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  • Biology, detection, and clinical implications of circulating tumor cells
    1. Simon A Joosse1,,
    2. Tobias M Gorges1, and
    3. Klaus Pantel*,1
    1. 1Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg‐Eppendorf, Hamburg, Germany
    1. *Corresponding author. Tel: +49 40 7410 53503; E‐mail: pantel{at}uke.de
    1. Contributed equally.

    An overview of the biology of tumor cell dissemination, including an in depth discussion of the current advances and limitations in the detection/isolation of circulating tumor cells and their potential prognostic and diagnostic value.

    • Disseminating tumor cells (DTC)
    • EMT
    • metastasis
    • tumor cell dormancy
    • tumor cell plasticity
    • Received July 15, 2014.
    • Revision received October 2, 2014.
    • Accepted October 20, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Simon A Joosse, Tobias M Gorges, Klaus Pantel
  • Assessing metastasis risk after pre‐operative anti‐angiogenic therapy
    1. Daniela Biziato1 and
    2. Michele De Palma (michele.depalma{at}epfl.ch) 1
    1. 1The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Anti‐angiogenic drugs are approved for the treatment of several cancer types, generally in the inoperable locally advanced or metastatic setting and in combination with other anti‐cancer agents. Recent clinical studies also suggest that anti‐angiogenic drugs can be useful in the pre‐operative (neoadjuvant) setting, by facilitating the shrinkage of the primary tumour and its surgical resection. However, the effects of neoadjuvant anti‐angiogenic therapy on the ability of tumours to form distant metastases are unclear. In this issue of EMBO Molecular Medicine, Ebos et al (2014) present carefully performed pre‐clinical studies in mice that analyse the effects of pre‐operative anti‐angiogenic therapy on tumour metastasis and survival.

    See also: JML Ebos et al

    Biziato and De Palma comment on a mouse pre‐clinical study from Ebos, Kerbel et al suggesting that low‐dose metronomic chemotherapy may be combined with multi‐kinase angiogenesis inhibitors in a neoadjuvant setting to improve efficacy and safety.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Daniela Biziato, Michele De Palma
  • Deletion of the von Hippel–Lindau gene causes sympathoadrenal cell death and impairs chemoreceptor‐mediated adaptation to hypoxia
    1. David Macías1,2,3,
    2. Mary Carmen Fernández‐Agüera1,2,3,
    3. Victoria Bonilla‐Henao1,2,3 and
    4. José López‐Barneo*,1,2,3
    1. 1Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
    2. 2Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
    3. 3Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
    1. *Corresponding author. Tel: +34 955 923007; E‐mail: lbarneo{at}us.es

    Instead of tumorigenesis, Vhl inactivation in rodent catecholaminergic cells in vivo causes atrophy of the adrenal medulla, carotid body (CB) and sympathetic ganglia. Hypoxia‐induced adult CB neurogenesis is inhibited and Vhl‐KO mice cannot acclimatize to hypoxia.

    Synopsis

    Instead of tumorigenesis, Vhl inactivation in rodent catecholaminergic cells in vivo causes atrophy of the adrenal medulla, carotid body (CB) and sympathetic ganglia. Hypoxia‐induced adult CB neurogenesis is inhibited and Vhl‐KO mice cannot acclimatize to hypoxia.

    • Contrary to generally held beliefs Vhl is not a tumor suppressor gene in all cells.

    • Vhl‐deficiency in mouse sympathoadrenal cells does not result in the appearance of tumors.

    • Pheochromocytomas in man could be associated with gain‐of‐function mutations in VHL.

    • Animals lacking Vhl exhibit atrophy of the CB and adrenal medulla and present a striking intolerance to systemic hypoxia that could give rise to death.

    • adult carotid body neurogenesis
    • intolerance to hypoxia
    • sympathoadrenal tumorigenesis
    • Vhl‐deficient mouse model
    • von Hippel–Lindau protein
    • Received April 8, 2014.
    • Revision received October 15, 2014.
    • Accepted October 20, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    David Macías, Mary Carmen Fernández‐Agüera, Victoria Bonilla‐Henao, José López‐Barneo
  • Suppressing nonsense—a surprising function for 5‐azacytidine
    1. Ada Shao1 and
    2. Miles F Wilkinson (mfwilkinson{at}ucsd.edu) 1
    1. 1Department of Reproductive Medicine, University of California, San Diego, CA, USA

    In this issue of EMBO Molecular Medicine, Bhuvanagiri et al report on a chemical means to convert molecular junk into gold. They identify a chemical inhibitor of a quality control pathway that is best known for its ability to clear cells of rubbish, but that in certain cases can be detrimental because it eliminates “useful” garbage. The chemical inhibitor identified by Bhuvanagiri et al perturbs Nonsense‐Mediated RNA Decay (NMD), a RNA surveillance pathway that targets mRNAs harboring premature termination codons (PTCs) for degradation (Kervestin & Jacobson, 2012).

