CDK4/6 Therapeutic Intervention and Viable Alternative to Taxanes in CRPC
Resistance to second-generation androgen receptor (AR) antagonists and CYP17 inhibitors in patients with castration-resistant prostate cancer (CRPC) develops rapidly through reactivation of the androgen signaling axis and has been attributed to AR overexpression, production of constitutively active AR splice variants, or the selection for AR mutants with altered ligand-binding specificity. It has been established that androgens induce cell-cycle progression, in part, through upregulation of cyclin D1 (CCND1) expression and subsequent activation of cyclin-dependent kinases 4 and 6 (CDK4/6). Thus, the efficacy of the newly d...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Stice, J. P., Wardell, S. E., Norris, J. D., Yllanes, A. P., Alley, H. M., Haney, V. O., White, H. S., Safi, R., Winter, P. S., Cocce, K. J., Kishton, R. J., Lawrence, S. A., Strum, J. C., McDonnell, D. P. Tags: Cell Death and Survival Source Type: research
The E3 Ligase CHIP Mediates p21 Degradation to Maintain Radioresistance
Lung cancer resists radiotherapy, making it one of the deadliest forms of cancer. Here, we show that human lung cancer cell lines can be rendered sensitive to ionizing radiation (IR) by RNAi knockdown of C-terminus of Hsc70-interacting protein (CHIP/STUB1), a U-box-type E3 ubiquitin ligase that targets a number of stress-induced proteins. Mechanistically, ubiquitin-dependent degradation of the cyclin-dependent kinase (CDK) inhibitor, p21 protein, is reduced by CHIP knockdown, leading to enhanced senescence of cells in response to exposure to IR. Cellular senescence and sensitivity to IR is prevented by CRISPR/Cas9-mediated...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Biswas, K., Sarkar, S., Du, K., Brautigan, D. L., Abbas, T., Larner, J. M. Tags: Cell Cycle and Senescence Source Type: research
Cancer Immunotherapy: Whence and Whither
The current concepts and practice of cancer immunotherapy evolved from classical experiments that distinguished "self" from "non-self" and the finding that humoral immunity is complemented by cellular immunity. Elucidation of the biology underlying immune checkpoints and interactions between ligands and ligand receptors that govern the immune system's ability to recognize tumor cells as foreign has led to the emergence of new strategies that mobilize the immune system to reverse this apparent tolerance. Some of these approaches have led to new therapies such as the use of mAbs to interfere with the immune checkpoint. Other...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Stambrook, P. J., Maher, J., Farzaneh, F. Tags: Review Source Type: research
Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research
A Transcriptional Program for Detecting TGF{beta}-Induced EMT in Cancer
Most cancer deaths are due to metastasis, and epithelial-to-mesenchymal transition (EMT) plays a central role in driving cancer cell metastasis. EMT is induced by different stimuli, leading to different signaling patterns and therapeutic responses. TGFβ is one of the best-studied drivers of EMT, and many drugs are available to target this signaling pathway. A comprehensive bioinformatics approach was employed to derive a signature for TGFβ-induced EMT which can be used to score TGFβ-driven EMT in cells and clinical specimens. Considering this signature in pan-cancer cell and tumor datasets, a number of cell ...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Foroutan, M., Cursons, J., Hediyeh-Zadeh, S., Thompson, E. W., Davis, M. J. Tags: Signal Transduction Source Type: research
Constitutive Phosphorylation of STAT3 by the CK2-BLNK-CD5 Complex
In chronic lymphocytic leukemia (CLL), STAT3 is constitutively phosphorylated on serine 727 and plays a role in the pathobiology of CLL. However, what induces constitutive phosphorylation of STAT3 is currently unknown. Mass spectrometry was used to identify casein kinase 2 (CK2), a serine/threonine kinase that coimmunoprecipitated with serine phosphorylated STAT3 (pSTAT3). Furthermore, activated CK2 incubated with recombinant STAT3 induced phosphorylation of STAT3 on serine 727. Although STAT3 and CK2 are present in normal B- and T cells, STAT3 is not constitutively phosphorylated in these cells. Further study found that C...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Rozovski, U., Harris, D. M., Li, P., Liu, Z., Jain, P., Veletic, I., Ferrajoli, A., Burger, J., O'Brien, S., Bose, P., Thompson, P., Jain, N., Wierda, W., Keating, M. J., Estrov, Z. Tags: Signal Transduction Source Type: research
