Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion
In this study, we use liquid chromatography–mass spectrometry analysis to demonstrate differences in HS disaccharide content and structure across four patient-derived tumorsphere lines (GBM1, 5, 6, 43) and between two murine tumorsphere lines derived from murine GBM with enrichment of mesenchymal and proneural gene expression (mMES and mPN, respectively) markers. In GBM, the heterogeneous HS content and structure across patient-derived tumorsphere lines suggested diverse functions in the GBM tumor microenvironment. In GBM5 and mPN, elevated expression of sulfatase 2 (SULF2), an extracellular enzyme that alters ligand...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Tran, V. M., Wade, A., McKinney, A., Chen, K., Lindberg, O. R., Engler, J. R., Persson, A. I., Phillips, J. J. Tags: Signal Transduction Source Type: research
ADAM12 Is a Novel Regulator of Tumor Angiogenesis via STAT3 Signaling
ADAM12, (A Disintegrin and metalloproteinase domain-containing protein 12), is upregulated in epithelial cancers and contributes to increased tumor proliferation, metastasis, and endocrine resistance. However, its role in tumor angiogenesis is unknown. Here, we report that ADAM12 is upregulated in the vessels of aggressive breast tumors and exerts key regulatory functions. ADAM12 significantly increases bFGF-mediated angiogenesis in vivo and ADAM12 levels are upregulated in tumors that have undergone a switch to the angiogenic phenotype. Importantly, ADAM12-overexpressing breast tumors display a higher microvessel density ...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Roy, R., Dagher, A., Butterfield, C., Moses, M. A. Tags: Signal Transduction Source Type: research
Early-Stage Metastasis Requires Mdm2 and Not p53 Gain of Function
Metastasis of cancer cells to distant organ systems is a complex process that is initiated with the programming of cells in the primary tumor. The formation of distant metastatic foci is correlated with poor prognosis and limited effective treatment options. We and others have correlated Mouse double minute 2 (Mdm2) with metastasis; however, the mechanisms involved have not been elucidated. Here, it is reported that shRNA-mediated silencing of Mdm2 inhibits epithelial–mesenchymal transition (EMT) and cell migration. In vivo analysis demonstrates that silencing Mdm2 in both post-EMT and basal/triple-negative breast ca...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Hauck, P. M., Wolf, E. R., Olivos, D. J., Batuello, C. N., McElyea, K. C., McAtarsney, C. P., Cournoyer, R. M., Sandusky, G. E., Mayo, L. D. Tags: Oncogenes and Tumor Suppressors Source Type: research
Selective MET Kinase Inhibition in MET-Dependent Glioma Models Alters Gene Expression and Induces Tumor Plasticity
The receptor tyrosine kinase (RTK) MET represents a promising tumor target in a subset of glioblastomas. Most RTK inhibitors available in the clinic today, including those inhibiting MET, affect multiple targets simultaneously. Previously, it was demonstrated that treatment with cabozantinib (MET/VEGFR2/RET inhibitor) prolonged survival of mice carrying orthotopic patient-derived xenografts (PDX) of the MET-addicted glioblastoma model E98, yet did not prevent development of recurrent and cabozantinib-resistant tumors. To exclude VEGFR2 inhibition-inflicted blood–brain barrier normalization and diminished tumor distri...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: van den Heuvel, C. N. A. M., Navis, A. C., de Bitter, T., Amiri, H., Verrijp, K., Heerschap, A., Rex, K., Dussault, I., Caenepeel, S., Coxon, A., Span, P. N., Wesseling, P., Hendriks, W., Leenders, W. P. J. Tags: Oncogenes and Tumor Suppressors Source Type: research
Nuclear Envelope Rupture Is Enhanced by Loss of p53 or Rb
In conclusion, the data indicate that NE rupture in cancer cells is likely due to loss of either the Rb or the p53 pathway.
