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Source: Cancer Research
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Total 807 results found since Jan 2013.
Abstract B43: Dose and context-dependent roles for Arid1a in liver tumorigenesis
Frequent Arid1a loss-of-function mutations suggest tumor suppressive roles, but the functional impact of Arid1a and SWI/SNF chromatin-remodeling aberrations in human cancer are not clear. Liver-specific Arid1a knockout mice do not develop cancer after 15 months and surprisingly, homozygous mice are potently protected from diethylnitrosamine (DEN) + carbon tetrachloride induced hepatocellular carcinoma (HCC). This is likely due to the fact that Arid1a deficient livers are resistant to chemical damage in a Cytochrome P450 dependent fashion. To determine if genetic drivers of cancer might reveal additional roles for Arid1a, w...
Source: Cancer Research - January 14, 2016 Category: Cancer & Oncology Authors: Sun, X., Wang, S., Nguyen, L., Zhu, H. Tags: Epigenetic Cancer Therapies Source Type: research
Th17 Recruitment via Cervical Cancer-Instructed Fibroblasts
In this study, we demonstrate that CCL20 was predominantly expressed in the stroma of cervical squamous cell carcinomas in situ. This correlated with stromal infiltration of CD4+/IL17+ cells and with advancing International Federation of Gynecology and Obstetrics (FIGO) stage. Furthermore, we show that cervical cancer cells instructed primary cervical fibroblasts to produce high levels of CCL20 and to attract CD4/IL17/CCR6-positive cells, generated in vitro, in a CCL20/CCR6-dependent manner. Further mechanistic investigations identified cervical cancer cell–derived IL6 as an important mediator of paracrine CCL20 inductio...
Source: Cancer Research - December 14, 2015 Category: Cancer & Oncology Authors: Walch–Ruckheim, B., Mavrova, R., Henning, M., Vicinus, B., Kim, Y.–J., Bohle, R. M., Juhasz–Boss, I., Solomayer, E.–F., Smola, S. Tags: Microenvironment and Immunology Source Type: research
Abstract A02: Identification of distinct BUB1B-sensitive and -resistant subtypes of glioblastoma with prognostic value
Glioblastoma multiforme is the most aggressive and common form of brain cancer in adults. The combined analysis of functional genetics with glioblastoma (GBM) network modeling identified BUB1B, a critical mitotic spindle checkpoint player, as a new requirement of glioblastoma tumors to suppress lethal consequences of altered kinetochore (KT) (1). Here, we further collected GBM stem-like cells (GSCs) including both BUB1B-sensitive and -resistant isolates, and performed whole-transcriptome sequencing that capture gene expression levels of each GSC. Based on the expression signature associated with BUB1B-sensitiveness from GS...
Source: Cancer Research - December 9, 2015 Category: Cancer & Oncology Authors: Lee, E., Paddison, P. J., Zhu, J. Tags: Computational Genomics and Evolutionary Dynamics Source Type: research
Abstract B12: GABP selectively binds and activates the mutant TERT promoter across multiple cancer types
Reactivation of telomerase reverse transcriptase (TERT) expression enables cells to overcome replicative senescence and escape apoptosis, fundamental steps in the initiation of human cancer. Multiple cancer types, including up to 83% of glioblastomas (GBM), harbor highly recurrent mutations in the TERT promoter specific to two nucleotide positions. The common mutation sites, G228A and G250A, may create de-novo ETS family transcription factor binding sites, but the precise mechanism of how these mutations confer increased TERT expression has been elusive. Here, we demonstrate the de-novo ETS motif to be critical for mutant ...
Source: Cancer Research - December 9, 2015 Category: Cancer & Oncology Authors: Bell, R. J. A., Rube, H. T., Kreig, A., Mancini, A., Fouse, S. F., Nagarajan, R. P., Choi, S., Hong, C., He, D., Pekmezci, M., Wiencke, J. K., Wrensch, M. R., Chang, S. M., Walsh, K. M., Myong, S., Song, J. S., Costello, J. F. Tags: Mutational Landscape in Brain Tumors Source Type: research
Abstract A26: Inhibition of MDM2 and AKT signaling networks synergize to activate Forkhead box O-class transcription factors and promote cell death in mutant p53 GBM cells
A multi-targeted approach will be necessary to eradicate glioblastoma multiforme (GBM) cells due to the immense genetic heterogeneity associated with GBM. Mouse double minute-2 (MDM2) regulates multiple signaling pathways and is a promising therapeutic target in GBM. In wild type (wt) p53 cells, MDM2 binds to wtp53, ubiquitinates it, and negatively regulates p53-mediated downstream events. In wtp53 and mutant (mt) p53 cells, MDM2 binds to and sequesters p73α thereby blocking p73α-mediated signaling. Our objective in the present studies was to determine if the p73α-MDM2 axis could be exploited to increase death of mtp53 ...
