bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oncosome Formation in Prostate Cancer: Association with a Region of Frequent Chromosomal Deletion in Metastatic Disease
Authors: Di Vizio Dolores , Kim Jayoung , Hager Martin H. , Morello Matteo , Yang Wei , Lafargue Christopher J. , True Lawrence D. , Rubin Mark A. , Adam Rosalyn M. , Beroukhim Rameen , Demichelis Francesca , Freeman Michael R. 
Published: July 2009

Abstract
Oncosomes have recently been described as membrane-derived microvesicles secreted by cancer cells, which transfer oncogenic signals and protein complexes across cell boundaries. Here, we show the rapid formation and secretion of oncosomes from DU145 and LNCaP human prostate cancer cells. Oncosome formation was stimulated by epidermal growth factor receptor activation and also by overexpression of membrane-targeted Akt1. Microvesicles shed from prostate cancer cells contained numerous signal transduction proteins and were capable of activating rapid phospho-tyrosine and Akt pathway signaling, and stimulating proliferation and migration, in recipient tumor cells. They also induced a stromal reaction in recipient normal cells. Knockdown of the actin nucleating protein Diaphanous Related Formin 3 (DRF3/Dia2) by RNA interference enhanced rates of oncosome formation, indicating that these structures resemble, and may be identical to, nonapoptotic membrane blebs, a feature of the amoeboid form of cell motility. Analysis of primary and metastatic human prostate tumors using 100K single nucleotide polymorphism arrays revealed a significantly higher frequency of deletion of the locus encoding DRF3 (DIAPH3) in metastatic tumors (P = 0.001) in comparison with organ-confined tumors. Fluorescence in situ hybridization confirmed increased chromosomal loss of DIAPH3 in metastatic tumors in a different cohort of patients (P = 0.006). These data suggest that microvesicles shed from prostate cancer cells can alter the tumor microenvironment in a manner that may promote disease progression. They also show that DRF3 is a physiologically relevant protein that seems to regulate this process. [Cancer Res 2009;69(13):5601–9]
Nanoscale Cellular Changes in Field Carcinogenesis Detected by Partial Wave Spectroscopy
Authors: Subramanian Hariharan , Roy Hemant K. , Pradhan Prabhakar , Goldberg Michael J. , Muldoon Joseph , Brand Randall E. , Sturgis Charles , Hensing Thomas , Ray Daniel , Bogojevic Andrej , Mohammed Jameel , Chang Jeen-Soo , Backman Vadim 
Published: July 2009

AbstractUnderstanding alteration of cell morphology in disease has been hampered by the diffraction-limited resolution of optical microscopy (&gt;200 nm). We recently developed an optical microscopy technique, partial wave spectroscopy (PWS), which is capable of quantifying statistical properties of cell structure at the nanoscale. Here we use PWS to show for the first time the increase in the disorder strength of the nanoscale architecture not only in tumor cells but also in the microscopically normal-appearing cells outside of the tumor. Although genetic and epigenetic alterations have been previously observed in the field of carcinogenesis, these cells were considered morphologically normal. Our data show organ-wide alteration in cell nanoarchitecture. This seems to be a general event in carcinogenesis, which is supported by our data in three types of cancer: colon, pancreatic, and lung. These results have important implications in that PWS can be used as a new method to identify patients harboring malignant or premalignant tumors by interrogating easily accessible tissue sites distant from the location of the lesion. [Cancer Res 2009;69(13):5357–63]
miR-15a and miR-16 Are Implicated in Cell Cycle Regulation in a Rb-Dependent Manner and Are Frequently Deleted or Down-regulated in Non–Small Cell Lung Cancer
Authors: Bandi Nora , Zbinden Samuel , Gugger Mathias , Arnold Marlene , Kocher Verena , Hasan Lara , Kappeler Andreas , Brunner Thomas , Vassella Erik 
Published: July 2009