    See also: M Bhuvanagiri et al

    Shao & Wilkinson comment on the finding by the Kulozik and Hentze laboratories that FDA‐approved 5AzaC is a NMD inhibitor that could be potentially repurposed for the treatment of NMD‐induced diseases.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Ada Shao, Miles F Wilkinson
  • Tipping the MYC–MIZ1 balance: targeting the HUWE1 ubiquitin ligase selectively blocks MYC‐activated genes
    1. Franz X Schaub1 and
    2. John L Cleveland (John.Cleveland{at}moffitt.org) 1
    1. 1Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    MYC family oncoproteins (MYC, N‐MYC and L‐MYC) function as basic helix‐loop‐helix‐leucine zipper (bHLH‐Zip) transcription factors that are activated (i.e., overexpressed) in well over half of all human malignancies (Boxer & Dang, 2001; Beroukhim et al, 2010). In this issue of EMBO Molecular Medicine, Eilers and colleagues (Peter et al, 2014) describe a novel approach to disable MYC, whereby inhibition of the ubiquitin ligase HUWE1 stabilizes MIZ1 and leads to the selective repression of MYC‐activated target genes.

    See also: S Peter et al

    Schaub and Cleveland comment on the finding by Peter, Eilers et al that MYC can be selectively targeted in cancer by disabling the HUWE1 ubiquitin ligase that normally controls MIZ1 protein levels.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Franz X Schaub, John L Cleveland
  • Neoadjuvant antiangiogenic therapy reveals contrasts in primary and metastatic tumor efficacy
    1. John M L Ebos*,1,
    2. Michalis Mastri1,
    3. Christina R Lee2,
    4. Amanda Tracz1,
    5. John M Hudson2,
    6. Kristopher Attwood3,
    7. William R Cruz‐Munoz2,
    8. Christopher Jedeszko2,
    9. Peter Burns2,4 and
    10. Robert S Kerbel2,4
    1. 1Genitourinary Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
    2. 2Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada
    3. 3Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
    4. 4Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
    1. *Corresponding author. Tel: +1 716 8454464; E‐mail: John.Ebos{at}roswellpark.org

    A novel preclinical methodology to examine efficacy of neoadjuvant therapy in a clinically relevant setting and a scoring system to predict drug combinations that maximize neoadjuvant VEGF RTKI treatment benefits.

    Synopsis

    A novel preclinical methodology to examine efficacy of neoadjuvant therapy in a clinically relevant setting and a scoring system to predict drug combinations that maximize neoadjuvant VEGF RTKI treatment benefits.

    • Antibodies blocking extracellular VEGF pathway components improve post‐surgical outcomes following neoadjuvant treatment.

    • Neoadjuvant VEGF receptor tyrosine kinase inhibitor (RTKI) treatment benefits in primary tumor do not consistently predict for benefits after surgery, with outcomes worsened in some models.

    • Increased doses and earlier surgery may significantly improve post‐surgical benefits of neoadjuvant VEGF RTKI treatment.

    • Anti‐metastatic effects of neoadjuvant low‐dose metronomic chemotherapy may improve limitations of VEGF RTKI treatment.

    • Development of a neoadjuvant efficacy score (NES) allows comparison of pre‐surgical treatment effects on post‐surgical disease recurrence to potentially guide treatment combinations to maximize benefit.

    • antibodies
    • neoadjuvant
    • surgery
    • tyrosine kinase inhibitors
    • VEGF
    • Received February 19, 2014.
    • Revision received September 23, 2014.
    • Accepted September 25, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    John M L Ebos, Michalis Mastri, Christina R Lee, Amanda Tracz, John M Hudson, Kristopher Attwood, William R Cruz‐Munoz, Christopher Jedeszko, Peter Burns, Robert S Kerbel
  • Cyclic‐di‐GMP signalling and biofilm‐related properties of the Shiga toxin‐producing 2011 German outbreak Escherichia coli O104:H4
    1. Anja M Richter1,,
    2. Tatyana L Povolotsky1,,
    3. Lothar H Wieler2 and
    4. Regine Hengge*,1
    1. 1Institute of Biology / Microbiology Humboldt‐Universität zu Berlin, Berlin, Germany
    2. 2Institute of Microbiology and Epizootics Freie Universität Berlin, Berlin, Germany
    1. *Corresponding author. Tel: +49 2093 8101; Fax: +49 2093 8102; E‐mail: Regine.hengge{at}hu-berlin.de
    1. These authors contributed equally to this work

    The detailed genomic and experimental characterization of cyclic‐di‐GMP signaling and production of biofilm and curli fibres, but not cellulose, reveals a unique combination of features that may provide clues to the high virulence of the 2011 German outbreak Escherichia coli O104:H4 strain.

    Synopsis

    The detailed genomic and experimental characterization of cyclic‐di‐GMP signaling and production of biofilm and curli fibres, but not cellulose, reveals a unique combination of features that may provide clues to the high virulence of the 2011 German outbreak Escherichia coli O104:H4 strain.

    • The outbreak strain has a novel c‐di‐GMP‐producing diguanylate cyclase (DgcX) with the highest expression observed to date for such an enzyme in E. coli.

    • Several other c‐di‐GMP‐related enzymes also show altered expression that can contribute to high c‐di‐GMP accumulation potential.

    • High levels of the c‐di‐GMP‐regulated biofilm regulator CsgD and amyloid curli fibres are produced at human body temperature, combined with an inability to generate cellulose.

    • Since curli fibres were previously shown to be highly inflammatory with cellulose counteracting this effect, this high production of ‘naked’, i.e. non‐cellulose‐associated curli fibres by the outbreak strain may enhance inflammation, thereby facilitating efficient transition of Stx into the blood stream and progression to HUS.

    • amyloid
    • curli
    • EAEC
    • EHEC
    • haemolytic uraemic syndrome
    • Received June 1, 2014.
    • Revision received October 2, 2014.
    • Accepted October 6, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Anja M Richter, Tatyana L Povolotsky, Lothar H Wieler, Regine Hengge