Source: Cancer Research - December 9, 2015 Category: Cancer & Oncology Authors: Saadatzadeh, M. R., Wang, H., Ding, J., Bailey, B. J., Tonsing-Carter, E., Cai, S., Dave, N., Shannon, H. E., Gadol, A. C.-, Pollok, K. E. Tags: Preclinical Therapeutics/Trials/Models Source Type: research
Abstract B26: MAPK-interacting kinase inhibition sensitizes glioblastoma and glioma stem cells to arsenic trioxide
In this study, we sought to determine the mechanisms by which MNK signaling regulates arsenic trioxide responses in GBM and glioma stem cells.GBM cell lines were treated with ATO in the presence or absence of MNK inhibitors or siRNA against MNK isoforms. Western blots of treated samples were analyzed with antibodies against phosphorylated eIF4E, the key downstream effector of the MNKs. Following treatment with ATO and MNK inhibitors, proliferation rate and apoptosis were determined by WST-1 assay and Annexin V-FITC/PI staining. GBM cell lines were grown under stem cell conditions and subjected to qPCR and flow cytometry to...
Source: Cancer Research - December 9, 2015 Category: Cancer & Oncology Authors: Bell, J. B., Eckerdt, F., Arslan, A. D., Iqbal, A., Alvarez, A. A., Cheng, S.-Y., Nakano, I., Platanias, L. C. Tags: Preclinical Therapeutics/Trials/Models Source Type: research
Abstract A2-18: The challenges of using large-scale genomics data to identify novel drivers of lung cancer
Lung cancer is one of the major causes of cancer deaths worldwide and only 30% of patients survive the disease for at least one year after diagnosis. Patients are often too frail to receive systemic chemotherapy and there is an urgent need for less toxic, efficacious, targeted therapies. Despite recent efforts with large-scale genomics data we still lack knowledge about driver mutations for the majority of lung cancers.Increasingly, cancer researchers are using online cancer genomic databases to identify novel targets to investigate. A comparison of two prominent databases from different institutes (CCLE and COSMIC) reveal...
Source: Cancer Research - November 15, 2015 Category: Cancer & Oncology Authors: Hudson, A. M., Yates, T., Wirth, C., Li, Y., Trotter, W., Fawdar, S., Miller, C., Brognard, J. Tags: Genomics and Target Discovery Source Type: research
Abstract A1-05: Elucidation of epigenetic driver genes in clear cell renal cell carcinoma using a newly developed assay, AcceSssIble
Conclusions: Our study revealed a vast number of chromatin accessibility and accompanying gene expression changes that occur in gene promoters in the development of ccRCC, both dependent and independent of DNA methylation changes. Each individual tumor has a unique profile of epigenetic alterations. Moreover, almost none of the genes that were found to undergo epigenetic and resulting gene expression changes overlap with TCGA's findings of commonly mutated genes in ccRCC. Overall, these studies represent novel approaches that can help identify new therapeutic target genes and treatment strategies for ccRCC, including perso...
Source: Cancer Research - November 15, 2015 Category: Cancer & Oncology Authors: Becket, E. C., Duymich, C., Chang, Y.-W., Pandiyan, K., Nichols, P., Jones, P., Gill, I., Liang, G. Tags: Cancer Genomics and Epigenomics Source Type: research
Aki1 Is a Therapeutic Target in DMM
Diffuse malignant mesothelioma (DMM) is a tumor of serosal membranes with propensity for progressive local disease. Because current treatment options are largely ineffective, novel therapeutic strategies based on molecular mechanisms and the disease characteristics are needed to improve the outcomes of patients with this disease. Akt kinase interacting protein 1 (Aki1; Freud-1/CC2D1A) is a scaffold protein for the PI3K–PDK1–Akt signaling module that helps determine receptor signal selectivity for EGFR. Aki1 has been suggested as a therapeutic target, but its potential has yet to be evaluated in a tumor setting. Here, w...
Source: Cancer Research - September 30, 2015 Category: Cancer & Oncology Authors: Yamada, T., Amann, J. M., Fukuda, K., Takeuchi, S., Fujita, N., Uehara, H., Iwakiri, S., Itoi, K., Shilo, K., Yano, S., Carbone, D. P. Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
C-Raf Colocalizes with DAPK in the Mitochondria
This study identified the interaction of C-Raf with S308 phosphorylated DAPK (pDAPKS308), which together became colocalized in the mitochondria to facilitate mitochondrial remodeling. Combined use of the Raf inhibitors sorafenib and GW5074 had synergistic anticancer effects in vitro and in vivo, but targeted mitochondrial function, rather than the canonical Raf signaling pathway. C-Raf depletion in knockout MEFC-Raf−/− or siRNA knockdown ACHN renal cancer cells abrogated the cytotoxicity of combination therapy. Crystal structure simulation showed that GW5074 bound to C-Raf and induced a C-Raf conformational change that...
