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Cancer Cell
This journal offers authors two options (open access or subscription) to publish research

Aug 12, 2013

Volume 24Issue 2p139-272
Open Archive
On the cover: This cover represents the identification of ELTD1 as a potential target to impair the tumor blood supply. The wool ball represents cancer angiogenesis. The thread and the knitting work represent the untangling of cancer angiogenesis using integrative approaches; the coloring pattern represents a heatmap-like view of transcriptional profiles in several cancer types. The red row across the knitted work represents ELTD1, which was identified as commonly expressed and related to key angiogenesis pathways in several cancer types. See Masiero et al., pp. 229–241. Cover design by Dr. Ruud van Stiphout....
On the cover: This cover represents the identification of ELTD1 as a potential target to impair the tumor blood supply. The wool ball represents cancer angiogenesis. The thread and the knitting work represent the untangling of cancer angiogenesis using integrative approaches; the coloring pattern represents a heatmap-like view of transcriptional profiles in several cancer types. The red row across the knitted work represents ELTD1, which was identified as commonly expressed and related to key angiogenesis pathways in several cancer types. See Masiero et al., pp. 229–241. Cover design by Dr. Ruud van Stiphout.

Previews

  • Emerging from NF-κB’s Shadow, SUMOylated IκBα Represses Transcription

    • Neil D. Perkins
    In this issue of Cancer Cell, Mulero and colleagues describe an NF-κB independent transcriptional repression function for SUMOylated IκBα. This compelling and provocative model links IκBα to the activity of the Polycomb repressors and provides a mechanism to link inflammatory signaling to skin homeostasis.
  • The Kinase-Independent, Second Life of CDK6 in Transcription

    • Tobias Otto,
    • Piotr Sicinski
    CDK6 is an oncogenic kinase regulating the cell cycle. In this issue of Cancer Cell, Kollmann and colleagues demonstrate that CDK6 performs a kinase-independent transcriptional function in regulating expression of VEGF-A and p16INK4a. These observations link the cell cycle machinery and angiogenesis and reveal the presence of a fail-safe antiproliferative mechanism.
  • The Origins of Tumor-Promoting Inflammation

    • Tanya Bondar,
    • Ruslan Medzhitov
    Inflammation is increasingly recognized as an essential component of tumor development, but the origin of tumor-associated inflammation remains largely unknown. In this issue of Cancer Cell, Pribluda and colleagues find that chronic stress initiates senescence-inflammatory response, which can promote tumorigenesis in the absence of exogenous inflammatory triggers.
  • IL-11: A Prominent Pro-Tumorigenic Member of the IL-6 Family

    • Sergei I. Grivennikov
    Cytokines have recently emerged as important players in tumor promotion and progression. In this issue of Cancer Cell, Putoczki and colleagues report the importance of interleukin 11 in a variety of gastrointestinal malignances and lay down a framework for its potential inhibition in a variety of human cancers.
  • HSF1 in Translation

    • Emmanuel de Billy,
    • Paul A. Clarke,
    • Paul Workman
    The master regulator of the classical cytoprotective “heat shock” response, heat shock factor 1 (HSF1), is increasingly implicated in cancer pathogenesis, but the mechanisms remain poorly understood. A recent study connects increased protein translation to activation of HSF1 in malignant cells and demonstrates the therapeutic benefit of targeting this link.

Articles

  • Chromatin-Bound IκBα Regulates a Subset of Polycomb Target Genes in Differentiation and Cancer

    • María Carmen Mulero,
    • Dolors Ferres-Marco,
    • Abul Islam,
    • Pol Margalef,
    • Matteo Pecoraro,
    • Agustí Toll,
    • Nils Drechsel,
    • Cristina Charneco,
    • Shelly Davis,
    • Nicolás Bellora,
    • Fernando Gallardo,
    • Erika López-Arribillaga,
    • Elena Asensio-Juan,
    • Verónica Rodilla,
    • Jessica González,
    • Mar Iglesias,
    • Vincent Shih,
    • M. Mar Albà,
    • Luciano Di Croce,
    • Alexander Hoffmann,
    • Shigeki Miyamoto,
    • Jordi Villà-Freixa,
    • Nuria López-Bigas,
    • William M. Keyes,
    • María Domínguez,
    • Anna Bigas,
    • Lluís Espinosa
    IκB proteins are the primary inhibitors of NF-κB. Here, we demonstrate that sumoylated and phosphorylated IκBα accumulates in the nucleus of keratinocytes and interacts with histones H2A and H4 at the regulatory region of HOX and IRX genes. Chromatin-bound IκBα modulates Polycomb recruitment and imparts their competence to be activated by TNFα. Mutations in the Drosophila IκBα gene cactus enhance the homeotic phenotype of Polycomb mutants, which is not counteracted by mutations in dorsal/NF-κB. Oncogenic transformation of keratinocytes results in cytoplasmic IκBα translocation associated with a massive activation of Hox.
  • A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis

    • Karoline Kollmann,
    • Gerwin Heller,
    • Christine Schneckenleithner,
    • Wolfgang Warsch,
    • Ruth Scheicher,
    • Rene G. Ott,
    • Markus Schäfer,
    • Sabine Fajmann,
    • Michaela Schlederer,
    • Ana-Iris Schiefer,
    • Ursula Reichart,
    • Matthias Mayerhofer,
    • Christoph Hoeller,
    • Sabine Zöchbauer-Müller,
    • Dontscho Kerjaschki,
    • Christoph Bock,
    • Lukas Kenner,
    • Gerald Hoefler,
    • Michael Freissmuth,
    • Anthony R. Green,
    • Richard Moriggl,
    • Meinrad Busslinger,
    • Marcos Malumbres,
    • Veronika Sexl
    In contrast to its close homolog CDK4, the cell cycle kinase CDK6 is expressed at high levels in lymphoid malignancies. In a model for p185BCR-ABL+ B-acute lymphoid leukemia, we show that CDK6 is part of a transcription complex that induces the expression of the tumor suppressor p16INK4a and the pro-angiogenic factor VEGF-A. This function is independent of CDK6’s kinase activity. High CDK6 expression thus suppresses proliferation by upregulating p16INK4a, providing an internal safeguard. However, in the absence of p16INK4a, CDK6 can exert its full tumor-promoting function by enhancing proliferation and stimulating angiogenesis.
  • A Genome-wide siRNA Screen Identifies Proteasome Addiction as a Vulnerability of Basal-like Triple-Negative Breast Cancer Cells

    • Fabio Petrocca,
    • Gabriel Altschuler,
    • Shen Mynn Tan,
    • Marc L. Mendillo,
    • Haoheng Yan,
    • D. Joseph Jerry,
    • Andrew L. Kung,
    • Winston Hide,
    • Tan A. Ince,
    • Judy Lieberman
    Basal-like triple-negative breast cancers (TNBCs) have poor prognosis. To identify basal-like TNBC dependencies, a genome-wide siRNA lethality screen compared two human breast epithelial cell lines transformed with the same genes: basal-like BPLER and myoepithelial HMLER. Expression of the screen’s 154 BPLER dependency genes correlated with poor prognosis in breast, but not lung or colon, cancer. Proteasome genes were overrepresented hits. Basal-like TNBC lines were selectively sensitive to proteasome inhibitor drugs relative to normal epithelial, luminal, and mesenchymal TNBC lines.
  • Amplification of Distant Estrogen Response Elements Deregulates Target Genes Associated with Tamoxifen Resistance in Breast Cancer

    • Pei-Yin Hsu,
    • Hang-Kai Hsu,
    • Xun Lan,
    • Liran Juan,
    • Pearlly S. Yan,
    • Jadwiga Labanowska,
    • Nyla Heerema,
    • Tzu-Hung Hsiao,
    • Yu-Chiao Chiu,
    • Yidong Chen,
    • Yunlong Liu,
    • Lang Li,
    • Rong Li,
    • Ian M. Thompson,
    • Kenneth P. Nephew,
    • Zelton D. Sharp,
    • Nameer B. Kirma,
    • Victor X. Jin,
    • Tim H.-M. Huang
    A causal role of gene amplification in tumorigenesis is well known, whereas amplification of DNA regulatory elements as an oncogenic driver remains unclear. In this study, we integrated next-generation sequencing approaches to map distant estrogen response elements (DEREs) that remotely control the transcription of target genes through chromatin proximity. Two densely mapped DERE regions located on chromosomes 17q23 and 20q13 were frequently amplified in estrogen receptor-α-positive luminal breast cancer.
  • Hexokinase 2 Is Required for Tumor Initiation and Maintenance and Its Systemic Deletion Is Therapeutic in Mouse Models of Cancer

