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    Roles for Innate Immunity in Combination Immunotherapies.
    Cancer Res 2017 Sep 19. Epub 2017 Sep 19.
    Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
    Immunity to infectious agents involves a coordinated response of innate and adaptive immune cells working in concert, with many feed-forward and regulatory interactions between both arms of the immune system. In contrast, many therapeutic strategies to augment immunity against tumors have focused predominantly on stimulation of adaptive immunity. However, a growing appreciation of the potential contributions of innate immune effectors to antitumor immunity, especially in the context of combination immunotherapy, is leading to novel strategies to elicit a more integrated immune response against cancer. Read More

    New Advances and Challenges of Targeting Cancer Stem Cells.
    Cancer Res 2017 Sep 19. Epub 2017 Sep 19.
    Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
    The second International Cancer Stem Cell Conference in Cleveland, Ohio, on September 20-23, 2016, convened 330 attendees from academic, industrial, and clinical organizations. It featured a debate on the concepts and challenges of the cancer stem cells (CSC) as well as CSC-centered scientific sessions on clinical trials, genetics and epigenetics, tumor microenvironment, immune suppression, metastasis, therapeutic resistance, and emerging novel concepts. The conference hosted 35 renowned speakers, 100 posters, 20 short talks, and a preconference workshop. Read More

    Targeting a Single Alternative Polyadenylation Site Coordinately Blocks Expression of Androgen Receptor mRNA Splice Variants in Prostate Cancer.
    Cancer Res 2017 Aug 15. Epub 2017 Aug 15.
    Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
    Prostate cancer is the second leading cause of male cancer deaths due to disease progression to castration-resistant prostate cancer (CRPC). Androgen receptor (AR) splice variants including AR-V7 function as constitutively active transcription factors in CRPC cells, thereby promoting resistance to AR-targeted therapies. To date, there are no AR variant-specific treatments for CRPC. Read More

    MCT1 inhibitor AZD3965 increases mitochondrial metabolism, facilitating combination therapy and non-invasive magnetic resonance spectroscopy.
    Cancer Res 2017 Sep 18. Epub 2017 Sep 18.
    Cancer Research UK Cancer Imaging Centre, The Institute of Cancer Research.
    Monocarboxylate transporters (MCT) modulate tumor cell metabolism and offer promising therapeutic targets for cancer treatment. Understanding the impact of MCT blockade on tumor cell metabolism may help develop combination strategies or identify pharmacodynamic biomarkers to support the clinical development of MCT inhibitors now in clinical trials. In this study, we assessed the impact of the MCT1 inhibitor AZD3965 on cancer cell metabolism in vitro and in vivo. Read More

    In silico modeling of immunotherapy and stroma-targeting therapies in human colorectal cancer.
    Cancer Res 2017 Sep 18. Epub 2017 Sep 18.
    Department of Medical Oncology, National Center for Tumor Diseases, University Medical Center Heidelberg
    Despite the fact that the local immunological microenvironment shapes the prognosis of colorectal cancer, immunotherapy has shown no benefit for the vast majority of colorectal cancer patients. A better understanding of the complex immunological interplay within the microenvironment is required. In this study, we utilized wet lab migration experiments and quantitative histological data of human colorectal cancer tissue samples (n=20) including tumor cells, lymphocytes, stroma and necrosis to generate a multi-agent spatial model. Read More

    Upregulation of Cystathionine-β-synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis.
    Cancer Res 2017 Sep 18. Epub 2017 Sep 18.
    Department of Surgery, University of Texas Medical Branch
    The transsulfuration enzyme cystathionine-β-synthase (CBS) and its product hydrogen sulfide (H2S) are aberrantly upregulated in colorectal cancers, where they contribute to tumor growth and progression by both autocrine and paracrine mechanisms. However, it is unknown whether the CBS/H2S axis plays a role in colorectal carcinogenesis. Here, we report upregulation of CBS in human biopsies of precancerous adenomatous polyps and show that forced upregulation of CBS in an adenoma-like colonic epithelial cell line is sufficient to induce metabolic and gene expression profiles characteristic of colorectal cancer cells. Read More

