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    50716 results match your criteria Cancer research[Journal]

    1 OF 1015

    Genetic Mosaicism and Cancer: Cause and Effect.
    Cancer Res 2018 Feb 22. Epub 2018 Feb 22.
    Institute of Carcinogenesis, N.N. Blokhin Cancer Research Center, Moscow, Russia.
    Increasing theoretical and experimental evidence suggests that the genomes of both normal and cancer cells are subject to continuous changes as a result of copying errors during replication, defects in chromosome segregation during mitosis, and direct chemical attacks by reactive oxygen species. The process of cellular genetic diversification begins during embryonic development and continues throughout life, leading to the phenomenon of somatic mosaicism. New information about the genetic diversity of cells composing the body makes us reconsider the existing concepts of cancer etiology and pathogenesis. Read More

    Mass spectrometry-based proteomics reveals potential roles of NEK9 and MAP2K4 in resistance to PI3K inhibitors in triple negative breast cancers.
    Cancer Res 2018 Feb 22. Epub 2018 Feb 22.
    Division of Oncology, Department of Internal Medicine, Washington University School of Medicine.
    Activation of phosphoinositide 3-kinase (PI3K) signaling is frequently observed in triple-negative breast cancer (TNBC), yet PI3K inhibitors have shown limited clinical activity. To investigate intrinsic and adaptive mechanisms of resistance, we analyzed a panel of patient-derived xenograft models of TNBC with varying responsiveness to buparlisib, a pan-PI3K inhibitor. In a subset of patient-derived xenografts, resistance was associated with incomplete inhibition of PI3K signaling and upregulated MAPK/MEK signaling in response to buparlisib. Read More

    A novel mechanism for activation of GLI1 by nuclear SMO that escapes anti-SMO inhibitors.
    Cancer Res 2018 Feb 20. Epub 2018 Feb 20.
    Centre for Cell Biology and Cutaneous Medicine, Blizard Institute.
    Small molecule inhibitors of the Hedgehog (HH) pathway receptor Smoothened (SMO) have been effective in treating some patients with basal cell carcinoma (BCC), where the HH pathway is often activated, but many patients are poorly responsive. In this study, we report the results of investigations on PTCH1 signalling in the HH pathway that suggest why most BCC patients respond poorly to SMO inhibitors. In immortalised human keratinocytes, PTCH1 silencing led to the generation of a compact, holoclone-like morphology with increased expression of SMO and the downstream HH pathway transcription factor GLI1. Read More

    Truncated glioma-associated oncogene homolog 1 (tGLI1) mediates mesenchymal glioblastoma via transcriptional activation of CD44.
    Cancer Res 2018 Feb 20. Epub 2018 Feb 20.
    Cancer Biology, Wake Forest University School of Medicine
    The molecular pathways driving mesenchymal glioblastoma (GBM) are still not well understood. We report here that truncated glioma-associated oncogene homolog 1 (tGLI1) is a tumor-specific transcription factor that facilitates GBM growth, is enriched in the mesenchymal subtype of GBM and glioma stem cells (GSC), and promotes mesenchymal GSC by upregulating transcription of CD44. In an orthotopic GBM xenograft mouse model, tGLI1-overexpressing tumors grew more aggressively with increased proliferation and angiogenesis compared to control and GLI1-overexpressing xenografts. Read More

    CrosstalkNet: A visualization tool for differential co-expression networks and communities.
    Cancer Res 2018 Feb 19. Epub 2018 Feb 19.
    Princess Margaret Research, University Health Network
    Variations in physiological conditions can rewire molecular interactions between biological compartments, which can yield novel insights into gain or loss of interactions specific to perturbations of interest. Networks are a promising tool to elucidate intercellular interactions, yet exploration of these large-scale networks remains a challenge due to their high dimensionality. To retrieve and mine interactions, we developed CrosstalkNet, a user friendly, web-based network visualization tool that provides a statistical framework to infer condition-specific interactions coupled with a community detection algorithm for bipartite graphs to identify significantly dense subnetworks. Read More

