The US-Japan HEP Collaboration 30th Anniversary Symposium Oct. 20- Oct.21 Koichiro Nishikawa (KEK)
Cancer Contents Researchand Hiroyoshi Nishikawa Precis: Contrary to a widely held but incorrect...
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BREAKING ADVANCES 1589 Highlights from Recent Cancer Literature REVIEWS 1591 Shedding Light on Melanocyte Pathobiology In Vivo M. Raza Zaidi, Edward C. De Fabo, Frances P. Noonan, and Glenn Merlino 1596 Mechanisms of Ploidy Increase in Human Cancers: A New Role for Cell Cannibalism Matej Krajcovic and Michael Overholtzer PERSPECTIVE 1602 Ribosome Biogenesis and Control of Cell Proliferation: p53 Is Not Alone Giulio Donati, Lorenzo Montanaro, and Massimo Derenzini PRIORITY REPORTS 1608 PARP-1 Inhibition as a Targeted Strategy to Treat Ewing's Sarcoma J. Chad Brenner, Felix Y. Feng, Sumin Han, Sonam Patel, Siddharth V. Goyal, Laura M. Bou-Maroun, Meilan Liu, Robert Lonigro, John R. Prensner, Scott A. Tomlins, and Arul M. Chinnaiyan Pr ecis: This study prompts immediate attention to reposition small-molecule inhibitors of the DNA damage response protein PARP-1, a new class of experimental agents currently in trials in the adult oncology clinic, for treatment of a particularly aggressive and deadly class of pediatric sarcomas. 1614 Receptor Tyrosine Kinase Genes Amplified in Glioblastoma Exhibit a Mutual Exclusivity in Variable Proportions Reflective of Individual Tumor Heterogeneity Suzanne E. Little, Sergey Popov, Alexa Jury, Dorine A. Bax, Lawrence Doey, Safa Al-Sarraj, Juliane M. Jurgensmeier, and Chris Jones Pr ecis: A major challenge facing the development of molecular cancer therapeutics is the complex heterogeneity of tumors at the cellular level, a factor poorly modeled in preclinical systems currently used in drug development, where molecular variegation in key pathways can limit a targeting principle depending on its proportional involvement in the tumor. CLINICAL STUDIES 1621 Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients Sari Pesonen, Iulia Diaconu, Lotta Kangasniemi, Tuuli Ranki, Anna Kanerva, Saila K. Pesonen, Ulrike Gerdemann, Ann M. Leen, Kalevi Kairemo, Minna Oksanen, Elina Haavisto, Sirkka-Liisa Holm, Aila Karioja-Kallio, Satu Kauppinen, Kaarina P. L. Partanen, Leena Laasonen, Tima Joensuu, Tuomo Alanko, Vincenzo Cerullo, and Akseli Hemminki Pr ecis: Clinical translation of oncolytic virotherapy has been mainly disappointing, but this study describes a modification that may improve the ability to trigger tumor clearance by defeating immune escape. INTEGRATED SYSTEMS AND TECHNOLOGIES 1632 Combinatorial Chemotherapeutic Efficacy in Non-Hodgkin Lymphoma Can Be Predicted by a Signaling Model of CD20 Pharmacodynamics John M. Harrold, Robert M. Straubinger, and Donald E. Mager Pr ecis: This study offers a mathematical model that can predict the efficacy of combinatorial chemotherapy regimens, which include the CD20 agonist rituximab, a drug that is being used to treat an increasing number of human cancers. MICROENVIRONMENT AND IMMUNOLOGY 1642 Dissection of T-cell Antigen Specificity in Human Melanoma Rikke Sick Andersen, Charlotte Albæk Thrue, Niels Junker, Rikke Lyngaa, Marco Donia, Eva Ellebæk, Inge Marie Svane, Ton N. Schumacher, Per thor Straten, and Sine Reker Hadrup Pr ecis: By defining the antigens recognized by tumor-infiltrating lymphocytes, one might improve their efficacy and, in turn, improve adoptive cell therapy in cancer. Contents Cancer Research April 1, 2012 Volume 72 Number 7 A Journal of the American Association for Cancer Research iii www.aacrjournals.org on June 28, 2020. © 2012 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from
Transcript of Cancer Contents Researchand Hiroyoshi Nishikawa Precis: Contrary to a widely held but incorrect...