Implications: These findings imply that tumor suppression by Rb and p53 includes the ability to prevent NE rupture, thereby protecting against genome alterations. Mol Cancer Res; 15(11); 1579–86. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Yang, Z., Maciejowski, J., de Lange, T. Tags: Oncogenes and Tumor Suppressors Source Type: research
miR-432 Induces NRF2 Stabilization by Directly Targeting KEAP1
NF-E2–related factor 2 (NRF2) is a master transcriptional regulator that integrates cellular stress responses and is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1) at the post-translational level. In human cancers, aberrantly stabilized NRF2, by the mutation of either NRF2 or KEAP1 or by the potential inhibition of autophagy, plays a vital role in tumor growth and chemoresistance through the activation of target genes. MicroRNAs (miRNA) are endogenous small noncoding RNAs that can negatively regulate gene expression by interfering with translation and/or stability of target transcripts. However, ...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Akdemir, B., Nakajima, Y., Inazawa, J., Inoue, J. Tags: Oncogenes and Tumor Suppressors Source Type: research
Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing
This study identified opportunities to improve early detection and treatment of patients with BE and esophageal adenocarcinoma. Mol Cancer Res; 15(11); 1558–69. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Maag, J. L. V., Fisher, O. M., Levert-Mignon, A., Kaczorowski, D. C., Thomas, M. L., Hussey, D. J., Watson, D. I., Wettstein, A., Bobryshev, Y. V., Edwards, M., Dinger, M. E., Lord, R. V. Tags: Genomics Source Type: research
Comprehensive Molecular Profiling of Olfactory Neuroblastoma Identifies Potentially Targetable FGFR3 Amplifications
Olfactory neuroblastomas (ONBs), also known as esthesioneuroblastomas, are malignant round-cell tumors that represent up to 5% of sinonasal malignancies. Despite their aggressive course, molecular studies of ONBs have been limited, and targeted therapies are lacking. To identify potential oncogenic drivers and targetable pathways in ONBs, we characterized 20 ONBs, including archived ONBs profiled by targeted, multiplexed PCR (mxPCR)–based DNA next-generation sequencing (NGS) of the coding sequence of over 400 cancer-relevant genes (n = 16), mxPCR-based RNA NGS of 108 target genes (n = 15), and 2 ONBs profiled by comp...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Lazo de la Vega, L., McHugh, J. B., Cani, A. K., Kunder, K., Walocko, F. M., Liu, C.-J., Hovelson, D. H., Robinson, D., Chinnaiyan, A. M., Tomlins, S. A., Harms, P. W. Tags: Genomics Source Type: research
Comprehensive Genomic Profiling of Metastatic Squamous Cell Carcinoma of the Anal Canal
Squamous cell carcinoma of the anal canal (SCCA) is a rare gastrointestinal malignancy with an increasing annual incidence globally. The majority of cases are linked to prior infection with the human papillomavirus (HPV). For patients with metastatic SCCA, no consensus standard treatment exists. Identification of relevant targeted agents as novel therapeutic approaches for metastatic SCCA has been limited by a lack of comprehensive molecular profiling. We performed whole-exome sequencing on tumor–normal pairs from 24 patients with metastatic SCCA. Tumor tissue from 17 additional patients was analyzed using a 263-gene...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Morris, V., Rao, X., Pickering, C., Foo, W. C., Rashid, A., Eterovic, K., Kim, T., Chen, K., Wang, J., Shaw, K., Eng, C. Tags: Genomics Source Type: research
CDK4/6 Inhibition on Glucose and Pancreatic Beta Cell Homeostasis in Young and Aged Rats
Genetic deletion of cyclin-dependent kinase 4 (Cdk4) is associated with pancreatic beta cell loss and glucose dysregulation in rodents. Palbociclib, one of the first selective CDK4/6 inhibitors approved for the treatment of advanced breast cancer, is currently being investigated as an adjuvant treatment in patients with early-stage breast cancer and in a variety of cancers covering a wide-range of patient populations. Hence, longer chronic toxicity studies were necessary to further examine its safety profile. The effects of different doses and duration of palbociclib administration on glucose and beta cell homeostasis in y...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Sacaan, A. I., Thibault, S., Hong, M., Kondegowda, N. G., Nichols, T., Li, R., Rosselot, C., Evering, W., Fenutria, R., Vitsky, A., Brown, T., Finkelstein, M., Garcia-Ocana, A., Khan, N., Stewart, A. F., Vasavada, R. C. Tags: Metabolism Source Type: research