    Single-cell transcriptome analyses reveal endothelial cell heterogeneity in tumors and changes following anti-angiogenic treatment.
    Cancer Res 2018 Feb 15. Epub 2018 Feb 15.
    Regeneron Pharmaceuticals, Inc.
    Angiogenesis involves dynamic interactions between specialized endothelial tip and stalk cells that are believed to be regulated in part by VEGF and Dll4-Notch signaling. However, our understanding of this process is hampered by limited knowledge of the heterogeneity of endothelial cells and the role of different signaling pathways in specifying endothelial phenotypes. Here we characterized by single cell transcriptomics the heterogeneity of mouse endothelial cells and other stromal cells during active angiogenesis in xenograft tumors as well as from adult normal heart, following pharmacologic inhibition of VEGF and Dll4-Notch signaling. Read More

    A distinct oncogenerative multinucleated cancer cell serves as a source of stemness and tumor heterogeneity.
    Cancer Res 2018 Feb 12. Epub 2018 Feb 12.
    Medizinische Klinik III - Haematologie/Onkologie, Marienhospital Herne.
    The effects of anticancer treatments on cell heterogeneity and their proliferative potential play an important role in tumor persistence and metastasis. However, little is known about de-polyploidization, cell fate, and physiological stemness of the resulting cell populations. Here we describe a distinctive cell type termed "pregnant" P1 cells found within chemotherapy refractory ovarian tumors, which generate and gestate daughter generation Gn-cells intracytoplasmically. Read More

    Crosstalk signaling between HER3 and HPV16 E6 and E7 mediates resistance to PI3K inhibitors in head and neck cancer.
    Cancer Res 2018 Feb 12. Epub 2018 Feb 12.
    Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco
    Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the phosphatidylinositol 3-kinase (PI3K) pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV(+) HNSCC. Read More

    RSK Regulates PFK-2 Activity to Promote Metabolic Rewiring in Melanoma.
    Cancer Res 2018 Feb 12. Epub 2018 Feb 12.
    IRIC, University of Montreal
    Metabolic reprogramming is a hallmark of cancer that includes increased glucose uptake and accelerated aerobic glycolysis. This phenotype is required to fulfill anabolic demands associated with aberrant cell proliferation and is often mediated by oncogenic drivers such as activated BRAF. In this study, we show that the MAPK-activated p90 ribosomal S6 kinase (RSK) is necessary to maintain glycolytic metabolism in BRAF-mutated melanoma cells. Read More

    Oncogenic kinase-induced PKM2 tyrosine 105 phosphorylation converts non-oncogenic PKM2 to a tumor promoter and induces cancer stem-like cells.
    Cancer Res 2018 Feb 12. Epub 2018 Feb 12.
    Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center
    The role of pyruvate kinase M2 isoform (PKM2) in tumor progression has been controversial. Previous studies showed that PKM2 promoted tumor growth in xenograft models; however, depletion of PKM2 in the Brca1-loss-driven mammary tumor mouse model accelerates tumor formation. Since oncogenic kinases are frequently activated in tumors and PKM2 phosphorylation promotes tumor growth, we hypothesized that phosphorylation of PKM2 by activated kinases in tumor cells confers PKM2 oncogenic function, whereas non-phosphorylated PKM2 is non-oncogenic. Read More

    FOXO transcription factors both suppress and support breast cancer progression.
    Cancer Res 2018 Feb 12. Epub 2018 Feb 12.
    Molecular Cancer Research, University Medical Center Utrecht
    FOXO transcription factors are regulators of cellular homeostasis and putative tumor suppressors, yet the role of FOXO in cancer progression remains to be determined. The data on FOXO function, particularly for epithelial cancers, are fragmentary and come from studies that focused on isolated aspects of cancer. To clarify the role of FOXO in epithelial cancer progression, we characterized the effects of inducible FOXO activation and loss in a mouse model of metastatic invasive lobular carcinoma. Read More