    • Krushna C. Patra,
    • Qi Wang,
    • Prashanth T. Bhaskar,
    • Luke Miller,
    • Zebin Wang,
    • Will Wheaton,
    • Navdeep Chandel,
    • Markku Laakso,
    • William J. Muller,
    • Eric L. Allen,
    • Abhishek K. Jha,
    • Gromoslaw A. Smolen,
    • Michelle F. Clasquin,
    • R. Brooks Robey,
    • Nissim Hay
    Accelerated glucose metabolism is a common feature of cancer cells. Hexokinases catalyze the first committed step of glucose metabolism. Hexokinase 2 (HK2) is expressed at high level in cancer cells, but only in a limited number of normal adult tissues. Using Hk2 conditional knockout mice, we showed that HK2 is required for tumor initiation and maintenance in mouse models of KRas-driven lung cancer, and ErbB2-driven breast cancer, despite continued HK1 expression. Similarly, HK2 ablation inhibits the neoplastic phenotype of human lung and breast cancer cells in vitro and in vivo.
  • A Core Human Primary Tumor Angiogenesis Signature Identifies the Endothelial Orphan Receptor ELTD1 as a Key Regulator of Angiogenesis

    • Massimo Masiero,
    • Filipa Costa Simões,
    • Hee Dong Han,
    • Cameron Snell,
    • Tessa Peterkin,
    • Esther Bridges,
    • Lingegowda S. Mangala,
    • Sherry Yen-Yao Wu,
    • Sunila Pradeep,
    • Demin Li,
    • Cheng Han,
    • Heather Dalton,
    • Gabriel Lopez-Berestein,
    • Jurriaan B. Tuynman,
    • Neil Mortensen,
    • Ji-Liang Li,
    • Roger Patient,
    • Anil K. Sood,
    • Alison H. Banham,
    • Adrian L. Harris,
    • Francesca M. Buffa
    Limited clinical benefits derived from anti-VEGF therapy have driven the identification of new targets involved in tumor angiogenesis. Here, we report an integrative meta-analysis to define the transcriptional program underlying angiogenesis in human cancer. This approach identified ELTD1, an orphan G-protein-coupled receptor whose expression is induced by VEGF/bFGF and repressed by DLL4 signaling. Extensive analysis of multiple cancer types demonstrates significant upregulation of ELTD1 in tumor-associated endothelial cells, with a higher expression correlating with favorable prognosis.
  • A Senescence-Inflammatory Switch from Cancer-Inhibitory to Cancer-Promoting Mechanism

    • Ariel Pribluda,
    • Ela Elyada,
    • Zoltan Wiener,
    • Haya Hamza,
    • Robert E. Goldstein,
    • Moshe Biton,
    • Ido Burstain,
    • Yael Morgenstern,
    • Guy Brachya,
    • Hana Billauer,
    • Sharon Biton,
    • Irit Snir-Alkalay,
    • Domagoj Vucic,
    • Katharina Schlereth,
    • Marco Mernberger,
    • Thorsten Stiewe,
    • Moshe Oren,
    • Kari Alitalo,
    • Eli Pikarsky,
    • Yinon Ben-Neriah
    Senescence, perceived as a cancer barrier, is paradoxically associated with inflammation, which promotes tumorigenesis. Here, we characterize a distinct low-grade inflammatory process in stressed epithelium that is related to para-inflammation; this process either represses or promotes tumorigenesis, depending on p53 activity. Csnk1a1 (CKIα) downregulation induces a senescence-associated inflammatory response (SIR) with growth arrest in colorectal tumors, which loses its growth control capacity in the absence of p53 and instead, accelerates growth and invasiveness.
  • Interleukin-11 Is the Dominant IL-6 Family Cytokine during Gastrointestinal Tumorigenesis and Can Be Targeted Therapeutically

    • Tracy L. Putoczki,
    • Stefan Thiem,
    • Andrea Loving,
    • Rita A. Busuttil,
    • Nicholas J. Wilson,
    • Paul K. Ziegler,
    • Paul M. Nguyen,
    • Adele Preaudet,
    • Ryan Farid,
    • Kirsten M. Edwards,
    • Yeliz Boglev,
    • Rodney B. Luwor,
    • Andrew Jarnicki,
    • David Horst,
    • Alex Boussioutas,
    • Joan K. Heath,
    • Oliver M. Sieber,
    • Irina Pleines,
    • Benjamin T. Kile,
    • Andrew Nash,
    • Florian R. Greten,
    • Brent S. McKenzie,
    • Matthias Ernst
    Among the cytokines linked to inflammation-associated cancer, interleukin (IL)-6 drives many of the cancer “hallmarks” through downstream activation of the gp130/STAT3 signaling pathway. However, we show that the related cytokine IL-11 has a stronger correlation with elevated STAT3 activation in human gastrointestinal cancers. Using genetic mouse models, we reveal that IL-11 has a more prominent role compared to IL-6 during the progression of sporadic and inflammation-associated colon and gastric cancers.

Errata

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