Source: Cancer Research - August 31, 2015 Category: Cancer & Oncology Authors: Tsai, Y.-T., Chuang, M.-J., Tang, S.-H., Wu, S.-T., Chen, Y.-C., Sun, G.-H., Hsiao, P.-W., Huang, S.-M., Lee, H.-J., Yu, C.-P., Ho, J.-Y., Lin, H.-K., Chen, M.-R., Lin, C.-C., Chang, S.-Y., Lin, V. C., Yu, D.-S., Cha, T.-L. Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Abstract 4: ABT-263 is effective in a subset of non-small cell lung cancer cell lines
Conclusion:We found that Calu3 and BID007 were sensitive to ABT-263. In the sensitive NSCLC cell lines, ABT-263 induces apoptosis irrespective of Mcl-1 expression levels.Citation Format: Aoi Kuroda, Keiko Ohgino, Hiroyuki Yasuda, Junko Hamamoto, Daisuke Arai, Kota Ishioka, Tetsuo Tani, Shigenari Nukaga, Ichiro Kawada, Katsuhiko Naoki, Kenzo Soejima, Tomoko Betsuyaku. ABT-263 is effective in a subset of non-small cell lung cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Kuroda, A., Ohgino, K., Yasuda, H., Hamamoto, J., Arai, D., Ishioka, K., Tani, T., Nukaga, S., Kawada, I., Naoki, K., Soejima, K., Betsuyaku, T. Tags: Molecular and Cellular Biology Source Type: research
Abstract 8: Differential roles of OCT3/4, SOX2 and NANOG for constitutive high NOXA expression levels in embryonal carcinoma (EC) cells
Recently we found that hypersensitivity of embryonal carcinoma (EC) to chemotherapy is mediated by high constitutive levels of NOXA protein. This pro-apoptotic BH3-only protein primes EC cells to undergo rapid and massive apoptosis in response to p53 activation. Both hypersensitivity as well as high NOXA protein levels were lost upon differentiation in these cells. We here investigated the role of three key regulators of pluripotency, namely OCT3/4, SOX2 and NANOG for NOXA protein and transcript (PMAIP1) expression in two EC cell lines, the pluripotent NTERA-2D1 and the nullipotent 2102EP. We found that siRNA-mediated sile...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Bayha, C., Gutekunst, M., Aulitzky, W. E., van der Kuip, H. Tags: Molecular and Cellular Biology Source Type: research
Abstract 11: Molecular mechanisms of inverse association between cancer and Alzheimer's disease
Apoptosis has been implicated in both cancer and neurodegenerative disease such as Alzheimer's disease (AD). Defective or inefficient apoptosis is an acquired hallmark of cancer cells, while cytochrome c-dependent apoptosis is a crucial pathway in AD related neuronal cell death. Notably, recent studies have revealed an inverse correlation between development of cancer and AD—AD patients show a reduced risk of cancer, while cancer survivors are less likely to acquire AD. Here we propose that amyloid β (Aβ), a widely accepted pathological culprit of AD, hijacks the intrinsic apoptotic pathway eliciting different symptoms...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Yang, Y., Lee, E., Kim, I.-S. Tags: Molecular and Cellular Biology Source Type: research
Abstract 12: Bclxl is a key regulator of mitochondria-induced apoptosis in ovarian cancer stem cells
Conclusion:Ovarian cancer stem cells have a unique mitochondrial phenotype and Bclxl is a key regulator of its stability and may play a role in resistance to chemotherapy-induced apoptosis. Targeting Bclxl may be an approach to complement current standard of care in ovarian cancer. The demonstration that apoptosis can be fully induced with minimal loss of Bclxl suggests an acceptable therapeutic window for Bclxl inhibitors.Citation Format: Ayesha B. Alvero, Mary Pitruzello, Michele Montagna, Eydis Lima, Gil Mor. Bclxl is a key regulator of mitochondria-induced apoptosis in ovarian cancer stem cells. [abstract]. In: Proceed...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Alvero, A. B., Pitruzello, M., Montagna, M., Lima, E., Mor, G. Tags: Molecular and Cellular Biology Source Type: research
Abstract 15: gp78 is a negative regulator of TRAIL-induced apoptosis in breast cancer cells
TNF-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in transformed cells by activating the extrinsic apoptotic pathway via its cognate receptors on the cell surface, TRAIL receptor 1 and TRAIL receptor 2. Triple negative breast cancer (TNBC) cells (so-called because TNBC lacks estrogen and progesterone receptor expression and Her-2 amplification) have been found to be sensitive to TRAIL while breast cancer cells of other subtypes of disease remain relatively resistant. Unfortunately, the mechanisms that govern sensitivity to TRAIL are not yet understood. The identification and characterization of no...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Dine, J. L., Garimella, S. V., Gehlhaus, K., Grandin, M., Letwin, D., Caplen, N., Lipkowitz, S. Tags: Molecular and Cellular Biology Source Type: research