    The Balance Players of the Adaptive Immune System.
    Cancer Res 2018 Feb 13. Epub 2018 Feb 13.
    Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark.
    Equilibrium between immune activation and suppression may be necessary to maintain immune homeostasis, because proinflammatory effector T cells (defined as antiregulatory T cells) counteract the functions of regulatory immune cells. These self-reactive T cells recognize human leukocyte antigen (HLA)-restricted epitopes derived from proteins expressed by regulatory immune cells such as IDO, PD-L1, PD-L2, or arginase. The activation of such proinflammatory effector T cells offers a novel way to directly target the tumor microenvironment, potentially giving them considerable clinical value, especially in patients with cancer. Read More

    A DDX31/mutant-p53/EGFR axis promotes multistep progression of muscle invasive bladder cancer.
    Cancer Res 2018 Feb 13. Epub 2018 Feb 13.
    Division of Genome Medicine, Institute for Genome Research, Tokushima University
    The p53 and EGFR pathways are frequently altered in bladder cancers, yet their contributions to its progression remain elusive. Here we report that DEAD box polypeptide 31 (DDX31) plays a critical role in the multistep progression of muscle invasive bladder cancer (MIBC) through its sequential interactions with mutant p53 (mutp53) and EGFR. In early MIBC cells, nuclear DDX31 bound mutp53/SP1 and enhanced mutp53 transcriptional activation, leading to migration and invasion of MIBC. Read More

    The FACT inhibitor CBL0137 synergizes with cisplatin in small cell lung cancer by increasing NOTCH1 expression and targeting tumor-initiating cells.
    Cancer Res 2018 Feb 13. Epub 2018 Feb 13.
    Lerner Research Institute, Cleveland Clinic
    Traditional treatments of small cell lung cancer (SCLC) with cisplatin, a standard of care therapy, spare the tumor-initiating cells (TIC) that mediate drug resistance. Here we report a novel therapeutic strategy that preferentially targets TIC in SCLC in which cisplatin is combined with CBL0137, an inhibitor of the histone chaperone facilitates chromatin transcription (FACT), which is highly expressed in TIC. Combination of cisplatin and CBL0137 killed patient-derived and murine SCLC cell lines synergistically. Read More

    SPON2 Promotes M1-like Macrophage Recruitment and Inhibits Hepatocellular Carcinoma Metastasis by Distinct Integrin-Rho GTPase-Hippo Pathways.
    Cancer Res 2018 Feb 13. Epub 2018 Feb 13.
    School of Medicine, Shanghai Jiao Tong University, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
    Tumor-associated macrophages (TAM) represent key regulators of the complex interplay between cancer and the immune microenvironment. Matricellular protein SPON2 is essential for recruiting lymphocytes and initiating immune responses. Recent studies have shown that SPON2 has complicated roles in cell migration and tumor progression. Read More

    Genetic hitchhiking and population bottlenecks contribute to prostate cancer disparities in men of African descent.
    Cancer Res 2018 Feb 8. Epub 2018 Feb 8.
    Epidemiology and Medical Oncology, Harvard TH Chan School of Public Health and Dana Farber Cancer Institute.
    Prostate cancer (CaP) incidence and mortality rates in African and African American men are greatly elevated compared to other ethnicities. This disparity is likely explained by a combination of social, environmental, and genetic factors. A large number of susceptibility loci have been reported by genome-wide association studies (GWAS), but the contribution of these loci to CaP disparities is unclear. Read More

    Nuclear receptor LRH-1 functions to promote castration-resistant growth of prostate cancer via its promotion of intratumoral androgen biosynthesis.
    Cancer Res 2018 Feb 8. Epub 2018 Feb 8.
    School of Biomedical Sciences, Chinese University of Hong Kong
    Targeting of steroidogenic enzymes (e.g. abiraterone acetate targeting CYP17A1) has been developed as a novel therapeutic strategy against metastatic castration-resistant prostate cancer (CRPC). Read More

