bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Aldehyde Dehydrogenase Activity Identifies Tumor-Initiating and Metastasis-Initiating Cells in Human Prostate Cancer
Authors: van den Hoogen Christel , van der Horst Geertje , Cheung Henry , Buijs Jeroen T. , Lippitt Jenny M. , Guzmán-Ramírez Natalia , Hamdy Freddie C. , Eaton Colby L. , Thalmann George N. , Cecchini Marco G. , Pelger Rob C.M. , van der Pluijm Gabri 
Published: June 2010

Abstract
Metastatic progression of advanced prostate cancer is a major clinical problem. Identifying the cell(s) of origin in prostate cancer and its distant metastases may permit the development of more effective treatment and preventive therapies. In this study, aldehyde dehydrogenase (ALDH) activity was used as a basis to isolate and compare subpopulations of primary human prostate cancer cells and cell lines. ALDH-high prostate cancer cells displayed strongly elevated clonogenicity and migratory behavior in vitro. More strikingly, ALDH-high cells readily formed distant metastases with strongly enhanced tumor progression at both orthotopic and metastatic sites in preclinical models. Several ALDH isoforms were expressed in human prostate cancer cells and clinical specimens of primary prostate tumors with matched bone metastases. Our findings suggest that ALDH-based viable cell sorting can be used to identify and characterize tumor-initiating and, more importantly perhaps, metastasis-initiating cells in human prostate cancer. Cancer Res; 70(12); 5163–73. ©2010 AACR.
Distinct Genomic Alterations in Prostate Cancers in Chinese and Western Populations Suggest Alternative Pathways of Prostate Carcinogenesis
Authors: Mao Xueying , Yu Yongwei , Boyd Lara K. , Ren Guoping , Lin Dongmei , Chaplin Tracy , Kudahetti Sakunthala C. , Stankiewicz Elzbieta , Xue Liyan , Beltran Luis , Gupta Manu , Oliver R. Tim D. , Lemoine Nick R. , Berney Daniel M. , Young Bryan D. , Lu Yong-Jie 
Published: June 2010

Abstract
Prostate cancer is significantly more common in Western men than in Asian men, but the basis for this difference remains unknown. Because genomic studies of Asian prostate cancer are very limited, we used a genome-wide approach to reveal the genomic alterations in Chinese prostate cancers. We found a significant reduction in the frequency of certain somatic genomic changes that are commonly found in Western prostate cancers, including the 21q22.2-22.3 deletion, which involves the TMPRSS2:ERG fusion gene, and 10q deletion, which causes PTEN inactivation. Array results were confirmed by PCR-based molecular copy-number counting in selected samples. The different frequencies of these genomic changes were further evaluated by fluorescent in situ hybridization and immunohistochemistry analyses of tissue microarray samples. These alterations might be key genetic changes underlying the regional/ethnic difference in clinical incidence and might be induced by specific environmental and/or genetic risk factors that Western men are exposed to. Our findings suggest that tumors arise in Western and Chinese populations by alternative pathogenetic mechanisms. Cancer Res; 70(13); 5207–12. ©2010 AACR.
A Mouse Model of Melanoma Driven by Oncogenic KRAS
Authors: Milagre Carla , Dhomen Nathalie , Geyer Felipe C. , Hayward Robert , Lambros Maryou , Reis-Filho Jorge S. , Marais Richard 
Published: June 2010