Combined TRAF6 Targeting and Proteasome Blockade Has Anti-myeloma and Anti-Bone Resorptive Effects
TNF receptor–associated factor 6 (TRAF6) has been implicated in polyubiquitin-mediated IL1R/TLR signaling through activation of IB kinase (IKK) to regulate the NF-B and JNK signaling pathways. Here, TRAF6 protein was determined to be overexpressed in bone marrow mononuclear cells (BMMC) from patients with multiple myeloma. TRAF6 expression in BMMCs from patients with progressive disease is significantly elevated as compared with individuals in complete remission, with monoclonal gammopathy of undetermined significance, or healthy subjects. Furthermore, TRAF6 dominant–negative (TRAF6dn) peptides were constructed...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Chen, H., Li, M., Sanchez, E., Wang, C. S., Lee, T., Soof, C. M., Casas, C. E., Cao, J., Xie, C., Udd, K. A., DeCorso, K., Tang, G. Y., Spektor, T. M., Berenson, J. R. Tags: Signal Transduction Source Type: research
Tumor-induced Stromal STAT1 Accelerates Breast Cancer via Deregulating Tissue Homeostasis
The tumor microenvironment (TME), the dynamic tissue space in which the tumor exists, plays a significant role in tumor initiation, and is a key contributor in cancer progression; however, little is known about tumor-induced changes in the adjacent tissue stroma. Herein, tumor-induced changes in the TME were explored at the morphologic and molecular level to further understand cancer progression. Tumor-adjacent mammary glands (TAG) displayed altered branching morphology, expansion of myofibroblasts, and increased mammosphere formation, broadly suggesting a tumor-induced field effect. FACS analysis of TAGs demonstrated an i...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Zellmer, V. R., Schnepp, P. M., Fracci, S. L., Tan, X., Howe, E. N., Zhang, S. Tags: Oncogenes and Tumor Suppressors Source Type: research
Novel Assay to Detect RNA Polymerase I Activity In Vivo
This report develops an analytically validated chromogenic in situ hybridization (CISH) assay using branched DNA signal amplification (RNAscope) for detecting the expression of the 5' external transcribed spacer (ETS) of the 45S ribosomal (r) RNA precursor in formalin-fixed and paraffin-embedded (FFPE) human tissues. 5'ETS/45S CISH was performed on standard clinical specimens and tissue microarrays (TMA) from untreated prostate carcinomas, high-grade prostatic intraepithelial neoplasia (PIN), and matched benign prostatic tissues. Signals were quantified using image analysis software. The 5'ETS rRNA signal was restricted to...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Guner, G., Sirajuddin, P., Zheng, Q., Bai, B., Brodie, A., Liu, H., af Hällström, T., Kulac, I., Laiho, M., De Marzo, A. M. Tags: Metabolism Source Type: research
Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type-Specific Differences
Endemic Burkitt lymphoma (eBL) is the most common pediatric cancer in malaria-endemic equatorial Africa and nearly always contains Epstein–Barr virus (EBV), unlike sporadic Burkitt lymphoma (sBL) that occurs with a lower incidence in developed countries. Given these differences and the variable clinical presentation and outcomes, we sought to further understand pathogenesis by investigating transcriptomes using RNA sequencing (RNAseq) from multiple primary eBL tumors compared with sBL tumors. Within eBL tumors, minimal expression differences were found based on: anatomical presentation site, in-hospital survival rate...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Kaymaz, Y., Oduor, C. I., Yu, H., Otieno, J. A., Ong'echa, J. M., Moormann, A. M., Bailey, J. A. Tags: Genomics Source Type: research
Genome-Wide Analysis Identifies MEN1 and MAX Mutations and a Neuroendocrine-Like Molecular Heterogeneity in Quadruple WT GIST