    Anti-CD137 suppresses tumor growth by blocking reverse signaling by CD137 ligand.
    Cancer Res 2017 Sep 18. Epub 2017 Sep 18.
    School of Biological Sciences, University of Ulsan
    CD137 (4-1BB) is a T cell co-stimulatory molecule and agonstic CD137 antibodies are currently being evaluated in clinic as cancer immunotherapy. Recently, it was found that CD137-/- mice or mice injected with agonistic anti-CD137 antibodies exhibit heightened antitumor responses, contrary to expectations based on other knowledge of CD137 function. Here we report findings related to reverse signaling by CD137 ligand (CD137L) in antigen-presenting dendritic cells (DC) in tumors that address these paradoxical results. Read More

    MetaLnc9 facilitates lung cancer metastasis via a PGK1-activated AKT/mTOR pathway.
    Cancer Res 2017 Sep 18. Epub 2017 Sep 18.
    Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University.
    Long non-coding RNAs participate in carcinogenesis and tumor progression in lung cancer. Here we report the identification of a lncRNA signature associated with metastasis of non-small cell lung cancer (NSCLC). In particular, elevated expression of LINC00963 (MetaLnc9) in human NSCLC specimens correlated with poor prognosis, promoted migration and invasion of NSCLC cells in vitro, and enhanced lung metastasis formation in vivo. Read More

    Genomic activation of PPARG reveals a candidate therapeutic axis in bladder cancer.
    Cancer Res 2017 Sep 18. Epub 2017 Sep 18.
    Cancer Program, Broad Institute.
    The PPARG gene encoding the nuclear receptor PPAR-gamma is activated in bladder cancer, either directly by gene amplification or mutation, or indirectly by mutation of the RXRA gene which encodes the heterodimeric partner of PPAR-gamma. Here we show that activating alterations of PPARG or RXRA lead to a specific gene expression signature in bladder cancers. Reducing PPARG activity, whether by pharmacologic inhibition or genetic ablation, inhibited proliferation of PPARG-activated bladder cancer cells. Read More

    Mitosis-mediated intravasation in a tissue-engineered tumor-microvessel platform.
    Cancer Res 2017 Sep 18. Epub 2017 Sep 18.
    Institute for Nanobiotechnology, Johns Hopkins University
    Intravasation involves the migration of tumor cells across the local endothelium and escape into vessel flow. While tumor cell invasiveness has been correlated to increased intravasation, the details of transendothelial migration and detachment into circulation are still unclear. Here we analyzed the intravasation of invasive human breast cancer cells within a tissue-engineered microvessel model of the tumor microenvironment. Read More

    Caveolae-Mediated Endocytosis is Critical for Albumin Cellular Uptake and Response to Albumin-Bound Chemotherapy.
    Cancer Res 2017 Sep 18. Epub 2017 Sep 18.
    Radiation Oncology, Ohio State University Medical Center
    Nab-paclitaxel, a nanoparticle conjugate of paclitaxel to human albumin, exhibits efficacy in pancreatic cancer, non-small cell lung cancer and breast cancer. However, there is a lack of predictive biomarkers to identify patients who might benefit most from its administration. This study addresses this gap in knowledge by identifying that caveolin-1 (Cav-1) is a candidate mechanism-based biomarker. Read More

    Adaptation to TKI treatment reactivates ERK signaling in tyrosine kinase-driven leukemias and other malignancies.
    Cancer Res 2017 Sep 18. Epub 2017 Sep 18.
    Oncology and Pediatrics, Johns Hopkins University School of Medicine
    FLT3 tyrosine kinase inhibitors (TKI) have been tested extensively to limited benefit in acute myeloid leukemia. We hypothesized that FLT3/ITD leukemia cells exhibit mechanisms of intrinsic signaling adaptation to TKI treatment that are associated with an incomplete response. Here we identified reactivation of ERK signaling within hours following treatment of FLT3/ITD AML cells with selective inhibitors of FLT3. Read More

