BREAKING ADVANCES

3733 Highlights from Recent CancerLiterature

REVIEW

3735 Roles of Sildenafil in Enhancing DrugSensitivity in CancerZhi Shi, Amit K. Tiwari, Atish S. Patel, Li-Wu Fu,and Zhe-Sheng Chen

PERSPECTIVE

3739 Evolved Tumor Suppression: Why AreWe So Good at Not Getting Cancer?James DeGregori

CLINICAL STUDIES

3745 Serial Magnetic ResonanceSpectroscopy Reveals a DirectMetabolic Effect of Cediranib inGlioblastomaHeisoog Kim, Ciprian Catana, Eva-Maria Ratai,Ovidiu C. Andronesi, Dominique L. Jennings,Tracy T. Batchelor, Rakesh K. Jain, andA. Gregory Sorensen

Pr�ecis: Metabolic changes in the tumor and braintissue during anti-VEGF therapy can serve asimaging biomarkers for predicting treatmentresponse in patients with recurrent malignantglioblastomas.

INTEGRATED SYSTEMS ANDTECHNOLOGIES

3753 Preclinical Validation ofElectrochemotherapy as an EffectiveTreatment for Brain TumorsBirgit Agerholm-Larsen, Helle K. Iversen,Per Ibsen, Jakob M. Moller, Faisal Mahmood,Kurt Svarre Jensen, and Julie Gehl

Pr�ecis: Enhancing drug uptake through the use of anovel electrode technology can achieve high rates ofcomplete response in a rat model of brain cancer.

MICROENVIRONMENT AND IMMUNOLOGY

3763 Chronic Inflammatory IFN-g SignalingSuppresses Hepatocarcinogenesis inMice by Sensitizing Hepatocytes forApoptosisStefan L€uth, J€org Schrader, Stefan Zander,Antonella Carambia, Juliane Buchkremer,Samuel Huber, Kurt Reifenberg,Ken-Ichi Yamamura, Peter Schirmacher,Ansgar W. Lohse, and Johannes Herkel

Pr�ecis: Findings highlight the central role ofinterferon-g in determining cancer-promotingversus cancer-suppressing inflammation.

3772 A Requirement of STAT3 DNA BindingPrecludes Th-1 ImmunostimulatoryGene Expression by NF-kB in TumorsHeehyoung Lee, Jiehui Deng, Hong Xin, Yong Liu,Drew Pardoll, and Hua Yu

Pr�ecis: This study addresses paradoxes concerningthe role of STAT3 and NF-kB as pro-oncogenic yetalso immunostimulatory to T-cell responses againstcancer.

3781 Proangiogenic Factor PlGF ProgramsCD11bþ Myelomonocytes in BreastCancer during Differentiation of TheirHematopoietic ProgenitorsJulien Laurent, Eveline Faes-van't Hull,Cedric Touvrey, Francois Kuonen, Qiang Lan,Girieca Lorusso, Marie-Agn�es Doucey,Laura Ciarloni, Natsuko Imaizumi,Gian Carlo Alghisi, Ernesta Fagiani, Khalil Zaman,Roger Stupp, Masabumi Shibuya,Jean-Francois Delaloye, Gerhard Christofori, andCurzio Ruegg

Pr�ecis: Findings reveal a previously unrecognizedactivity of placental growth factor, a proangiogenicfactor that contributes to tumor angiogenesis andprogression in many types of cancer.

3792 Exosomes Released by Melanoma CellsPrepare Sentinel Lymph Nodes forTumor MetastasisJoshua L. Hood, Susana San Roman, andSamuel A. Wickline

Pr�ecis: Preparation of the metastatic niche inlymph nodes relies in part on the ability of aprimary tumor to secrete nanovesicles that canremodel the nodal microenvironment and permitits colonization by tumor cells.

ContentsCancerResearchJune 1, 2011 � Volume 71 � Number 11

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MOLECULAR AND CELLULARPATHOBIOLOGY

3802 CD24 Offers a Therapeutic Target forControl of Bladder Cancer MetastasisBased on a Requirement for LungColonizationJonathan B. Overdevest, Shibu Thomas,Glen Kristiansen, Donna E. Hansel,Steven C. Smith, and Dan Theodorescu

Pr�ecis: Findings offer preclinical proof-of-conceptfor antibody targeting of a marker of metastaticprogression as a potential new adjuvant therapyfor clinical investigation.

3812 An EGFR-ERK-SOX9 Signaling CascadeLinks Urothelial Development andRegeneration to CancerShizhang Ling, Xiaofei Chang, Luciana Schultz,Thomas K. Lee, Alcides Chaux,Luigi Marchionni, George J. Netto,David Sidransky, and David M. Berman

Pr�ecis: Cells undergoing injury turn on EGF ligandproduction, which induces the developmentaltranscription factor SOX9 and supports emergenceof a migratory, invasive phenotype.