    Mitotic Phosphorylation of SENP3 Regulates De-SUMOylation of Chromosome-Associated Proteins and Chromosome Stability.
    Cancer Res 2018 Feb 8. Epub 2018 Feb 8.
    Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine.
    Progression of mitotic cell cycle as well as chromosome condensation and segregation are controlled by posttranslational protein modifications such as phosphorylation and SUMOylation. However, how SUMO isopeptidases (SENP) regulate cell mitotic procession is largely unknown. Here we demonstrate that precise phosphorylation of SENP3 during mitosis suppresses SENP3 de-SUMOylation activity towards chromosome-associated proteins including Topoisomerase IIα (Topo IIα). Read More

    Perspective on Circulating Tumor Cell Clusters: Why It Takes a Village to Metastasize.
    Cancer Res 2018 Feb 2;78(4):845-852. Epub 2018 Feb 2.
    Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
    Circulating tumor cell (CTC) clusters may represent one of the key mechanisms initiating the metastasis process. However, the series of pathophysiologic events by which CTC clusters originate, enter the circulation, and reach the distant sites remain to be identified. The cellular and molecular mechanisms that provide survival advantage for CTC clusters during the transit in the blood stream are also still largely unknown. Read More

    Expression of adipocyte/macrophage fatty acid binding protein in tumor associated macrophages promotes breast cancer progression.
    Cancer Res 2018 Feb 6. Epub 2018 Feb 6.
    Microbiology and Immunology, University of Louisville
    Tumor associated macrophages (TAM) play a critical role in cancer development and progression. However, the heterogeneity of TAM presents a major challenge to identify clinically-relevant markers for pro-tumor TAM. Here, we report that expression of adipocyte/macrophage fatty acid binding protein (A-FABP) in TAM promotes breast cancer progression. Read More

    Proteolytic release of the p75NTR intracellular domain by ADAM10 promotes metastasis and resistance to anoikis.
    Cancer Res 2018 Feb 6. Epub 2018 Feb 6.
    Oral & Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology
    Resistance to anoikis allows cancer cells to survive during systemic circulation, however, the mechanism underlying anoikis resistance remains unclear. Here we show that A disintegrin and metalloprotease 10 (ADAM10)-mediated cleavage of p75 neurotrophin receptor (p75NTR) and subsequent generation of the p75NTR intracellular domain (ICD) endows cancer cells with resistance to anoikis. p75NTR ICD promoted expression of TNF receptor associated factor 6 (TRAF6), a critical intermediary in p75NTR ICD-mediated signal transduction, at the translational level. Read More

    Targeting Cyclin D-CDK4/6 sensitizes immune-refractory cancer by blocking the SCP3-NANOG axis.
    Cancer Res 2018 Feb 6. Epub 2018 Feb 6.
    Division of Infection and Immunology, Korea University, Graduate School of Medicine
    Immune editing caused by anti-tumor immunity drives tumor cells to acquire refractory phenotypes. We demonstrated previously that tumor antigen-specific T cells edit these cells such that they become resistant to CTL killing and enrich NANOGhigh cancer stem cell-like (CSC-like) cells. In the current study, we show that synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, is overexpressed in immune-edited cells and upregulates NANOG by hyperactivating the Cyclin D1-CDK4/6 axis. Read More

    NRAS-mutated rhabdomyosarcoma cells are vulnerable to mitochondrial apoptosis induced by co-inhibition of MEK and PI3Kα.
    Cancer Res 2018 Feb 6. Epub 2018 Feb 6.
    Goethe University, Institute for Experimental Cancer Research in Pediatrics.
    Sequencing studies have revealed recurrent mutations in the RAS pathway in rhabdomyosarcoma (RMS). However, RAS effector pathways in RMS are poorly defined. Here we report that co-inhibition of NRAS or MEK plus PI3Kα triggers widespread apoptosis in NRAS-mutated RMS cells. Read More