Abstract
MicroRNAs (miRNA) are negative regulators of gene expression at the posttranscriptional level, which are involved in tumorigenesis. Two miRNAs, miR-15a and miR-16, which are located at chromosome 13q14, have been implicated in cell cycle control and apoptosis, but little information is available about their role in solid tumors. To address this question, we established a protocol to quantify miRNAs from laser capture microdissected tissues. Here, we show that miR-15a/miR-16 are frequently deleted or down-regulated in squamous cell carcinomas and adenocarcinomas of the lung. In these tumors, expression of miR-15a/miR-16 inversely correlates with the expression of cyclin D1. In non–small cell lung cancer (NSCLC) cell lines, cyclins D1, D2, and E1 are directly regulated by physiologic concentrations of miR-15a/miR-16. Consistent with these results, overexpression of these miRNAs induces cell cycle arrest in G1-G0. Interestingly, H2009 cells lacking Rb are resistant to miR-15a/miR-16–induced cell cycle arrest, whereas reintroduction of functional Rb resensitizes these cells to miRNA activity. In contrast, down-regulation of Rb in A549 cells by RNA interference confers resistance to these miRNAs. Thus, cell cycle arrest induced by these miRNAs depends on the expression of Rb, confirming that G1 cyclins are major targets of miR-15a/miR-16 in NSCLC. Our results indicate that miR-15a/miR-16 are implicated in cell cycle control and likely contribute to the tumorigenesis of NSCLC. [Cancer Res 2009;69(13):5553–9]
Expression of WSX1 in Tumors Sensitizes IL-27 Signaling-Independent Natural Killer Cell Surveillance
Authors: Dibra Denada , Cutrera Jeffry J. , Xia Xueqing , Birkenbach Mark P. , Li Shulin 
Published: July 2009

Abstract
It is well known that the interleukin (IL)-27 receptor WSX1 is expressed in immune cells and induces an IL-27–dependent immune response. Opposing this conventional dogma, this study reveals a much higher level of WSX1 expression in multiple types of epithelial tumor cells when compared with normal epithelial cells. Expression of exogenous WSX1 in epithelial tumor cells suppresses tumorigenicity in vitro and inhibits tumor growth in vivo. Different from the role of WSX1 in immune cells, the antitumor activity of WSX1 in epithelial tumor cells is independent of IL-27 signaling but is mainly dependent on natural killer (NK) cell surveillance. Deficiency of either the IL-27 subunit EBV-induced gene 3 or the IL-27 receptor WSX1 in the host animals had no effect on tumor growth inhibition induced by WSX1 expression in tumor cells. Expression of WSX1 in epithelial tumor cells enhances NK cell cytolytic activity against tumor cells, whereas the absence of functional NK cells impairs the WSX1-mediated inhibition of epithelial tumor growth. The underlying mechanism by which WSX1 expression in tumor cells enhances NK cytolytic activity is dependent on up-regulation of NKG2D ligand expression. Our results reveal an IL-27–independent function of WSX1: sensitizing NK cell-mediated antitumor surveillance via a NKG2D-dependent mechanism. [Cancer Res 2009;69(13):5505–13]
Microcephalin Regulates BRCA2 and Rad51-Associated DNA Double-Strand Break Repair
Authors: Wu Xianglin , Mondal Gourish , Wang Xianshu , Wu Jianmin , Yang Lin , Pankratz Vernon S. , Rowley Matthew , Couch Fergus J. 
Published: July 2009

AbstractMicrocephalin (MCPH1) is a BRCA1 COOH terminal (BRCT) domain containing protein involved in the cellular response to DNA damage that has been implicated in autosomal recessive primary microcephaly. MCPH1 is recruited to sites of DNA double-strand breaks by phosphorylated histone H2AX (γH2AX), but the mechanism by which MCPH1 contributes to the repair process remains to be determined. Here, we show that MCPH1 binds to BRCA2 and regulates the localization of BRCA2 and Rad51 at sites of DNA damage. The interaction occurs through the NH2 terminus of BRCA2 and the COOH terminal BRCT domains of MCPH1. Disruption of the interaction between MCPH1 and BRCA2 has no effect on the ability of BRCA2 to form a complex with Rad51 but is associated with substantially reduced levels of both BRCA2 and Rad51 at sites of DNA double-strand breaks. Uncoupling of MCPH1 from BRCA2 also interferes with Rad51-dependent and BRCA2-dependent homologous recombination repair activity. These results suggest that the role of MCPH1 in the DNA damage response is in part associated with the ability to localize BRCA2 to sites of DNA double-stand breaks. [Cancer Res 2009;69(13):5531–6]
Plasminogen Kringle 5 Induces Apoptosis of Brain Microvessel Endothelial Cells: Sensitization by Radiation and Requirement for GRP78 and LRP1
Authors: McFarland Braden C. , Stewart Jerry , Hamza Amal , Nordal Robert , Davidson Donald J. , Henkin Jack , Gladson Candece L. 
Published: July 2009