BREAKING ADVANCES
1589 Highlights from Recent CancerLiterature
REVIEWS
1591 Shedding Light on MelanocytePathobiology In VivoM. Raza Zaidi, Edward C. De Fabo,Frances P. Noonan, and Glenn Merlino
1596 Mechanisms of Ploidy Increase inHuman Cancers: A New Role for CellCannibalismMatej Krajcovic and Michael Overholtzer
PERSPECTIVE
1602 Ribosome Biogenesis and Control ofCell Proliferation: p53 Is Not AloneGiulio Donati, Lorenzo Montanaro, andMassimo Derenzini
PRIORITY REPORTS
1608 PARP-1 Inhibition as a TargetedStrategy to Treat Ewing's SarcomaJ. Chad Brenner, Felix Y. Feng, Sumin Han,Sonam Patel, Siddharth V. Goyal,Laura M. Bou-Maroun, Meilan Liu,Robert Lonigro, John R. Prensner,Scott A. Tomlins, and Arul M. Chinnaiyan
Pr�ecis: This study prompts immediate attentionto reposition small-molecule inhibitors of the DNAdamage response protein PARP-1, a new class ofexperimental agents currently in trials in theadult oncology clinic, for treatment of aparticularly aggressive and deadly class ofpediatric sarcomas.
1614 Receptor Tyrosine Kinase GenesAmplified in Glioblastoma Exhibit aMutual Exclusivity in VariableProportions Reflective of IndividualTumor HeterogeneitySuzanne E. Little, Sergey Popov, Alexa Jury,Dorine A. Bax, Lawrence Doey, Safa Al-Sarraj,Juliane M. Jurgensmeier, and Chris Jones
Pr�ecis: A major challenge facing the developmentof molecular cancer therapeutics is the complexheterogeneity of tumors at the cellular level, afactor poorly modeled in preclinical systemscurrently used in drug development, wheremolecular variegation in key pathways can limit atargeting principle depending on its proportionalinvolvement in the tumor.
CLINICAL STUDIES
1621 Oncolytic Immunotherapy of AdvancedSolid Tumors with a CD40L-ExpressingReplicating Adenovirus: Assessment ofSafety and Immunologic Responses inPatientsSari Pesonen, Iulia Diaconu, Lotta Kangasniemi,Tuuli Ranki, Anna Kanerva, Saila K. Pesonen,Ulrike Gerdemann, AnnM. Leen, Kalevi Kairemo,Minna Oksanen, Elina Haavisto,Sirkka-Liisa Holm, Aila Karioja-Kallio,Satu Kauppinen, Kaarina P. L. Partanen,Leena Laasonen, Tima Joensuu, Tuomo Alanko,Vincenzo Cerullo, and Akseli Hemminki
Pr�ecis: Clinical translation of oncolytic virotherapyhas been mainly disappointing, but this studydescribes a modification that may improve theability to trigger tumor clearance by defeatingimmune escape.
INTEGRATED SYSTEMS ANDTECHNOLOGIES
1632 Combinatorial ChemotherapeuticEfficacy in Non-Hodgkin LymphomaCan Be Predicted by a Signaling Modelof CD20 PharmacodynamicsJohn M. Harrold, Robert M. Straubinger, andDonald E. Mager
Pr�ecis: This study offers a mathematical modelthat can predict the efficacy of combinatorialchemotherapy regimens, which include the CD20agonist rituximab, a drug that is being used to treatan increasing number of human cancers.
MICROENVIRONMENT AND IMMUNOLOGY
1642 Dissection of T-cell Antigen Specificityin Human MelanomaRikke Sick Andersen, Charlotte Albæk Thrue,Niels Junker, Rikke Lyngaa, Marco Donia,Eva Ellebæk, Inge Marie Svane,Ton N. Schumacher, Per thor Straten, andSine Reker Hadrup
Pr�ecis: By defining the antigens recognized bytumor-infiltrating lymphocytes, one might improvetheir efficacy and, in turn, improve adoptive celltherapy in cancer.