    MicroRNA-1246 is an exosomal biomarker for aggressive prostate cancer.
    Cancer Res 2018 Feb 1. Epub 2018 Feb 1.
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco
    Due to high heterogeneity, molecular characterization of prostate cancer (PCa) based on biopsy sampling is often challenging. Hence, a minimally invasive method to determine the molecular imprints of a patient's tumor for risk stratification would be advantageous. In this study, we employ a novel, digital amplification-free quantification method using the nCounter technology (Nanostring Technologies) to profile exosomal serum miRNAs (ex-miRNA) from aggressive PCa cases, benign prostatic hyperplasia (BPH), and disease-free controls. Read More

    Pyruvate dehydrogenase PDH-E1β controls tumor progression by altering the metabolic status of cancer cells.
    Cancer Res 2018 Feb 7. Epub 2018 Feb 7.
    Medical Research Institute, Tokyo Medical and Dental University
    Downregulation of pyruvate dehydrogenase (PDH) is critical for the aberrant preferential activation of glycolysis in cancer cells under normoxic conditions. Phosphorylation-dependent inhibition of PDH is a relevant event in this process, but it is not durable since it relies on PDH kinases which are activated ordinarily under hypoxic conditions. Thus, it remains unclear how PDH is durably downregulated in cancer cells that are not hypoxic. Read More

    CXCL12γ Promotes Development of Metastatic Castration Resistant Prostate Cancer by Induction of Cancer Stem Cell and Neuroendocrine Phenotypes.
    Cancer Res 2018 Feb 5. Epub 2018 Feb 5.
    Periodontics and Oral Medicine, University of Michigan School of Dentistry
    There is evidence that cancer stem-like cells (CSC) and neuroendocrine (NE) behavior play critical roles in the pathogenesis and clinical course of metastatic castration-resistant prostate cancer (m-CRPC). However, there is limiting mechanistic understanding of how CSC and NE phenotypes impact the development of m-CRPC, which could improve opportunities to identify useful biomarkers and therapeutics. In this study, we explored the role of the intracellular chemokine CXCL12γ in CSC induction and NE differentiation and its impact on m-CRPC. Read More

    S-nitrosylation of cIAP1 switches cancer cell fate from TNFα/TNFR1-mediated cell survival to cell death.
    Cancer Res 2018 Feb 5. Epub 2018 Feb 5.
    UFR Sciences de Santé, EPHE-université de Bourgogne
    Tumor necrosis factor alpha (TNFα) is a prominent proinflammatory cytokine and a critical mediator for the development of many types of cancer such as breast, colon, prostate, cervical, skin, liver, and chronic lymphocytic leukemia. Binding of TNFα to TNFR1 can lead to divergent signaling pathways promoting predominantly NF-kB activation but also cell death. We report here that the nitric oxide donor glyceryl trinitrate (GTN) converts TNFα, generated from immune cells or cancer cells stimulated by chemotherapy, into a pro-death mediator in colon and mammary cancer cells. Read More

    Silencing the Snail-dependent RNA splice regulator ESRP1 drives malignant transformation of human pulmonary epithelial cells.
    Cancer Res 2018 Feb 5. Epub 2018 Feb 5.
    University of California Los Angeles.
    Epithelial-to-mesenchymal transition (EMT) is organized in cancer cells by a set of key transcription factors, but the significance of this process is still debated including in non-small cell lung cancer (NSCLC). Here we report increased expression of the EMT-inducing transcription factor Snail in premalignant pulmonary lesions, relative to histologically normal pulmonary epithelium. In immortalized human pulmonary epithelial cells and isogenic derivatives, we documented Snail-dependent anchorage-independent growth in vitro and primary tumor growth and metastatic behavior in vivo. Read More

    Germline mutations in the mitochondrial 2-oxoglutarate/malate carrier SLC25A11 gene confer a predisposition to metastatic paragangliomas.
    Cancer Res 2018 Feb 5. Epub 2018 Feb 5.
    U970, INSERM
    Comprehensive genetic analyses have identified germline SDHB and FH gene mutations as predominant causes of metastatic paraganglioma and pheochromocytoma. However, some suspicious cases remain unexplained. In this study, we performed whole-exome sequencing of a paraganglioma exhibiting a SDHx-like molecular profile in the absence of SDHx or FH mutations and identified a germline mutation in the SLC25A11 gene, which encodes the mitochondrial 2-oxoglutarate/malate carrier. Read More

