate the cellular composition and the origin of nonimmortalized (PrEC) and immortalized (PZ-HPV7, CA-HPV10, RWPE-1, and 957E/hTERT) human prostate cell lines. These studies documented that immortalized and nonimmortalized prostate epithelial cells established and maintained in low (i.e., &lt;300 μmol/L) Ca2+ serum-free defined (SFD) medium were all derived from normal nonmalignant prostate tissues and contain CD133+/ABCG2+/α2β1Hi/p63−/PSCA−/AR−/PSA− prostate stem cells. In these cultures, prostate stem cells are able to self-renew and generate two distinct cell lineages: the minor proliferatively quiescent neuroendocrine lineage and the major transit-amplifying cell lineage. Subsequently, CD133−/ABCG2−/α2β1Hi/p63+/PSCA−/AR−/PSA− transit-amplifying cells proliferate frequently and eventually mature into proliferatively quiescent CD133−/ABCG2−/α2β1Lo/p63−/PSCA+/AR−/PSA− intermediate cells. Such proliferatively quiescent intermediate cells, however, do not complete their full maturation into CD133−/ABCG2−/α2β1Lo/p63−/PSCA−/AR+/PSA+ luminal-secretory cells in low Ca2+ SFD medium. Addition of universal type I IFN and synthetic androgen (R1881) to culture medium resulted in up-regulation of androgen receptor protein expression. However, it failed to induce full differentiation of intermediate cells into AR+/PSA+ luminal-secretory cells. Our results indicate that such inability of prostate epithelial cells to complete their differentiation is due to continuous expression of Notch-1 receptor and its downstream effector, Hey-1 protein, which actively suppresses differentiation via its ability to transcriptionally repress a series of genes, including the GATA family of transcription factors. (Cancer Res 2006; 66(17): 8598-607)