Abstract
The small G-protein NRAS is mutated in 22% of human melanomas, whereas the related proteins KRAS and HRAS are mutated in only 2% and 1% of melanomas, respectively. We have developed a mouse model of melanoma in which Cre recombinase/LoxP technology is used to drive inducible expression of G12VKRAS in the melanocytic lineage. The mice develop skin hyperpigmentation, nevi, and tumors that bear many of the cardinal histopathology features and molecular characteristics of human melanoma. These tumors invade and destroy the underlying muscles and cells derived from them can grow as subcutaneous tumors and colonize the lungs of nude mice. These data establish that oncogenic KRAS can be a founder event in melanomagenesis. Cancer Res; 70(13); 5549–57. ©2010 AACR.
Molecular Causes for BUBR1 Dysfunction in the Human Cancer Predisposition Syndrome Mosaic Variegated Aneuploidy
Authors: Suijkerbuijk Saskia J.E. , van Osch Maria H.J. , Bos Frank L. , Hanks Sandra , Rahman Nazneen , Kops Geert J.P.L. 
Published: June 2010

Abstract
Genetic mutations in the mitotic regulatory kinase BUBR1 are associated with the cancer-susceptible disorder mosaic variegated aneuploidy (MVA). In patients with biallelic mutations, a missense mutation pairs with a truncating mutation. Here, we show that cell lines derived from MVA patients with biallelic mutations have an impaired mitotic checkpoint, chromosome alignment defects, and low overall BUBR1 abundance. Ectopic expression of BUBR1 restored mitotic checkpoint activity, proving that BUBR1 dysfunction causes chromosome segregation errors in the patients. Combined analysis of patient cells and functional protein replacement shows that all MVA mutations fall in two distinct classes: those that impose specific defects in checkpoint activity or microtubule attachment and those that lower BUBR1 protein abundance. Low protein abundance is the direct result of the absence of transcripts from truncating mutants combined with high protein turnover of missense mutants. In this group of missense mutants, the amino acid change consistently occurs in or near the BUBR1 kinase domain. Our findings provide a molecular explanation for chromosomal instability in patients with biallelic genetic mutations in BUBR1. Cancer Res; 70(12); 4891–900. ©2010 AACR.
Reduced Reactive Oxygen Species–Generating Capacity Contributes to the Enhanced Cell Growth of Arsenic-Transformed Epithelial Cells
Authors: Chang Qingshan , Pan Jingju , Wang Xing , Zhang Zhuo , Chen Fei , Shi Xianglin 
Published: June 2010

Abstract
Reactive oxygen species (ROS) have been implicated in the activation of protein kinases, DNA damage responses, and cell apoptosis. The details of how ROS regulate these intracellular biochemical and genetic processes remain to be fully understood. By establishing transformed bronchial epithelial cells through chronic low-dose arsenic treatment, we showed that the capacity of ROS generation induced by arsenic is substantially reduced in the transformed cells relative to the nontransformed cells. Such a reduction in ROS generation endows cells with premalignant features, including rapid growth, resistance to arsenic toxicity, and increased colony formation of the transformed cells. To validate these observations, the capability of ROS generation was restored in the transformed cells by treatment with inhibitors or siRNAs to silence the function of superoxide dismutase (SOD) or catalase and cell growth was determined following these treatments. Enhancement in ROS generation suppressed cell growth and colony formation of the transformed cells significantly. Despite the fact that the transformed cells showed a decreased expression of NF-κB signaling proteins IKKβ and IKKγ, the proteolytic processing p105 and p100 and NF-κB DNA binding activity were elevated in these cells. Increasing ROS generation by silencing SOD and catalase reduced the DNA binding activity of NF-κB in the transformed cells. Taken together, the transformed cells induced by arsenic exhibited a decrease in ROS generation, which is responsible for the enhanced cell growth and colony formation of the transformed cells, most likely through a sustained alternative activation of the NF-κB transcription factor. Cancer Res; 70(12); 5127–35. ©2010 AACR.
Taspase1 Functions as a Non-Oncogene Addiction Protease that Coordinates Cancer Cell Proliferation and Apoptosis
Authors: Chen David Y. , Liu Han , Takeda Shugaku , Tu Ho-Chou , Sasagawa Satoru , Van Tine Brian A. , Lu Dongsi , Cheng Emily H-Y. , Hsieh James J-D. 
Published: June 2010