ContentsCancerResearchApril 1, 2012 � Volume 72 � Number 7
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1651 Oncolytic Virus and Anti–4-1BBCombination Therapy Elicits StrongAntitumor Immunity againstEstablished CancerLiza B. John, Linda J. Howland,Jacqueline K. Flynn, Alison C. West,Christel Devaud, Connie P. Duong,Trina J. Stewart, Jenny A. Westwood,Z. Sheng Guo, David L. Bartlett, Mark J. Smyth,Michael H. Kershaw, and Phillip K. Darcy
Pr�ecis: The preclinical proof-of-concept offered bythis study suggests a strategy to improve theclinical efficacy of oncolytic viruses for cancerimmunotherapy by combining them with animmune agonist antibody that may help overcometumor-mediated immune suppression.
1661 Preclinical Evaluation of TriMix andAntigen mRNA-Based AntitumorTherapySandra Van Lint, Cleo Goyvaerts,Sarah Maenhout, Lode Goethals, Aur�elie Disy,Daphn�e Benteyn, Joeri Pen, Aude Bonehill,Carlo Heirman, Karine Breckpot, andKris Thielemans
Pr�ecis: This study presents important progress inthe rapid development of simpler kinds ofdendritic cell vaccines, the first ever of which wasapproved for patient treatment in the UnitedStates last year.
1672 Intracellular Tumor-AssociatedAntigens Represent Effective Targetsfor Passive ImmunotherapyTakuro Noguchi, Takuma Kato, Linan Wang,Yuka Maeda, Hiroaki Ikeda, Eiichi Sato,Alexander Knuth, Sacha Gnjatic, Gerd Ritter,Shimon Sakaguchi, Lloyd J. Old, Hiroshi Shiku,and Hiroyoshi Nishikawa
Pr�ecis: Contrary to a widely held but incorrectbelief in the field, intracellular tumor antigens canoffer highly effective targets for monoclonalantibody–directed therapy, as shown by thispreclinical study.
1683 Reprogramming Tumor-AssociatedDendritic Cells In Vivo Using miRNAMimetics Triggers ProtectiveImmunity against Ovarian CancerJuan R. Cubillos-Ruiz, Jason R. Baird,Amelia J. Tesone, Melanie R. Rutkowski,Uciane K. Scarlett, Ana L. Camposeco-Jacobs,Jorge Anadon-Arnillas, Noah M. Harwood,Murray Korc, Steven N. Fiering,Lorenzo F. Sempere, and Jose R. Conejo-Garcia
Pr�ecis: Findings suggest it may be feasible tomodulate microRNA activities in leukocytes in thetumor microenvironment without need of viralvectors or difficult clinical implementations.
1694 Vascular Normalization by Loss ofSiah2 Results in IncreasedChemotherapeutic EfficacyChristina S.F. Wong, Jaclyn Sceneay,Colin M. House, Heloise M. Halse, Mira C.P. Liu,Joshy George, Titaina C.U. Potdevin Hunnam,Belinda S. Parker, Izhak Haviv, Ze'ev Ronai,Carleen Cullinane, David D. Bowtell, andAndreas M€oller
Pr�ecis: Findings offer preclinical proof-of-conceptthat targeting the Siah2 ubiquitin ligase thatregulates the hypoxia response factor HIF-1a canrelieve hypoxia, normalize tumor vasculature, andimprove responses to chemotherapy.
1705 Vanilloid Receptor-1 RegulatesNeurogenic Inflammation in Colonand Protects Mice from Colon CancerAmaya G. Vinuesa, Rocío Sancho,Carmen García-Limones, Axel Behrens,Peter ten Dijke, Marco A. Calzado, andEduardo Muñoz
Pr�ecis: This important study offers compellinggenetic support for the intriguing concept thatneuronally controlled processes of inflammationmay underlie the root inflammatorymicroenvironment that drives the developmentand progression of colon cancer, with implicationsfor targeting neuroinflammatory receptors thatcontrol these processes as a wholly novel strategyto prevent or treat this major disease.