    TET-mediated sequestration of miR-26 drives EZH2 expression and gastric carcinogenesis.
    Cancer Res 2017 Sep 18. Epub 2017 Sep 18.
    Guangzhou Medical University, Cancer Research Institute and Cancer Hospital.
    DNA demethylases of the TET family function as tumor suppressors in various human cancers but their pathogenic contributions and mechanisms of action in gastric carcinogenesis and progression remain unclear. Here we report that TET is transcriptionally upregulated in gastric cancer (GC) where it correlates with poor prognosis. Mechanistic investigations revealed that TET facilitated gastric carcinogenesis through a non-coding function of the 3'UTR which interacted with miR-26. Read More

    GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome.
    Cancer Res 2017 Sep;77(18):5095-5106
    Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
    High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury. Read More

    T cells deficient in diacylglycerol kinase-ζ are resistant to PD-1 inhibition and help create persistent host immunity to leukemia.
    Cancer Res 2017 Sep 15. Epub 2017 Sep 15.
    Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin
    Efforts to improve the efficacy of adoptive T cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the anti-leukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase-zeta (DGKζ) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKζ-deficient (DGKζ-/-) mice than wild-type mice. Read More

    Tenascin-C and integrin α9 mediate interactions of prostate cancer with the bone microenvironment.
    Cancer Res 2017 Sep 15. Epub 2017 Sep 15.
    Molecular and Cellular Biology, Baylor College of Medicine and Michael E. DeBakey Veterans Association Medical Center
    Deposition of the extracellular matrix protein tenascin-C is part of the reactive stroma response, which has a critical role in prostate cancer progression. Here we report that tenascin-C is expressed in the bone endosteum and involved associated with formation of prostate bone metastases. Metastatic cells cultured on osteo-mimetic surfaces coated with tenascin-C exhibited enhanced adhesion and colony formation as mediated by integrin α9β1. Read More

    Chemotherapy-induced macrophage infiltration into tumors enhances nanographene-based photodynamic therapy.
    Cancer Res 2017 Sep 15. Epub 2017 Sep 15.
    Radiation Medicine, Peking University
    Increased recruitment of tumor-associated macrophages (TAM) to tumors following chemotherapy promotes tumor resistance and recurrence and correlates with poor prognosis. TAM depletion suppresses tumor growth, but is not highly effective due to the effects of tumorigenic mediators from other stromal sources. Here we report that adoptive macrophage transfer led to a dramatically enhanced photodynamic therapy (PDT) effect of 2-(1-hexyloxyethyl)-2-devinyl pyropheophor-bide-alpha (HPPH)-coated polyethylene glycosylated nanographene oxide [GO(HPPH)-PEG] by increasing its tumor accumulation. Read More

    Tethering IL2 to its receptor IL2Rβ enhances anti-tumor activity and expansion of natural killer NK92 cells.
    Cancer Res 2017 Sep 15. Epub 2017 Sep 15.
    Massachusetts General Hospital.
    Interleukin-2 (IL2) is an immunostimulatory cytokine for key immune cells including T cells and natural killer (NK) cells. Systemic IL2 supplementation could enhance NK-mediated immunity in a variety of diseases ranging from neoplasms to viral infection. However, its systemic use is restricted by its serious side effects and limited efficacy due to activation of T regulatory cells (Tregs). Read More

    Biallelic Dicer1 loss mediated by aP2-Cre drives angiosarcoma.
    Cancer Res 2017 Sep 15. Epub 2017 Sep 15.
    Oncology, St. Jude Children's Research Hospital
    Angiosarcoma is an aggressive vascular sarcoma with an extremely poor prognosis. Due to the relative rarity of this disease, its molecular drivers and optimal treatment strategies are obscure. DICER1 is an RNase III endoribonuclease central to microRNA biogenesis, and germline DICER1 mutations result in a cancer predisposition syndrome, associated with an increased risk of many tumor types. Read More