    TRIM59 promotes gliomagenesis by inhibiting TC45 dephosphorylation of STAT3.
    Cancer Res 2018 Jan 31. Epub 2018 Jan 31.
    School of Medicine, Ren Ji Hospital, Shanghai Jiao Tong University
    Aberrant epidermal growth factor receptor (EGFR) signaling is a common driver of glioblastoma (GBM) pathogenesis, however, the downstream effectors that sustain this oncogenic pathway remain unclarified. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59) acts as a new downstream effector of EGFR signaling by regulating STAT3 activation in GBM. EGFR signaling led to TRIM59 upregulation through SOX9 and enhanced the interaction between TRIM59 and nuclear STAT3, which prevents STAT3 dephosphorylation by the nuclear form of T cell protein tyrosine phosphatase (TC45), thereby maintaining transcriptional activation and promoting tumorigenesis. Read More

    Lysophosphatidic Acid Induces Metabolic Reprogramming in Ovarian Cancer via a Pseudohypoxic Response.
    Cancer Res 2018 Jan 31. Epub 2018 Jan 31.
    Stephenson Cancer Center, University of Oklahoma Health Sciences Center
    Although hypoxia has been shown to reprogram cancer cells toward glycolytic shift, the identity of extrinsic stimuli that induce metabolic reprogramming independent of hypoxia, especially in ovarian cancer, is largely unknown. In this study, we use patient-derived ovarian cancer cells and high-grade serous ovarian cancer cell lines to demonstrate that lysophosphatidic acid (LPA), a lipid growth factor and GPCR ligand whose levels are substantially increased in ovarian cancer patients, triggers glycolytic shift in ovarian cancer cells. Inhibition of the G protein α-subunit Gαi2 disrupted LPA-stimulated aerobic glycolysis. Read More

    Tumorigenic and anti-proliferative properties of the TALE-transcription factors MEIS2D and MEIS2A in neuroblastoma.
    Cancer Res 2018 Jan 30. Epub 2018 Jan 30.
    Institute of Neurology (Edinger Institute), University Hospital Frankfurt
    Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Read More

    Spatial heterogeneity and evolutionary dynamics modulate time to recurrence in continuous and adaptive cancer therapies.
    Cancer Res 2018 Jan 30. Epub 2018 Jan 30.
    Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute
    Treatment of advanced cancers has benefited from new agents that supplement or bypass conventional therapies. However, even effective therapies fail as cancer cells deploy a wide range of resistance strategies. We propose that evolutionary dynamics ultimately determine survival and proliferation of resistant cells. Read More

    Modulation of Macropinocytosis-Mediated Internalization Decreases Ocular Toxicity of Antibody-Drug Conjugates.
    Cancer Res 2018 Jan 30. Epub 2018 Jan 30.
    Translational Research, Agensys, Inc.
    AGS-16C3F is an antibody-drug conjugate (ADC) against ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) containing the mcMMAF linker-payload currently in development for treatment of metastatic renal cell carcinoma. AGS-16C3F and other ADC have been reported to cause ocular toxicity in patients by unknown mechanisms. To investigate this toxicity, we developed an in vitro assay using human corneal epithelial cells (HCEC) and show that HCEC internalized AGS-16C3F and other ADCs by macropinocytosis, causing inhibition of cell proliferation. Read More

    HER2 overexpression triggers an IL-1α pro-inflammatory circuit to drive tumorigenesis and promote chemotherapy resistance.
    Cancer Res 2018 Jan 30. Epub 2018 Jan 30.
    Biological Science, University of South Carolina
    Systemic inflammation in breast cancer correlates with poor prognosis but the molecular underpinnings of this connection are not well understood. In this study, we explored the relationship between HER2 overexpression, inflammation and expansion of the mammary stem/progenitor and cancer stem-like cell (CSC) population in breast cancer. HER2-positive epithelial cells initiated and sustained an inflammatory milieu needed to promote tumorigenesis. Read More

    Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer.
    Cancer Res 2018 Jan 30. Epub 2018 Jan 30.
    Molecular Cell Biology, Cancer Research UK Beatson Institute
    The myotonic dystrophy-related Cdc42-binding kinases MRCKα and MRCKβ contribute to the regulation of actin-myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphological changes in cancer cells along with inhibition of their motility and invasive character. Read More

    RNF6 promotes colorectal cancer by activating the Wnt/β-catenin pathway via ubiquitination of TLE3.
    Cancer Res 2018 Jan 26. Epub 2018 Jan 26.
    Medicine & Therapeutics, Chinese University of Hong Kong
    Gene amplification is a hallmark of cancer and is frequently observed in colorectal cancer (CRC). Previous whole-genome sequencing of CRC clinical specimens identified amplification of Ring finger protein 6 (RNF6), a RING-domain E3 ubiquitin ligase. In this study, we show that RNF6 is upregulated in 73. Read More

    MicroRNA-508 defines the stem-like/mesenchymal subtype in colorectal cancer.
    Cancer Res 2018 Jan 26. Epub 2018 Jan 26.
    Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Labor
    Colorectal cancer (CRC) includes an invasive stem-like/mesenchymal subtype but its genetic drivers, functional and clinical relevance are uncharacterized. Here we report the definition of an altered microRNA (miR) signature defining this subtype which includes a major genomic loss of miR-508. Mechanistic investigations showed that this microRNA affected the expression of cadherin CDH1 and the transcription factors ZEB1, SALL4, BMI1 and BMI1. Read More

    Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer.
    Cancer Res 2018 Jan 26. Epub 2018 Jan 26.
    Medicine, Northwestern University.
    Metformin is a broadlyprescribed drug for type 2 diabetes that exerts antitumor activity, yet the mechanisms underlying this activity remain unclear. We show here that metformin treatment blocks the suppressive function of myeloid-derived suppressor cells (MDSC) in patients with ovarian cancer (OC) by downregulating the expression and ectoenzymatic activity of CD39 and CD73 on monocytic and polymononuclear MDSC subsets. Metformin triggered activation of AMP-activated protein kinase α (AMPKα) and subsequently suppressed hypoxia-inducible factor-α (HIF-1α), which was critical for induction of CD39/CD73 expression in MDSC. Read More

    Forkhead box F2 suppresses gastric cancer through a novel FOXF2-IRF2BPL-β-catenin signaling axis.
    Cancer Res 2018 Jan 26. Epub 2018 Jan 26.
    Medicine & Therapeutics, Chinese University of Hong Kong
    DNA methylation has been identified as a hallmark of gastric cancer (GC). Identifying genes that are repressed by DNA promoter methylation is essential in providing insights into the molecular pathogenesis of GC. Using genome-wide methylation studies we identified that transcription factor forkhead box F2 (FOXF2) was preferentially methylated in GC. Read More

    Fc-mediated Anomalous Biodistribution of Therapeutic Antibodies in Immunodeficient Mouse Models.
    Cancer Res 2018 Jan 23. Epub 2018 Jan 23.
    Department of Radiology, Memorial Sloan Kettering Cancer Center
    A critical benchmark in the development of antibody-based therapeutics is demonstration of efficacy in preclinical mouse models of human disease, many of which rely on immunodeficient mice. However, relatively little is known about how the biology of various immunodeficient strains impacts the in vivo fate of these drugs. Here we used immunoPET radiotracers prepared from humanized, chimeric and murine monoclonal antibodies against four therapeutic oncologic targets to interrogate their biodistribution in four different strains of immunodeficient mice bearing lung, prostate, and ovarian cancer xenografts. Read More