Abstract
Recombinant plasminogen kringle 5 (rK5) has been shown to induce apoptosis of dermal microvessel endothelial cells (MvEC) in a manner that requires glucose-regulated protein 78 (GRP78). As we are interested in antiangiogenic therapy for glioblastoma tumors, and the effectiveness of antiangiogenic therapy can be enhanced when combined with radiation, we investigated the proapoptotic effects of rK5 combined with radiation on brain MvEC. We found that rK5 treatment of brain MvEC induced apoptosis in a dose- and time-dependent manner and that prior irradiation significantly sensitized (500-fold) the cells to rK5-induced apoptosis. The rK5-induced apoptosis of both unirradiated and irradiated MvEC required expression of GRP78 and the low-density lipoprotein receptor-related protein 1 (LRP1), a scavenger receptor, based on down-regulation studies with small interfering RNA, and blocking studies with either a GRP78 antibody or a competitive inhibitor of ligand binding to LRP1. Furthermore, p38 mitogen-activated protein kinase was found to be a necessary downstream effector for rK5-induced apoptosis. These data suggest that irradiation sensitizes brain MvEC to the rK5-induced apoptosis and that this signal requires LRP1 internalization of GRP78 and the activation of p38 mitogen-activated protein kinase. Our findings suggest that prior irradiation would have a dose-sparing effect on rK5 antiangiogenic therapy for brain tumors and further suggest that the effects of rK5 would be tumor specific, as the expression of GRP78 protein is up-regulated on the brain MvEC in glioblastoma tumor biopsies compared with the normal brain. [Cancer Res 2009;69(13):5537–45]
Acetyl-11-Keto-β-Boswellic Acid Inhibits Prostate Tumor Growth by Suppressing Vascular Endothelial Growth Factor Receptor 2–Mediated Angiogenesis
Authors: Pang Xiufeng , Yi Zhengfang , Zhang Xiaoli , Sung Bokyung , Qu Weijing , Lian Xiaoyuan , Aggarwal Bharat B. , Liu Mingyao 
Published: July 2009

AbstractThe role of angiogenesis in tumor growth and metastasis is well established. Identification of a small molecule that blocks tumor angiogenesis and is safe and affordable has been a challenge in drug development. In this study, we showed that acetyl-11-keto-β-boswellic acid (AKBA), an active component from an Ayurvedic medicinal plant (Boswellia serrata), could strongly inhibit tumor angiogenesis. AKBA suppressed tumor growth in the human prostate tumor xenograft mice treated daily (10 mg/kg AKBA) after solid tumors reached ∼100 mm3 (n = 5). The inhibitory effect of AKBA on tumor growth was well correlated with suppression of angiogenesis. When examined for the molecular mechanism, we found that AKBA significantly inhibited blood vessel formation in the Matrigel plug assay in mice and effectively suppressed vascular endothelial growth factor (VEGF)–induced microvessel sprouting in rat aortic ring assay ex vivo. Furthermore, AKBA inhibited VEGF-induced cell proliferation, chemotactic motility, and the formation of capillary-like structures from primary cultured human umbilical vascular endothelial cells in a dose-dependent manner. Western blot analysis and in vitro kinase assay revealed that AKBA suppressed VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR2) kinase (KDR/Flk-1) with IC50 of 1.68 μmol/L. Specifically, AKBA suppressed the downstream protein kinases of VEGFR2, including Src family kinase, focal adhesion kinase, extracellular signal-related kinase, AKT, mammalian target of rapamycin, and ribosomal protein S6 kinase. Our findings suggest that AKBA potently inhibits human prostate tumor growth through inhibition of angiogenesis induced by VEGFR2 signaling pathways. [Cancer Res 2009;69(14):5893–900]
Functional Phosphodiesterase 11A Mutations May Modify the Risk of Familial and Bilateral Testicular Germ Cell Tumors
Authors: Horvath Anelia , Korde Larissa , Greene Mark H. , Libe Rossella , Osorio Paulo , Faucz Fabio Rueda , Raffin-Sanson Marie Laure , Tsang Kit Man , Drori-Herishanu Limor , Patronas Yianna , Remmers Elaine F. , Nikita Maria Eleni , Moran Jason , Greene Joseph , Nesterova Maria , Merino Maria , Bertherat Jerome , Stratakis Constantine A. 
Published: July 2009