EWS/FLI is a Master Regulator of Metabolic Reprogramming in Ewing Sarcoma
Ewing sarcoma is a bone malignancy driven by a translocation event resulting in the fusion protein EWS/FLI1 (EF). EF functions as an aberrant and oncogenic transcription factor that misregulates the expression of thousands of genes. Previous work has focused principally on determining important transcriptional targets of EF, as well as characterizing important regulatory partnerships in EF-dependent transcriptional programs. Less is known, however, about EF-dependent metabolic changes or their role in Ewing sarcoma biology. Therefore, the metabolic effects of silencing EF in Ewing sarcoma cells were determined. Metabolomic...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Tanner, J. M., Bensard, C., Wei, P., Krah, N. M., Schell, J. C., Gardiner, J., Schiffman, J., Lessnick, S. L., Rutter, J. Tags: Metabolism Source Type: research
EGFR Mutations Compromise Hypoxia-Associated Radiation Resistance through Impaired Replication Fork-Associated DNA Damage Repair
This study demonstrates that within an altered DNA damage response of hypoxic NSCLC cells, mutant EGFR expression, or EGFR blockade by cetuximab exerts a synthetic lethality effect and significantly compromises radiation resistance in hypoxic tumor cells. Mol Cancer Res; 15(11); 1503–16. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Saki, M., Makino, H., Javvadi, P., Tomimatsu, N., Ding, L.-H., Clark, J. E., Gavin, E., Takeda, K., Andrews, J., Saha, D., Story, M. D., Burma, S., Nirodi, C. S. Tags: DNA Damage and Repair Source Type: research
Dual Src Kinase/Pretubulin Inhibitor KX-01, Sensitizes ER{alpha}-negative Breast Cancers to Tamoxifen through ER{alpha} Reexpression
Unlike breast cancer that is positive for estrogen receptor-α (ERα), there are no targeted therapies for triple-negative breast cancer (TNBC). ERα is silenced in TNBC through epigenetic changes including DNA methylation and histone acetylation. Restoring ERα expression in TNBC may sensitize patients to endocrine therapy. Expression of c-Src and ERα are inversely correlated in breast cancer suggesting that c-Src inhibition may lead to reexpression of ERα in TNBC. KX-01 is a peptide substrate–targeted Src/pretubulin inhibitor in clinical trials for solid tumors. KX-01 (1 mg/kg body w...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Anbalagan, M., Sheng, M., Fleischer, B., Zhang, Y., Gao, Y., Hoang, V., Matossian, M., Burks, H. E., Burow, M. E., Collins-Burow, B. M., Hangauer, D., Rowan, B. G. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research
Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/{beta}-catenin Signaling
Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer. The Wnt-transcription factor, TCF7L2, is overexpressed in primary rectal cancers that are resistant to chemoradiotherapy and TCF7L2 mediates resistance to chemoradiotherapy. However, it is unclear whether the resistance is mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. Here, inhibition of β-catenin by siRNAs or a small-molecule inhibitor (XAV-939) resulted in sensitization of colorectal cancer cells to chemoradiotherapy. To investigate the potential role of Wnt/&...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Emons, G., Spitzner, M., Reineke, S., Möller, J., Auslander, N., Kramer, F., Hu, Y., Beissbarth, T., Wolff, H. A., Rave-Fränk, M., Hessmann, E., Gaedcke, J., Ghadimi, B. M., Johnsen, S. A., Ried, T., Grade, M. Tags: Cell Death and Survival Source Type: research
Targeting AR Variant-Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities
This study demonstrates the potential therapeutic utility of inhibiting constitutively active AR-V signaling by disrupting coactivator binding. Such an approach is significant, as AR-Vs are emerging as important drivers of CRPC that are particularly recalcitrant to current therapies. Mol Cancer Res; 15(11); 1469–80. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Magani, F., Peacock, S. O., Rice, M. A., Martinez, M. J., Greene, A. M., Magani, P. S., Lyles, R., Weitz, J. R., Burnstein, K. L. Tags: Cell Death and Survival Source Type: research