    YAP suppresses lung squamous cell carcinoma progression via deregulation of the DNp63-GPX2 axis and ROS accumulation.
    Cancer Res 2017 Sep 15. Epub 2017 Sep 15.
    Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences
    Lung squamous cell carcinoma (SCC), accounting for approximately 30% of non-small cell lung cancer, is often refractory to therapy. Screening a small molecule library, we identified digitoxin as a high potency compound for suppressing human lung SCC growth in vitro and in vivo. Mechanistic investigations revealed that digitoxin attenuated YAP phosphorylation and promoted YAP nuclear sequestration. Read More

    LSD1-Mediated Epigenetic Reprogramming Drives CENPE Expression and Prostate Cancer Progression.
    Cancer Res 2017 Sep 15. Epub 2017 Sep 15.
    Medical Biophysics, Princess Margaret Cancer Centre
    Androgen receptor (AR) signaling is a key driver of prostate cancer (PCa), and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant PCa (CRPC). Here we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. Read More

    Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency.
    Cancer Res 2017 Sep;77(18):4755-4762
    Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Mismatch repair (MMR)-deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Read More

    PD-1 status in CD8(+) T cells associates with survival and anti-PD-1 therapeutic outcomes in head and neck cancer.
    Cancer Res 2017 Sep 13. Epub 2017 Sep 13.
    Cancer Immunology Program, University of Pittsburgh Cancer Institute
    Improved understanding of expression of immune checkpoint receptors (ICR) on tumor-infiltrating lymphocytes (TIL) may facilitate more effective immunotherapy in head and neck cancer (HNC) patients. A higher frequency of PD-1(+) TIL has been reported in human papillomavirus (HPV)(+) HNC patients, despite the role of PD-1 in T cell exhaustion. This discordance led us to hypothesize that the extent of PD-1 expression more accurately defines T cell function and prognostic impact, since PD-1(high) T cells may be more exhausted than PD-1(low) T cells and may influence clinical outcome and response to anti-PD-1 immunotherapy. Read More

    ANGPTL1 interacts with integrin α1β1 to suppress HCC angiogenesis and metastasis by inhibiting JAK2/STAT3 signaling.
    Cancer Res 2017 Sep 13. Epub 2017 Sep 13.
    Department of Clinical Oncology, The University of Hong Kong
    Downregulation of tumor suppressor signaling plays an important role in the pathogenesis of hepatocellular carcinoma (HCC). Here we report that downregulation of the angiopoietin-like protein ANGPTL1 is associated with vascular invasion, tumor thrombus, metastasis and poor prognosis in HCC. Ectopic expression of ANGPTL1 in HCC cells effectively decreased their in vitro and in vivo tumorigenicity, cell motility and angiogenesis. Read More

    Structurally novel antiestrogens elicit differential responses from constitutively active mutant estrogen receptors in breast cancer cells and tumors.
    Cancer Res 2017 Sep 13. Epub 2017 Sep 13.
    Department of Chemistry, University of Illinois at Urbana Champaign.
    Many ERα-positive breast cancers develop resistance to endocrine therapy via mutation of estrogen receptors (ER) whose constitutive activation is associated with shorter patient survival. Because there is now a clinical need for new antiestrogens (AE) against these mutant ER, we describe here our development and characterization of three chemically novel AE that effectively suppress proliferation of breast cancer cells and tumors. Our AE are effective against wild type and Y537S and D538G ER, the two most commonly occurring constitutively active ER. Read More

    Anti-Jagged immunotherapy inhibits MDSCs and overcomes tumor-induced tolerance.
    Cancer Res 2017 Sep 13. Epub 2017 Sep 13.
    Georgia Cancer Center, Augusta University
    Myeloid-derived suppressor cells (MDSCs) are a major obstacle to promising forms of cancer immunotherapy, but tools to broadly limit their immunoregulatory effects remain lacking. In this study, we assessed the therapeutic effect of the humanized anti-Jagged1/2 blocking antibody CTX014 on MDSC-mediated T cell suppression in tumor-bearing mice. CTX014 decreased tumor growth, impacted the accumulation and tolerogenic activity of MDSCs in tumors, and inhibited the expression of immunosuppressive factors arginase I and iNOS. Read More