Abstract
Taspase1, the mixed lineage leukemia and TFIIAα-β cleaving protease, enables cell proliferation and permits oncogenic initiation. Here, we show its critical role in cancer maintenance and thus offer a new anticancer target. Taspase1 is overexpressed in primary human cancers, and deficiency of Taspase1 in cancer cells not only disrupts proliferation but also enhances apoptosis. Mechanistically, loss of Taspase1 induces the levels of CDK inhibitors (CDKI: p16, p21, and p27) and reduces the level of antiapoptotic MCL-1. Therapeutically, deficiency of Taspase1 synergizes with chemotherapeutic agents and ABT-737, an inhibitor of BCL-2/BCL-XL, to kill cancer cells. Taspase1 alone or in conjunction with MYC, RAS, or E1A fails to transform NIH/3T3 cells or primary mouse embryonic fibroblasts, respectively, but plays critical roles in cancer initiation and maintenance. Therefore, Taspase1 is better classified as a “non-oncogene addiction” protease, the inhibition of which may offer a novel anticancer therapeutic strategy. The reliance of oncogenes on subordinate non-oncogenes during tumorigenesis underscores the non-oncogene addiction hypothesis in which a large class of non-oncogenes functions to maintain cancer phenotypes and presents attractive anticancer therapeutic targets. The emergence of successful cancer therapeutics targeting non-oncogenes to which cancers are addicted supports the future development and potential application of small-molecule Taspase1 inhibitors for cancer therapy. Cancer Res; 70(13); 5358–67. ©2010 AACR.
Periostin, a Cell Adhesion Molecule, Facilitates Invasion in the Tumor Microenvironment and Annotates a Novel Tumor-Invasive Signature in Esophageal Cancer
Authors: Michaylira Carmen Z. , Wong Gabrielle S. , Miller Charles G. , Gutierrez Christie M. , Nakagawa Hiroshi , Hammond Rachel , Klein-Szanto Andres J. , Lee Ju-Seog , Kim Sang Bae , Herlyn Meenhard , Diehl J. Alan , Gimotty Phyllis , Rustgi Anil K. 
Published: June 2010

Abstract
Human squamous cell cancers are the most common epithelially derived malignancies. One example is esophageal squamous cell carcinoma (ESCC), which is associated with a high mortality rate that is related to a propensity for invasion and metastasis. Here, we report that periostin, a highly expressed cell adhesion molecule, is a key component of a novel tumor-invasive signature obtained from an organotypic culture model of engineered ESCC. This tumor-invasive signature classifies with human ESCC microarrays, underscoring its utility in human cancer. Genetic modulation of periostin promotes tumor cell migration and invasion as revealed in gain-of-loss and loss-of-function experiments. Inhibition of epidermal growth factor receptor signaling and restoration of wild-type p53 function were each found to attenuate periostin, suggesting the interdependence of two common genetic alterations with periostin function. Collectively, our studies reveal periostin as an important mediator of ESCC tumor invasion and they indicate that organotypic (three-dimensional) culture can offer an important tool to discover novel biological effectors in cancer. Cancer Res; 70(13); 5281–92. ©2010 AACR.
BNC105: A Novel Tubulin Polymerization Inhibitor That Selectively Disrupts Tumor Vasculature and Displays Single-Agent Antitumor Efficacy
Authors: Kremmidiotis Gabriel , Leske Annabell F. , Lavranos Tina C. , Beaumont Donna , Gasic Jelena , Hall Allison , O'Callaghan Michael , Matthews Clayton A. , Flynn Bernard 
Published: June 2010