1717 Cancer Vaccination Drives Nanog-Dependent Evolution of Tumor Cellstoward an Immune-Resistant andStem-like PhenotypeKyung Hee Noh, Young-Ho Lee, Ju-Hong Jeon,Tae Heung Kang, Chih-Ping Mao, T.-C. Wu, andTae Woo Kim
Pr�ecis: An important stem cell transcriptionfactor is found to drive development of tumoralimmune resistance after therapeutic vaccinations,suggesting possible strategies to enhance cancerimmunotherapy.
1728 RORa Suppresses Breast TumorInvasion by Inducing SEMA3FExpressionGaofeng Xiong, Chi Wang, B. Mark Evers,Binhua P. Zhou, and Ren Xu
Pr�ecis: Findings point to an important role for theTh17 immune transcription factor RORa inpreventing the establishment of an immune-suppressive tumor microenvironment inmammary tissue.
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MOLECULAR AND CELLULARPATHOBIOLOGY
1740 Dmp1 Physically Interacts with p53and Positively Regulates p53'sStability, Nuclear Localization, andFunctionDonna P. Frazier, Robert D. Kendig,Fumitake Kai, DejanMaglic, Takayuki Sugiyama,Rachel L. Morgan, Elizabeth A. Fry,Sarah J. Lagedrost, Guangchao Sui, andKazushi Inoue
Pr�ecis: The results of this study show a novelmechanism for p53 activation through directphysical interaction between Dmp1 and p53,which plays critical roles in antagonizing Mdm2-p53 interaction.
1751 MiR-155 Is a Liposarcoma OncogeneThat Targets Casein Kinase-1a andEnhances b-Catenin SignalingPingyu Zhang, Katelynn Bill, Juehui Liu,Eric Young, Tingsheng Peng,Svetlana Bolshakov, Aviad Hoffman,Yechun Song, Elizabeth G. Demicco,Dolores Lopez Terrada, Chad J. Creighton,Matthew L. Anderson, Alexander J. Lazar,George G. Calin, Raphael E. Pollock, andDina Lev
Pr�ecis: Findings reveal key functions for miR-155and b-catenin signaling in progression ofliposarcoma, with implications for prognosis andtherapy of dedifferentiated deadly forms of thisdisease.
1763 miRNA-130a Targets ATG2B andDICER1 to Inhibit Autophagy andTrigger Killing of ChronicLymphocytic Leukemia CellsValentina Kovaleva, Rodrigo Mora,Yoon Jung Park, Christoph Plass,Abhilash I. Chiramel, Ralf Bartenschlager,Hartmut D€ohner, Stephan Stilgenbauer,Armin Pscherer, Peter Lichter, andMartina Seiffert
Pr�ecis: Findings suggest a feedback loop involvinga microRNA that controls expression of a mastermicroRNA regulatory gene with an impact on theautophagic susceptibility of cancer cells, therebyaffecting treatment efficacy and posttreatmentrelapse.
1773 Hypoxia-Induced Autophagy PromotesTumor Cell Survival and Adaptation toAntiangiogenic Treatment inGlioblastomaYu-Long Hu, Michael DeLay, Arman Jahangiri,Annette M. Molinaro, Samuel D. Rose,W. Shawn Carbonell, and Manish K. Aghi
Pr�ecis: This important study has immediateclinical implications because it suggests ways thatautophagy inhibitors such as chloroquine might becombined with antiangiogenic therapies to limit amechanism of resistance and thereby extendefficacy.
1784 Tumor Cell–Derived Angiopoietin-likeProtein ANGPTL2 Is a Critical Driver ofMetastasisMotoyoshi Endo, Masahiro Nakano,Tsuyoshi Kadomatsu, Shigetomo Fukuhara,Hiroaki Kuroda, Shuji Mikami, Tai Hato, Jun Aoi,Haruki Horiguchi, Keishi Miyata, Haruki Odagiri,Tetsuro Masuda, Masahiko Harada,Hirotoshi Horio, Tsunekazu Hishima,Hiroaki Nomori, Takaaki Ito, Yutaka Yamamoto,Takashi Minami, Seiji Okada,Takashi Takahashi, Naoki Mochizuki,Hirotaka Iwase, and Yuichi Oike
Pr�ecis: Findings have implications for a broad-basedantibody-mediated strategy to blunt metastasis invarious human cancers where an angiogenesis-related factor is implicated in this process.