    Optical coherence tomography detects necrotic regions and volumetrically quantifies multicellular tumor spheroids.
    Cancer Res 2017 Sep 13. Epub 2017 Sep 13.
    Electrical and Computer Engineering, Bioengineering, Lehigh University
    Three-dimensional (3D) tumor spheroid models have gained increased recognition as important tools in cancer research and anti-cancer drug development. However, currently available imaging approaches employed in high-throughput screening drug discovery platforms e.g. Read More

    Exercise-Induced Catecholamines Activate the Hippo Tumor Suppressor Pathway to Reduce Risks of Breast Cancer Development.
    Cancer Res 2017 Sep;77(18):4894-4904
    Centre of Inflammation and Metabolism (CIM) and Centre for Physical Activity Research (CFAS), Rigshospitalet, Faculty of Health Science, University of Copenhagen, Denmark.
    Strong epidemiologic evidence documents the protective effect of physical activity on breast cancer risk, recurrence, and mortality, but the underlying mechanisms remain to be identified. Using human exercise-conditioned serum for breast cancer cell incubation studies and murine exercise interventions, we aimed to identify exercise factors and signaling pathways involved in the exercise-dependent suppression of breast cancer. Exercise-conditioned serum from both women with breast cancer (n = 20) and healthy women (n = 7) decreased MCF-7 (hormone-sensitive) and MDA-MB-231 (hormone-insensitive) breast cancer cell viability in vitro by 11% to 19% and reduced tumorigenesis by 50% when preincubated MCF-7 breast cancer cells were inoculated into NMRI-Foxn1(nu) mice. Read More

    ATG5 mediates a positive feedback loop between Wnt signaling and autophagy in melanoma.
    Cancer Res 2017 Sep 8. Epub 2017 Sep 8.
    Tumor Microenvironment and Metastasis Program, The Wistar Institute
    Autophagy mediates resistance to various anticancer agents. In melanoma, resistance to targeted therapy has been linked to expression of Wnt5A, an intrinsic inhibitor of β-catenin, which also promotes invasion. In this study, we assessed the interplay between Wnt5A and autophagy by combining expression studies in human clinical biopsies with functional analyses in cell lines and mouse models. Read More

    FSTL1 promotes metastasis and chemoresistance in esophageal squamous cell carcinoma through NFκB-BMP signaling crosstalk.
    Cancer Res 2017 Sep 7. Epub 2017 Sep 7.
    School of Biomedical Sciences, The University of Hong Kong
    Esophageal squamous cell carcinoma (ESCC) has a generally poor prognosis and molecular markers to improve early detection and predict outcomes are greatly needed. Here we report that the BMP-binding follistatin-like protein FSTL1 is overexpressed in ESCCs where it correlates with poor overall survival. Genetic amplification of FSTL1 or chromosome 3q where it is located occurred frequently in ESCC, where FSTL1 copy number correlated positively with higher FSTL1 protein expression. Read More

    CD155T/TIGIT Signaling Regulates CD8+ T Cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer.
    Cancer Res 2017 Sep 7. Epub 2017 Sep 7.
    Pathology, First Affiliated Hospital of Sun Yat-sen University
    The T cell surface molecule TIGIT is an immune checkpoint molecule that inhibits T cell responses, but its roles in cancer are little understood. In this study, we evaluated the role TIGIT checkpoint plays in the development and progression of gastric cancer (GC). We show that the percentage of CD8 T cells that are TIGIT+ was increased in GC patients compared to healthy individuals. Read More

    Discovery of human-similar gene fusions in canine cancers.
    Cancer Res 2017 Sep 7. Epub 2017 Sep 7.
    Institut de Génétique et Développement de Rennes, Université de Rennes 1-CNRS.
    Canine cancers represent a tremendous natural resource due to their incidence and striking similarities to human cancers, sharing similar clinical and pathological features as well as oncogenic events including identical somatic mutations. Considering the importance of gene fusions as driver alterations, we explored their relevance in canine cancers. We focused on three distinct human-comparable canine cancers representing different tissues and embryonic origins. Read More