Abstract
Inactivating germline mutations in phosphodiesterase 11A (PDE11A) have been implicated in adrenal tumor susceptibility. PDE11A is highly expressed in endocrine steroidogenic tissues, especially the testis, and mice with inactivated Pde11a exhibit male infertility, a known testicular germ cell tumor (TGCT) risk factor. We sequenced the PDE11A gene-coding region in 95 patients with TGCT from 64 unrelated kindreds. We identified 8 nonsynonymous substitutions in 20 patients from 15 families: four (R52T, F258Y, G291R, and V820M) were newly recognized, three (R804H, R867G, and M878V) were functional variants previously implicated in adrenal tumor predisposition, and one (Y727C) was a known polymorphism. We compared the frequency of these variants in our patients to unrelated controls that had been screened and found negative for any endocrine diseases: only the two previously reported variants, R804H and R867G, known to be frequent in general population, were detected in these controls. The frequency of all PDE11A-gene variants (combined) was significantly higher among patients with TGCT (P = 0.0002), present in 19% of the families of our cohort. Most variants were detected in the general population, but functional studies showed that all these mutations reduced PDE activity, and that PDE11A protein expression was decreased (or absent) in TGCT samples from carriers. This is the first demonstration of the involvement of a PDE gene in TGCT, although the cyclic AMP signaling pathway has been investigated extensively in reproductive organ function and their diseases. In conclusion, we report that PDE11A-inactivating sequence variants may modify the risk of familial and bilateral TGCT. [Cancer Res 2009;69(13):5301–6]
Sample Type Bias in the Analysis of Cancer Genomes
Authors: Solomon David A. , Kim Jung-Sik , Ressom Habtom W. , Sibenaller Zita , Ryken Timothy , Jean Walter , Bigner Darell , Yan Hai , Waldman Todd 
Published: July 2009

Abstract
There is widespread agreement that cancer gene discovery requires high-quality tumor samples. However, whether primary tumors or cultured samples are superior for cancer genomics has been a longstanding subject of debate. This debate has recently become more important because federally funded cancer genomics has been centralized under The Cancer Genome Atlas, which has chosen to focus exclusively on primary tumors. Here, we provide a data-driven “perspective” on the effect of sample type selection on cancer genomics research. We show that, in the case of glioblastoma multiforme, primary tumors and xenografts are best for the identification of amplifications, whereas xenografts and cell lines are superior for the identification of homozygous deletions. We also note that many of the most important oncogenes and tumor suppressor genes have been discovered through the use of cell lines and xenografts, and highlight the lack of published evidence supporting the dogma that ex vivo culture generates artifactual genetic lesions. Based on this analysis, we suggest that cancer genomics projects such as The Cancer Genome Atlas should include a variety of sample types such as xenografts and cell lines in their integrated genomic analysis of cancer. [Cancer Res 2009;69(14):5630–3]
Polyps Wrap Mast Cells and Treg within Tumorigenic Tentacles
Authors: Colombo Mario P. , Piconese Silvia 
Published: July 2009

Abstract
Gounaris and colleagues describe a previously unrecognized cross-talk between mast cells and Treg in colon adenomatous polyposis (Gounaris et al., Cancer Res 2009;69:5490–7). Adoptively transferred Treg suppress the focal mastocytosis that fosters tumor initiation and progression. In contrast, endogenous Treg, which abundantly infiltrate polyps, show proinflammatory activity under unknown microenvironmental cues that promote mast cell differentiation and expansion. Compartmentalized Treg plasticity seems to be a key factor in establishing the optimal milieu for cancer development in the intestines. Treg partnership with mast cells recapitulates the complexity of innate-adaptive networks characterizing gut inflammation and represents a novel target for cancer immunotherapy. [Cancer Res 2009;69(14):5619–22]
Endothelin B Receptor, a New Target in Cancer Immune Therapy
Authors: Kandalaft Lana E. , Facciabene Andrea , Buckanovich Ron J. , Coukos George 
Published: July 2009

Abstract
The endothelins and their G protein-coupled receptors A and B have been implicated in numerous diseases and have recently emerged as pivotal players in a variety of malignancies. Tumors overexpress the endothelin 1 (ET-1) ligand and the endothelin-A-receptor (ETAR). Their interaction induces tumor growth and metastasis by promoting tumor cell survival and proliferation, angiogenesis, and tissue remodeling. On the basis of results from xenograft models, drug development efforts have focused on antagonizing the autocrine-paracrine effects mediated by ET-1/ETAR. In this review, we discuss a novel role of the endothelin-B-receptor (ETBR) in tumorigenesis and the effect of its blockade during cancer immune therapy. We highlight key characteristics of the B receptor such as its specific overexpression in the tumor compartment; and specifically, in the tumor endothelium, where its activation by ET-1 suppresses T-cell adhesion and homing to tumors. We also review our recent findings on the effects of ETBR-specific blockade in increasing T-cell homing to tumors and enhancing the efficacy of otherwise ineffective immunotherapy.
Differential Expression of Axl and Gas6 in Renal Cell Carcinoma Reflecting Tumor Advancement and Survival
Authors: Gustafsson Anna , Martuszewska Danuta , Johansson Martin , Ekman Carl , Hafizi Sassan , Ljungberg Börje , Dahlbäck Björn 
Published: July 2009