1795 19p13.1 Is a Triple-Negative–SpecificBreast Cancer Susceptibility LocusKristen N. Stevens, Zachary Fredericksen,Celine M. Vachon, Xianshu Wang, Sara Margolin,Annika Lindblom, Heli Nevanlinna, Dario Greco,Kristiina Aittom€aki, Carl Blomqvist,Jenny Chang-Claude, Alina Vrieling,Dieter Flesch-Janys, Hans-Peter Sinn,Shan Wang-Gohrke, Stefan Nickels,Hiltrud Brauch on behalf of the GENICANetwork,Yon-Dschun Ko, Hans-Peter Fischer,Rita K. Schmutzler, Alfons Meindl,Claus R. Bartram, Sarah Schott, Christoph Engel,Andrew K. Godwin, JoEllen Weaver,Harsh B. Pathak, Priyanka Sharma,Hermann Brenner, Heiko M€uller, Volker Arndt,Christa Stegmaier, Penelope Miron,Drakoulis Yannoukakos, Alexandra Stavropoulou,George Fountzilas, Helen J. Gogas, Ruth Swann,Miriam Dwek, Annie Perkins, Roger L. Milne,Javier Benítez, María Pilar Zamora,Jos�e Ignacio Arias P�erez, Stig E. Bojesen,Sune F. Nielsen, Børge G. Nordestgaard,Henrik Flyger, Pascal Gu�enel, Th�er�ese Truong,Florence Menegaux, Emilie Cordina-Duverger,Barbara Burwinkel, Frederick Marm�e,Andreas Schneeweiss, Christof Sohn,Elinor Sawyer, Ian Tomlinson, Michael J. Kerin,Julian Peto, Nichola Johnson, Olivia Fletcher,Isabel dos Santos Silva, Peter A. Fasching,Matthias W. Beckmann, Arndt Hartmann,Arif B. Ekici, Artitaya Lophatananon,Kenneth Muir, Puttisak Puttawibul,Surapon Wiangnon, Marjanka K. Schmidt,Annegien Broeks, Linde M. Braaf,Efraim H. Rosenberg, John L. Hopper,CarmelApicella,Daniel J. Park,MelissaC. Southey,Anthony J. Swerdlow, Alan Ashworth,Nicholas Orr, Minouk J. Schoemaker,Hoda Anton-Culver, Argyrios Ziogas,Leslie Bernstein, Christina Clarke Dur,Chen-Yang Shen, Jyh-Cherng Yu, Huan-MingHsu,Chia-NiHsiung,UteHamann,ThomasD€unnebier,Thomas R€udiger, Hans Ulrich Ulmer,Paul P. Pharoah, Alison M. Dunning,Manjeet K. Humphreys, Qin Wang, Angela Cox,Simon S. Cross, Malcom W. Reed, Per Hall,Kamila Czene, Christine B. Ambrosone,Foluso Ademuyiwa, Helena Hwang,
vi Cancer Research
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Diana M. Eccles, Montserrat Garcia-Closas,Jonine D. Figueroa, Mark E. Sherman,Jolanta Lissowska, Peter Devilee,Caroline Seynaeve, Rob A.E.M. Tollenaar,Maartje J. Hooning, Irene L. Andrulis,Julia A. Knight, Gord Glendon,Anna Marie Mulligan, Robert Winqvist,Katri Pylk€as, Arja Jukkola-Vuorinen, Mervi Grip,Esther M. John, Alexander Miron,Grethe Grenaker Alnæs, Vessela Kristensen,Anne-Lise Børresen-Dale, Graham G. Giles,Laura Baglietto, Catriona A. McLean,Gianluca Severi, Matthew L. Kosel, V.S. Pankratz,Susan Slager, Janet E. Olson, Paolo Radice,Paolo Peterlongo, Siranoush Manoukian,Monica Barile, Diether Lambrechts, Sigrid Hatse,Anne-Sophie Dieudonne, Marie-Rose Christiaens,Georgia Chenevix-Trench, on behalf of kConFabInvestigators and the AOCS Group,Jonathan Beesley, Xiaoqing Chen,Arto Mannermaa, Veli-Matti Kosma,Jaana M. Hartikainen, Ylermi Soini,Douglas F. Easton, and Fergus J. Couch
Pr�ecis: Findings establish a significant associationbetween genomic variants at 19p13.1 andtriple-negative breast cancer, providing convincingevidence that there is a genetic susceptibility todifferent breast tumor subtypes and that theyarise through distinct etiologic pathways.