    Genetic dissociation of glycolysis and the TCA cycle affects neither normal nor neoplastic proliferation.
    Cancer Res 2017 Sep 7. Epub 2017 Sep 7.
    The Division of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh
    Rapidly proliferating cells increase glycolysis at the expense of oxidative phosphorylation (oxphos) to generate sufficient levels of glycolytic intermediates for use as anabolic substrates. The pyruvate dehydrogenase complex (PDC) is a critical mitochondrial enzyme that catalyzes pyruvate's conversion to acetyl coenzyme A (AcCoA), thereby connecting these two pathways in response to complex energetic, enzymatic and metabolic cues. Here we utilized a mouse model of hepatocyte-specific PDC inactivation to determine the need for this metabolic link during normal hepatocyte regeneration and malignant transformation. Read More

    KDM4 inhibition targets breast cancer stem-like cells.
    Cancer Res 2017 Sep 7. Epub 2017 Sep 7.
    Central Clinical Research, Freiburg University Medical Center
    Traditional treatments for breast cancer fail to address therapy-resistant cancer stem-like cells that have been characterized by changes in epigenetic regulators such as the lysine demethylase KDM4. Here we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. To assess the anti-tumor properties of QC6352, we established a method to isolate and propagate breast cancer stem-like cells (BCSC) from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy. Read More

    Enhanced acid sphingomyelinase activity drives immune evasion and tumor growth in non-small cell lung carcinoma.
    Cancer Res 2017 Sep 7. Epub 2017 Sep 7.
    Molecular Pneumology, University of Erlangen
    The lipid hydrolase enzyme acid sphingomyelinase (ASM) is required for the conversion of the lipid cell membrane component sphingomyelin into ceramide. In cancer cells, ASM-mediated ceramide production is important for apoptosis, cell proliferation and immune modulation, highlighting ASM as a potential multimodal therapeutic target. In this study, we demonstrate elevated ASM activity in the lung tumor environment and blood serum of patients with non-small cell lung cancer (NSCLC). Read More

    miR-193b-regulated signaling networks serve as tumor suppressors in liposarcoma and promote adipogenesis in adipose-derived stem cells.
    Cancer Res 2017 Sep 7. Epub 2017 Sep 7.
    Sarcoma Biology Laboratory, Sarcoma Disease Management Program, Department of Surgery, Memorial Sloan Kettering Cancer Center
    Well-differentiated and dedifferentiated liposarcomas (WDLS/DDLS) account for approximately 13% of all soft tissue sarcoma in adults and cause substantial morbidity or mortality in the majority of patients. In this study, we evaluated the functions of miRNA (miR-193b) in liposarcoma in vitro and in vivo. Deep RNA sequencing on 93 WDLS, 145 DDLS and 12 normal fat samples demonstrated that miR-193b was significantly underexpressed in DDLS compared to normal fat. Read More

    Transplantation of iPS-derived tumor cells with a homozygous MHC haplotype induces GRP94 antibody production in MHC-matched macaques.
    Cancer Res 2017 Sep 7. Epub 2017 Sep 7.
    Division of Pathology and Disease Regulation, Shiga University of Medical Science.
    Immune surveillance is a critical component of the anti-tumor response in vivo, yet the specific components of the immune system involved in this regulatory response remain unclear. In this study, we demonstrate that autoantibodies can mitigate tumor growth in vitro and in vivo. We generated two cancer cell lines, embryonal carcinoma and glioblastoma cell lines, from monkey induced pluripotent stem cells (iPSC) carrying a homozygous haplotype of major histocompatibility complex (MHC, Mafa in Macaca fascicularis). Read More

    Exosomes from Glioma-Associated Mesenchymal Stem Cells Increase the Tumorigenicity of Glioma Stem-like Cells via Transfer of miR-1587.
    Cancer Res 2017 Aug 30. Epub 2017 Aug 30.
    Department of Neurosurgery, The University of Texas MD Anderson Cancer Center
    Tumor-stromal communications impact tumorigenesis in ways that are incompletely understood. Here we show that Glioma Associated-human Mesenchymal Stem Cells (GA-hMSCs), a newly identified stromal component of glioblastoma, release exosomes that increase the proliferation and clonogenicity of tumor-initiating Glioma Stem-like Cells (GSCs). This event leads to a significantly greater tumor burden and decreased host survival compared with untreated GSCs in orthotopic xenografts. Read More