    Keratin 19 expression in hepatocellular carcinoma is regulated by fibroblast-derived HGF via a MET-ERK1/2-AP1 and SP1 axis.
    Cancer Res 2018 Jan 23. Epub 2018 Jan 23.
    Department of Pathology, Yonsei University College of Medicine
    Keratin (KRT) 19 is a poor prognostic marker for hepatocellular carcinoma (HCC), however regulatory mechanisms underlying its expression remain unclear. We have previously reported the presence of fibrous tumor stroma in KRT19-positive HCC, suggesting that crosstalk between cancer-associated fibroblasts (CAF) and tumor epithelial cells could regulate KRT19 expression. This was investigated in this study using an in vitro model of paracrine interaction between HCC cell lines (HepG2, SNU423) and hepatic stellate cells (HSC), a major source of hepatic myofibroblasts. Read More

    Myeloma Cells are Activated in Bone Marrow Microenvironment by the CD180/MD-1 Complex which Senses Lipopolysaccharide.
    Cancer Res 2018 Jan 23. Epub 2018 Jan 23.
    Stem Cell Regulation, Jichi Medical University
    Multiple myeloma (MM) cells acquire dormancy and drug resistance via interaction with bone marrow stroma cells (BMSC) in a hypoxic microenvironment. Elucidating the mechanisms underlying the regrowth of dormant clones may contribute to further improvement of the prognosis of MM patients. In this study, we find that the CD180/MD-1 complex, a non-canonical LPS receptor, is expressed on MM cells but not on normal counterparts, and its abundance is markedly upregulated under adherent and hypoxic conditions. Read More

    Downregulation of membrane trafficking proteins and lactate conditioning determine loss of dendritic cell function in lung cancer.
    Cancer Res 2018 Jan 23. Epub 2018 Jan 23.
    Cellular Immunology, ICGEB
    Restoring antigen presentation for efficient and durable activation of tumor-specific CD8+ T cell responses is pivotal to immunotherapy, yet the mechanisms that cause subversion of dendritic cells (DC) functions are not entirely understood, limiting the development of targeted approaches. In this study, we show that bone fide DC resident in lung tumor tissues or DC exposed to factors derived from whole lung tumors become refractory to endosomal and cytosolic sensor stimulation and fail to secrete IL-12 and IFN-I. Tumor conditioned DC exhibited downregulation of the SNARE VAMP3, a regulator of endosomes trafficking we found to be required for cross-presentation of tumor antigens and DC-mediated tumor rejection. Read More

    Tumor-stroma IL-1β-IRAK4 feedforward circuitry drives tumor fibrosis, chemoresistance, and poor prognosis in pancreatic cancer.
    Cancer Res 2018 Jan 23. Epub 2018 Jan 23.
    Department of Internal Medicine, Division of Oncology, Washington University School of Medicine
    Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but success in the clinic has thus far been limited. Preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAF) carries a risk of accelerating PDAC progression, underscoring the need to concurrently target key signaling mechanisms that drive the malignant attributes of both CAF and PDAC cells. We previously reported that inhibition of interleukin-1 receptor associated kinase 4 (IRAK4) suppresses NF-κB activity and promotes response to chemotherapy in PDAC cells. Read More

    Anti-estrogen therapy increases plasticity and cancer stemness of prolactin-induced ERα+ mammary carcinomas.
    Cancer Res 2018 Jan 23. Epub 2018 Jan 23.
    Comparative Biosciences, University of Wisconsin-Madison
    Although anti-estrogen therapies are successful in many patients with estrogen receptor alpha-positive (ERα+) breast cancer, 25-40% fail to respond. Although multiple mechanisms underlie evasion of these treatments, including tumor heterogeneity and drug-resistant cancer stem cells (CSCs), further investigations have been limited by the paucity of preclinical ERα+ tumor models. Here we examined a mouse model of prolactin-induced aggressive ERα+ breast cancer, which mimics the epidemiologic link between prolactin exposure and increased risk for metastatic ERα+ tumors. Read More

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