Abstract
Vascular disruption agents (VDA) cause occlusion of tumor vasculature, resulting in hypoxia-driven tumor cell necrosis. Tumor vascular disruption is a therapeutic strategy of great potential; however, VDAs currently under development display a narrow therapeutic margin, with cardiovascular toxicity posing a dose-limiting obstacle. Discovery of new VDAs, which display a wider therapeutic margin, may allow attainment of improved clinical outcomes. To identify such compounds, we used an in vitro selectivity screening approach that exploits the fact that tumor endothelial cells are in a constant state of activation and angiogenesis and do not undergo senescence. Our effort yielded the compound BNC105. This compound acts as a tubulin polymerization inhibitor and displays 80-fold higher potency against endothelial cells that are actively proliferating or are engaged in the formation of in vitro capillaries compared with nonproliferating endothelial cells or endothelium found in stable capillaries. This selectivity was not observed with CA4, a VDA currently under evaluation in phase III clinical trials. BNC105 is more potent and offers a wider therapeutic window. CA4 produces 90% vascular disruption at its no observed adverse event level (NOAEL), whereas BNC105 causes 95% vascular disruption at 1/8th of its NOAEL. Tissue distribution analysis of BNC105 in tumor-bearing mice showed that while the drug is cleared from all tissues 24 hours after administration, it is still present at high concentrations within the solid tumor mass. Furthermore, BNC105 treatment causes tumor regressions with complete tumor clearance in 20% of treated animals. Mol Cancer Ther; 9(6); 1562–73. ©2010 AACR.
Blockade of Rac1 Activity Induces G1 Cell Cycle Arrest or Apoptosis in Breast Cancer Cells through Downregulation of Cyclin D1, Survivin, and X-Linked Inhibitor of Apoptosis Protein
Authors: Yoshida Tatsushi , Zhang Yaqin , Rivera Rosado Leslie A. , Chen Junjie , Khan Tahira , Moon Sun Young , Zhang Baolin 
Published: June 2010

Abstract
Rac1 GTPase regulates a variety of signaling pathways that are implicated in malignant phenotypes. Here, we show that selective inhibition of Rac1 activity by the pharmacologic inhibitor NSC23766 suppressed cell growth in a panel of human breast cancer cell lines, whereas it had little toxicity to normal mammary epithelial cells. NSC23766 elicits its cytotoxicity via two distinct mechanisms in a cell line–dependent manner: induction of G1 cell cycle arrest in cell lines (MDA-MB-231, MCF7, and T47D) that express retinoblastoma (Rb) protein or apoptosis in Rb-deficient MDA-MB-468 cells. In MDA-MB-231 cells, Rac1 inhibition induced G1 cell cycle arrest through downregulation of cyclin D1 and subsequent dephosphorylation/inactivation of Rb. By contrast, MDA-MB-468 cells underwent substantial apoptosis that was associated with loss of antiapoptotic proteins survivin and X-linked inhibitor of apoptosis protein (XIAP). Rac1 knockdown by RNAi interference confirmed the specificity of NSC23766 and requirement for Rac1 in the regulation of cyclin D1, survivin, and XIAP in breast cancer cells. Further, NF-κB, but not c-Jun NH2-terminal kinase or p38 pathways, mediates the survival signal from Rac1. Overall, our results indicate that Rac1 plays a central role in breast cancer cell survival through regulation of NF-κB–dependent gene products. Mol Cancer Ther; 9(6); 1657–68. ©2010 AACR.
Bortezomib Sensitizes Human Esophageal Squamous Cell Carcinoma Cells to TRAIL–Mediated Apoptosis via Activation of Both Extrinsic and Intrinsic Apoptosis Pathways
Authors: Seki Naoko , Toh Uhi , Sayers Thomas J. , Fujii Teruhiko , Miyagi Motoshi , Akagi Yoshito , Kusukawa Jingo , Kage Masayoshi , Shirouzu Kazuo , Yamana Hideaki 
Published: June 2010

Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive human cancers, and novel treatment modalities are required. We investigated the therapeutic potential of the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL/Apo2L) in combination with the proteasome inhibitor bortezomib (Velcade) on human ESCC cell lines. Bortezomib enhanced the susceptibility to TRAIL in 12 of the 15 ESCC cell lines tested, although most showed low sensitivity to TRAIL as a single agent. The enhancement of TRAIL-induced apoptosis by bortezomib was caspase dependent. Increased processing of caspase-8 often accompanied enhancement of TRAIL-induced apoptosis by bortezomib. However, the increased cell surface expression of death receptors observed on bortezomib treatment did not seem to be crucial for this effect. For some ESCC, bortezomib treatment resulted in a more efficient recruitment of caspase-8 and the Fas-associated death domain to the death-inducing signaling complex. Additional downregulation of the cellular FLICE-inhibitory protein long isoform [c-FLIP(L)] could cooperate in the activation of the extrinsic pathway in some cases. For other ESCC, the crucial effect of bortezomib treatment seemed to be increased signaling via the intrinsic apoptotic pathway on subsequent exposure to TRAIL. Thus, bortezomib could sensitize ESCC to TRAIL apoptosis by multiple molecular mechanisms of action. Therefore, the combination of bortezomib and TRAIL might be a novel therapeutic strategy for ESCC patients who fail to respond to standard chemoradiotherapy that predominantly targets the mitochondrial apoptotic pathway. Mol Cancer Ther; 9(6); 1842–51. ©2010 AACR.
Improved Antitumor Activity and Tumor Targeting of NH2-Terminal–Specific PEGylated Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand
Authors: Chae Su Young , Kim Tae Hyung , Park Kyeongsoon , Jin Cheng-Hao , Son Sohee , Lee Seulki , Youn Yu Seok , Kim Kwangmeyung , Jo Dong-Gyu , Kwon Ick Chan , Chen Xiaoyuan , Lee Kang Choon 
Published: June 2010

AbstractTumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is considered an attractive anticancer agent due to its tumor cell–specific cytotoxicity. However, its low stability, solubility, unexpected side effects, and weak pharmacokinetic profiles restrict its successful clinical application. To develop efficient TRAIL-based anticancer biotherapeutics, a new version of trimeric TRAIL was constructed by incorporating trimer-forming zipper sequences (HZ-TRAIL), and then NH2-terminal–specific PEGylation was done to produce PEGylated TRAIL (PEG-HZ-TRAIL). The biological, physicochemical, and pharmaceutical characteristics of PEG-HZ-TRAIL were then investigated using various in vitro and in vivo experiments, including a cell-based cytotoxicity test, a solubility test, pharmacokinetic analysis, and antitumor efficacy evaluations. Although slight activity loss occurred after PEGylation, PEG-HZ-TRAIL showed excellent tumor cell–specific cytotoxic effects via apoptotic pathways with negligible normal cell toxicity. The stability and pharmacokinetic problems of HZ-TRAIL were successfully overcome by PEGylation. Furthermore, in vivo antitumor tests revealed that PEG-HZ-TRAIL treatment enhanced therapeutic potentials compared with HZ-TRAIL in tumor xenograft animal models, and these enhancements were attributed to its better pharmacokinetic properties and tumor-targeting performance. These findings show that PEG-HZ-TRAIL administration provides an effective antitumor treatment, which exhibits superior tumor targeting and better inhibits tumor growth, and suggest that PEG-HZ-TRAIL should be considered a potential candidate for antitumor biotherapy. Mol Cancer Ther; 9(6); 1719–29. ©2010 AACR.
Docetaxel-Resistant Prostate Cancer Cells Remain Sensitive toS-Trityl-l-Cysteine–Mediated Eg5 Inhibition
Authors: Wiltshire Carolyn , Singh Babloo L. , Stockley Jacqueline , Fleming Janis , Doyle Brendan , Barnetson Robert , Robson Craig N. , Kozielski Frank , Leung Hing Y. 
Published: June 2010