THERAPEUTICS, TARGETS, ANDCHEMICAL BIOLOGY
1804 Enhanced Apoptosis and TumorGrowth Suppression Elicited byCombination of MEK (Selumetinib)and mTOR Kinase Inhibitors(AZD8055)Sarah V. Holt, Armelle Logie, Barry R. Davies,Denis Alferez, Sarah Runswick, Sarah Fenton,Christine M. Chresta, Yi Gu, Jingchuan Zhang,Yi-Long Wu, Robert W. Wilkinson,Sylvie M. Guichard, and Paul D. Smith
Pr�ecis: Findings offer a preclinical proof-of-conceptfor combiningMAPKandmTORkinase inhibitors inclinical trials to achieve robust tumor growthinhibition while limiting risks of chemoresistance.
1814 Paclitaxel Enhances TherapeuticEfficacy of the F8-IL2 Immunocytokineto EDA-Fibronectin–Positive MetastaticHuman Melanoma XenograftsMichele Moschetta, Francesca Pretto,Alexander Berndt, Kerstin Galler, Petra Richter,Andrea Bassi, Paolo Oliva, Edoardo Micotti,Giovanni Valbusa, Kathrin Schwager,Manuela Kaspar, Eveline Trachsel,Hartwig Kosmehl, Maria Rosa Bani, Dario Neri,and Raffaella Giavazzi
Pr�ecis: Findings offer a preclinical proof-of-conceptfor an effective application of IL-2–basedimmunochemotherapy for melanoma that istargeted to fibronectin, an extracellular matrixprotein expressed by many melanomas.
1825 Retinoic Acid/Alpha-InterferonCombination Inhibits Growth andPromotes Apoptosis in Mantle CellLymphoma through Akt-DependentModulation of Critical TargetsJessica Dal Col, Katy Mastorci,Damiana Antonia Fa�e, Elena Muraro,Debora Martorelli, Giorgio Inghirami, andRiccardo Dolcetti
Pr�ecis: A clinical drug combination explored fortreatment of numerous types of cancer may beespecially suited to treatment of a deadly type ofnon-Hodgkin lymphoma that remains particularlydifficult to treat.
1836 Rapamycin Resistance Is Linked toDefective Regulation of Skp2Hana Totary-Jain, Despina Sanoudou,Cula N. Dautriche, Hillary Schneller,Lester Zambrana, and Andrew R. Marks
Pr�ecis: This study defines a candidate drugresponse marker for mTOR inhibitors, animportant class of experimental therapeuticsof growing interest for the generalizedtreatment of human cancer, with immediateimplications for clinical evaluation in mTORinhibitor trials.
1844 A Universal Strategy for AdoptiveImmunotherapy of Cancer throughUse of a Novel T-cell Antigen ReceptorKatarzyna Urbanska, Evripidis Lanitis,Mathilde Poussin, Rachel C. Lynn,Brian P. Gavin, Sander Kelderman, Jason Yu,Nathalie Scholler, and Daniel J. Powell Jr
Pr�ecis: This study suggests a universalimmune receptor strategy to tailor and vastlyexpand the number of tumor antigens recognizedby engineered T cells for adoptiveimmunotherapy, perhaps greatly enhancingthe general use of this technology for cancertreatment.