    Sensitivity to BUB1B inhibition defines an alternative classification of glioblastoma.
    Cancer Res 2017 Aug 30. Epub 2017 Aug 30.
    Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
    Glioblastoma multiforme (GBM) remains a mainly incurable disease in desperate need of more effective treatments. In this study, we develop evidence that the mitotic spindle checkpoint molecule BUB1B may offer a predictive marker for aggressiveness and effective drug response. A subset of GBM tumor isolates require BUB1B to suppress lethal kinetochore-microtubule attachment defects. Read More

    The blebbishield emergency program overrides chromosomal instability and phagocytosis checkpoints in cancer stem cells.
    Cancer Res 2017 Aug 30. Epub 2017 Aug 30.
    Urology, M.D. Anderson Cancer Center.
    Genomic instability and immune evasion are hallmarks of cancer. Apoptotic cancer stem cells can evade cell death by undergoing cellular transformation by constructing "blebbishields" from apoptotic bodies. In this study, we report a novel linkage between genomic instability and phagocytosis evasion which is coordinated by the blebbishield emergency program. Read More

    CD73 promotes resistance to HER2/ErbB2 antibody therapy.
    Cancer Res 2017 Aug 30. Epub 2017 Aug 30.
    Institut du Cancer de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal
    Expression of the ectonucleotidase CD73 by tumor cells, stromal cells, and immune cells is associated in cancer with immune suppression. In this study, we investigated the role of CD73 on the activity of the anti-HER2/ErbB2 monoclonal antibody (mAb) trastuzumab. In a prospective randomized phase III clinical trial evaluating the activity of trastuzumab, high levels of CD73 gene expression associated significantly with poor clinical outcome. Read More

    Therapeutic targeting of oncogenic tyrosine phosphatases.
    Cancer Res 2017 Aug 30. Epub 2017 Aug 30.
    Medicinal Chemistry and Molecular Pharmacology, Purdue University
    Protein tyrosine phosphatases (PTPs) are exciting and novel targets for cancer drug discovery that work in concert with protein tyrosine kinases (PTKs) in controlling cellular homeostasis. Given the activating role that some PTKs play in initiating growth factor-mediated cellular processes, PTPs are usually perceived as the negative regulators of these events and therefore tumor suppressive in nature. However, mounting evidence indicate that PTPs do not always antagonize the activity of PTKs in regulating tyrosine phosphorylation, but can also play dominant roles in the initiation and progression of signaling cascades that regulate cell functions. Read More

    Bone-induced expression of integrin β3 enables targeted nanotherapy of breast cancer metastases.
    Cancer Res 2017 Aug 30. Epub 2017 Aug 30.
    Internal Medicine, Washington University School of Medicine
    Bone metastases occur in ~70% of metastatic breast cancer patients often leading to skeletal injuries. Current treatments are mainly palliative and underscore the unmet clinical need for improved therapies. In this study, we provide preclinical evidence for an antimetastatic therapy based on targeting integrin β3 (β3) which is selectively induced on breast cancer cells in bone by the local bone microenvironment. Read More

    Shrimp miR-S8 suppresses the stemness of human melanoma stem-like cells by targeting the transcription factor YB-1.
    Cancer Res 2017 Aug 30. Epub 2017 Aug 30.
    College of Life Sciences, Zhejiang University
    Cross-species regulation of gene expression by microRNA is a possible untapped opportunity for miRNA-based therapy. In this study, we report a novel approach to ablate melanoma stem-like cells by targeting the transcription factor YB-1, which is significantly and selectively upregulated in these cells in melanoma. Silencing YB-1 expression was sufficient to significantly inhibit the stemness of melanoma stem-like cells. Read More

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