AbstractCastrate-resistant prostate cancer remains a major clinical challenge. Due to the toxicity profile of taxane-based chemotherapy and treatment failure in some patients, novel agents with improved efficacy to side effect profiles are urgently needed. Eg5, a member of the kinesin-5 family, controls the formation of the bipolar spindle during cell division, and suppressed Eg5 function leads to mitotic arrest. S-Trityl-l-cysteine (STLC) is a novel Eg5-specific small-molecule inhibitor. Here, we report the first study to evaluate its use in prostate cancer. In a panel of prostate cancer cells, LNCaP and PC3 cells were the most and least sensitive to STLC treatment, with a 7.2-fold difference in their respective GI50 values: 250 nmol/L and 1.8 μmol/L. In LNCaP cells, treatment with either STLC or docetaxel resulted in transient G2-M arrest and subsequent caspase-mediated cell death. However, STLC- and docetaxel-treated PC3M cells have distinct fates: STLC induced a transient G2-M arrest, followed by polyploidy; in contrast, docetaxel-treated PC3M cells progressed to apoptosis after a transient G2-M arrest. Docetaxel-resistant LNCaP-derived (LDocR) cells respond to STLC in a similar manner to the parental cells. Although the docetaxel-resistant PC3M-derived (PDocR) cell line and its parental PC3M cells have similar GI50 to STLC treatment, PDocR cells showed significantly more G2-M arrest and less apoptosis. Hence, although docetaxel-resistant prostate cancer cells remain responsive to Eg5 inhibition with STLC, there are key differences at the cell cycle level, which may have implication in future development. Mol Cancer Ther; 9(6); 1730–9. ©2010 AACR.
ErbB-Inhibitory Protein: A Modified Ectodomain of Epidermal Growth Factor Receptor Synergizes with Dasatinib to Inhibit Growth of Breast Cancer Cells
Authors: Nautiyal Jyoti , Yu Yingjie , Aboukameel Amro , Kanwar Shailender S. , Das Jayanta K. , Du Jianhua , Patel Bhaumik B. , Sarkar Fazlul H. , Rishi Arun K. , Mohammad Ramzi M. , Majumdar Adhip P.N. 
Published: June 2010

Abstract
Many solid tumors, including breast cancer, show increased activation of several growth factor receptors, specifically epidermal growth factor receptor (EGFR) and its family members as well as c-Src, a nonreceptor tyrosine kinase that promotes proliferation, inhibits apoptosis, and induces metastasis. We hypothesize that inhibition of c-Src and EGFRs will be an effective therapeutic strategy for triple-negative breast cancer. To test our hypothesis, we used a c-Src–specific inhibitor dasatinib (BMS-354825; Bristol-Myers Squibb) and our newly developed ErbB-inhibitory protein (EBIP), a potential pan-ErbB inhibitor, in breast cancer cells. EBIP is composed of 1 to 448 amino acids of the ectodomain of human EGFR to which the 30–amino acid epitope (known as “U” region) of rat EGFR-related protein is fused at the COOH-terminal end. The combination of dasatinib and EBIP was found to be highly effective in inhibiting the growth of four different breast cancer cells (MDA-MB-468, SKBr-3, MDA-MB-453, and MDA-MB-231) that express different levels of EGFRs. In EGFR-overexpressing MDA-MB-468 cells, the combination, but not monotherapy, markedly stimulated apoptosis mediated by caspase-9 and caspase-8 and attenuated activation of EGFR and Src as well as tyrosine kinase activity. EBIP also inhibited heregulin-induced activation of HER-2 and HER-3 in MDA-MB-453 breast cancer cells. The combination therapy was highly effective in suppressing tumor growth (∼90% inhibition) in MDA-MB-468–derived xenografts in severe combined immunodeficient mice. The latter could be attributed to induction of apoptosis. We conclude that combining dasatinib and EBIP could be an effective therapeutic strategy for breast cancer by targeting EGFRs and Src signaling. Mol Cancer Ther; 9(6); 1503–14. ©2010 AACR.