Abstract
Purpose: Overexpression of the receptor tyrosine kinase Axl is implicated in several cancers. Therefore, we conducted this study to determine the expression of Axl and its ligand Gas6 in various renal cell carcinoma (RCC) types and in oncocytoma.
Experimental Design: Real-time quantitative reverse transcription-PCR was used to quantify tumor mRNA levels for Axl and Gas6 in a cohort (n = 221) of RCC patients. Serum levels of soluble sAxl and Gas6 proteins were measured using specific ELISA assays (n = 282). The presence of Axl protein in tumor tissue was evaluated by immunohistochemistry (n = 294). Results were correlated to tumor-associated variables, clinical biochemical tests, and patient survival.
Results: Tumor Axl mRNA levels correlated independently to survival when assessed against tumor stage and grade. In the study group, the median cancer-specific survival of all RCC patients during 307 months of follow-up was 55 months (confidence interval, ±40.4). The 25% of patients with lowest tumor Axl mRNA levels had significantly better survival than the rest (P = 0.0005), with 70% of the patients still alive at the end of follow-up. In contrast, in patients with medium-high Axl mRNA, only 25% were alive at the end of follow-up. Tumor Gas6 mRNA levels correlated to survival, tumor-associated variables, and disease severity as did serum levels of soluble sAxl and Gas6 protein. However, no correlation between Axl protein in tumor tissue and survival was found.
Conclusions: Axl and Gas6 expression in RCC are associated with tumor advancement and patient survival. In particular, low tumor Axl mRNA levels independently correlated with improved survival.
Release of HMGB1 in Response to Proapoptotic Glioma Killing Strategies: Efficacy and Neurotoxicity
Authors: Candolfi Marianela , Yagiz Kader , Foulad David , Alzadeh Gabrielle E. , Tesarfreund Matthew , Muhammad A.K.M. Ghulam , Puntel Mariana , Kroeger Kurt M. , Liu Chunyan , Lee Sharon , Curtin James F. , King Gwendalyn D. , Lerner Jonathan , Sato Katsuaki , Mineharu Yohei , Xiong Weidong , Lowenstein Pedro R. , Castro Maria G. 
Published: July 2009

Abstract
Purpose: In preparation for a phase I clinical trial using a combined cytotoxic/immunotherapeutic strategy with adenoviruses (Ad) expressing Flt3L (Ad-Flt3L) and thymidine kinase (Ad-TK) to treat glioblastoma (GBM), we tested the hypothesis that Ad-TK+GCV would be the optimal tumor-killing agent in relation to efficacy and safety when compared with other proapoptotic approaches.
Experimental Design: The efficacy and neurotoxicity of Ad-TK+GCV was compared with Ads encoding the proapoptotic cytokines [tumor necrosis factor-α, tumor necrosis factor–related apoptosis-inducing factor (TRAIL), and Fas ligand (FasL)], alone or in combination with Ad-Flt3L. In rats bearing small GBMs (day 4), only Ad-TK+GCV or Ad-FasL improved survival.
Results: In rats bearing large GBMs (day 9), the combination of Ad-Flt3L with Ad-FasL did not improve survival over FasL alone, whereas Ad-Flt3L combined with Ad-TK+GCV led to 70% long-term survival. Expression of FasL and TRAIL caused severe neuropathology, which was not encountered when we used Ad-TK+/−Ad-Flt3L. In vitro, all treatments elicited release of high mobility group box 1 protein (HMGB1) from dying tumor cells. In vivo, the highest levels of circulating HMGB1 were observed after treatment with Ad-TK+GCV+Ad-Flt3L; HMGB1 was necessary for the therapeutic efficacy of AdTK+GCV+Ad-Flt3L because its blockade with glycyrrhizin completely blocked tumor regression. We also showed the killing efficacy of Ad-TK+GCV in human GBM cell lines and GBM primary cultures, which also elicited release of HMGB1.
Conclusions: Our results indicate that Ad-TK+GCV+Ad-Flt3L exhibit the highest efficacy and safety profile among the several proapoptotic approaches tested. The results reported further support the implementation of this combined approach in a phase I clinical trial for GBM.