TUMOR AND STEM CELL BIOLOGY
1853 Cancer Stem Cell Vaccination ConfersSignificant Antitumor ImmunityNing Ning, Qin Pan, Fang Zheng,Seagal Teitz-Tennenbaum, Martin Egenti, Ji Yet,Mu Li, Christophe Ginestier, Max S. Wicha,Jeffrey S. Moyer, Mark E.P. Prince, Yingxin Xu,Xiao-Lian Zhang, Shiang Huang, Alfred E. Chang,and Qiao Li
Pr�ecis: Vaccines that use purified cancer stemcells are highly immunogenic and triggerantitumor immunity with greater potency thanthat triggered by vaccines composed of unselectedtumor cells.
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1865 miRNA Signatures Associate withPathogenesis and Progression ofOsteosarcomaKevin B. Jones, Zaidoun Salah, Sara Del Mare,Marco Galasso, Eugenio Gaudio,Gerard J. Nuovo, Francesca Lovat,Kimberly LeBlanc, Jeff Palatini, R. Lor Randall,Stefano Volinia, Gary S. Stein, Carlo M. Croce,Jane B. Lian, and Rami I. Aqeilan
Pr�ecis: Osteosarcoma is a leading cause ofdeath in adolescents yet remains mainly devoid ofdevelopment of sounder tools to improve prognosisor therapy.
1878 Pten Loss and RAS/MAPK ActivationCooperate to Promote EMT andMetastasis Initiated from ProstateCancer Stem/Progenitor CellsDavid J. Mulholland, Naoko Kobayashi,Marcus Ruscetti, Allen Zhi, Linh M. Tran,Jiaoti Huang, Martin Gleave, and Hong Wu
Pr�ecis: Development of a prostate cancer modelthat addresses the major metastatic burdenaccompanying late-stage human diseaseaddresses a gap in the field that may permit thedevelopment of more effective targeted treatmentstrategies.
1890 Jab1/CSN5 Negatively Regulates p27and Plays a Role in the Pathogenesis ofNasopharyngeal CarcinomaYunbao Pan, Qingxiu Zhang, Ling Tian,Xin Wang, Xiaohang Fan, Huizhong Zhang,Francois X. Claret, and Huiling Yang
Pr�ecis: Definition of a cell-cycle regulatory role fora component of the signalosome, a proteinturnover complex analogous to the proteosome butless understood, suggests new strategies to treat anaggressive cancer endemic in East Asia.
LETTERS TO THE EDITOR
1901 Lactate-Induced IL-8 Pathway inEndothelial Cells—LetterC�eline Pinheiro, Adhemar Longatto-Filho,Rosete Nogueira, Fernando Schmitt, andF�atima Baltazar
1903 Lactate-Induced IL-8 Pathway inEndothelial Cells—ResponseFr�ed�erique V�egran, Emmanuel Seront,Pierre Sonveaux, and Olivier Feron
CORRECTION
1905 Correction: Significance of MAD2Expression to Mitotic CheckpointControl in Ovarian Cancer Cells
ABOUT THE COVER
Tumor metastasis represents a major cause of cancer mortality. Despiteintense effort, strategies designed to inhibit metastasis have beenunsuccessful, in part due to lack of understanding of mechanisms underlyingthe process. In this study, a shortened period of disease-free survival wasobserved after surgery in lung cancer patients showing high angiopoietin-likeprotein 2 (ANGPTL2) expression in tumor cells within primary tumor sites.Furthermore, tumor cell–derived ANGPTL2 increased tumor cell motilityand invasive capacity in an autocrine/paracrine manner, resulting inacquisition of metastatic tumor phenotypes. In tumor cell–implanted mousemodels, tumor cell–derived ANGPTL2 accelerated metastasis and shortenedsurvival periods; conversely, decreasing ANGPTL2 expression in tumor cellssignificantly attenuated metastasis and extended survival periods. Thisimage represents CD44-stained human breast tumor cells expressingANGPTL2 in lung metastasis in mice. For details, see the article by Endo andcolleagues on page 1784 of this issue.
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2012;72:1589-1905. Cancer Res 72 (7)
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