This study provides novel insights into the biology of quadruple WT GIST that potentially resembles neuroendocrine tumors and should promote the development of specific therapeutic approaches. Mol Cancer Res; 15(5); 553–62. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Pantaleo, M. A., Urbini, M., Indio, V., Ravegnini, G., Nannini, M., De Luca, M., Tarantino, G., Angelini, S., Gronchi, A., Vincenzi, B., Grignani, G., Colombo, C., Fumagalli, E., Gatto, L., Saponara, M., Ianni, M., Paterini, P., Santini, D., Pirini, M. G. Tags: Genomics Source Type: research
Distinctive Histogenesis and Immunological Microenvironment Based on Transcriptional Profiles of Follicular Dendritic Cell Sarcomas
Follicular dendritic cell (FDC) sarcomas are rare mesenchymal tumors with variable clinical, morphologic, and phenotypic characteristics. Transcriptome analysis was performed on multiple FDC sarcomas and compared with other mesenchymal tumors, microdissected Castleman FDCs, and normal fibroblasts. Using unsupervised analysis, FDC sarcomas clustered with microdissected FDCs, distinct from other mesenchymal tumors and fibroblasts. The specific endowment of FDC-related gene expression programs in FDC sarcomas emerged by applying a gene signature of differentially expressed genes (n = 1,289) between microdissected FDCs and fib...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Laginestra, M. A., Tripodo, C., Agostinelli, C., Motta, G., Hartmann, S., Döring, C., Rossi, M., Melle, F., Sapienza, M. R., Tabanelli, V., Pileri, A., Fuligni, F., Gazzola, A., Mannu, C., Sagramoso, C. A., Lonardi, S., Lorenzi, L., Bacci, F., Sab Tags: Genomics Source Type: research
Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma
In conclusion, we determined mutual associations of tumor purity with MGMT methylation and pTERT mutations and found that the extent of MGMT methylation reflects tumor purity. In turn, tumor purity is prognostic in IDH1 wild-type GBM.
Implications: Tumor purity is an independent prognostic marker in glioblastoma and is associated with the extent of MGMT methylation. Mol Cancer Res; 15(5); 532–40. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Schulze Heuling, E., Knab, F., Radke, J., Eskilsson, E., Martinez-Ledesma, E., Koch, A., Czabanka, M., Dieterich, C., Verhaak, R. G., Harms, C., Euskirchen, P. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research
Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155
In this study, high-throughput drug screening identified a potent synergy between high-androgen therapy and YM155, a transcriptional inhibitor of survivin (BIRC5). This interaction was mediated by the direct transcriptional upregulation of the YM155 transporter SLC35F2 by the AR. Androgen-mediated YM155-induced cell death was completely blocked by the overexpression of multidrug resistance transporter ABCB1. SLC35F2 expression was significantly correlated with intratumor androgen levels in four distinct patient-derived xenograft models, and with AR activity score in a large gene expression dataset of castration-resistant m...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Nyquist, M. D., Corella, A., Burns, J., Coleman, I., Gao, S., Tharakan, R., Riggan, L., Cai, C., Corey, E., Nelson, P. S., Mostaghel, E. A. Tags: Cell Death and Survival Source Type: research
Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression
IDH1 mutations occur in the majority of low-grade gliomas and lead to the production of the oncometabolite, D-2-hydroxyglutarate (D-2HG). To understand the effects of tumor-associated mutant IDH1 (IDH1-R132H) on both the neural stem cell (NSC) population and brain tumorigenesis, genetically faithful cell lines and mouse model systems were generated. Here, it is reported that mouse NSCs expressing Idh1-R132H displayed reduced proliferation due to p53-mediated cell-cycle arrest as well as a decreased ability to undergo neuronal differentiation. In vivo, Idh1-R132H expression reduced proliferation of cells within the germinal...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Pirozzi, C. J., Carpenter, A. B., Waitkus, M. S., Wang, C. Y., Zhu, H., Hansen, L. J., Chen, L. H., Greer, P. K., Feng, J., Wang, Y., Bock, C. B., Fan, P., Spasojevic, I., McLendon, R. E., Bigner, D. D., He, Y., Yan, H. Tags: Cell Cycle and Senescence Source Type: research