3822 Epithelial Cell OrganizationSuppresses Myc Function byAttenuating Myc ExpressionDavid R. Simpson, Min Yu, Siyuan Zheng,Zhongming Zhao, Senthil K. Muthuswamy, andWilliam P. Tansey

Pr�ecis: This study finds that epithelial cellorganization does not pose a barrier to Myconcogenicity, pointing to roles for tumorsuppression mechanisms other than three-dimensional structure in antagonizing Myc duringcarcinogenesis.

3831 Bone Marrow Stroma–SecretedCytokines Protect JAK2V617F-MutatedCells from the Effects of a JAK2InhibitorTaghi Manshouri, Zeev Estrov,Alfonso Quint�as-Cardama, Jan Burger,Ying Zhang, Ana Livun, Liza Knez, David Harris,Chad J. Creighton, Hagop M. Kantarjian, andSrdan Verstovsek

Pr�ecis: Myeloproliferative neoplasms rely onsupport from stromal cells in the bone marrowmicroenvironment that release IL-6, FGF, andCXCL10.

3841 A Genome-Wide Search for PromotersThat Respond to Increased MYCNReveals Both New Oncogenic andTumor Suppressor MicroRNAsAssociated with AggressiveNeuroblastomaJason M. Shohet, Rajib Ghosh, Cristian Coarfa,Andrew Ludwig, Ashley L. Benham,Zaowen Chen, Danielle M. Patterson,Eveline Barbieri, Pieter Mestdagh,Denae N. Sikorski, Aleksandar Milosavljevic,Eugene S. Kim, and Preethi H. Gunaratne

Pr�ecis: N-Myc activation is associated with directrepression of a microRNA program that is notgenerally suppressive to neuroblastoma cells, withpossible implications for how to better attack thisaggressive pediatric cancer.

3852 The Melanoma-Upregulated LongNoncoding RNA SPRY4-IT1 ModulatesApoptosis and InvasionDivya Khaitan, Marcel E. Dinger, Joseph Mazar,Joanna Crawford, Martin A. Smith,John S. Mattick, and Ranjan J. Perera

Pr�ecis: Long noncoding RNAs (lncRNAs) are arapidly emerging area of cancer research becauseof their suspected roles in interacting withmessenger RNAs, regulatory microRNAs, andproteins and modulating their functions.

3863 Mutationally Activated BRAFV600E

Elicits Papillary Thyroid Cancer in theAdult MouseRoch-Philippe Charles, Gioia Iezza,Elena Amendola, David Dankort, andMartin McMahon

Pr�ecis: Studies of thyroid cancer, the mostcommon endocrine cancer, will benefit from thedevelopment of a high-penetrance, genetically-engineered mouse model, which recapitulates keyfeatures of the genetics and pathophysiology of thehuman disease.

3872 Mild Elevation of Body TemperatureReduces Tumor Interstitial FluidPressure and Hypoxia and EnhancesEfficacy of Radiotherapy in MurineTumor ModelsArindam Sen, Maegan L. Capitano,Joseph A. Spernyak, John T. Schueckler,Seneca Thomas, Anurag K. Singh,Sharon S. Evans, Bonnie L. Hylander, andElizabeth A. Repasky

Pr�ecis: Preclinical findings show how mildsystemic hyperthermia in mice bearing tumors canincrease tumor blood flow and improve theefficacy radiation therapy, prompting immediateattention for clinical evaluation.

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PREVENTION AND EPIDEMIOLOGY

3881 A Multistage Association StudyIdentifies a Breast Cancer GeneticLocus at NCOA7Kathryn S.P. Higginbotham, Joan P. Breyer,Kevin M. Bradley, Peggy A. Schuyler,W. Dale Plummer, Jr., Marcia E. Freudenthal,Amy Trentham-Dietz, Polly A. Newcomb,Melinda E. Sanders, David L. Page, Fritz F. Parl,Kathleen M. Egan, William D. Dupont, andJeffrey R. Smith

Pr�ecis: A large genetic association study of growthfactor signaling and estrogenmetabolism defines avariant in an estrogen receptor-bindingtranscriptional co-activator that may confer areduced risk of breast cancer.

3889 Physical Activity after Diagnosis andRisk of Prostate Cancer Progression:Data from the Cancer of the ProstateStrategic Urologic Research EndeavorErin L. Richman, Stacey A. Kenfield,Meir J. Stampfer, Alan Paciorek, Peter R. Carroll,and June M. Chan

Pr�ecis: Brisk walking after diagnosis may inhibitor delay prostate cancer progression among mendiagnosed with clinically localized prostatecancer.

3896 LIN28B Polymorphisms InfluenceSusceptibility to Epithelial OvarianCancerJennifer Permuth-Wey, Donghwa Kim,Ya-Yu Tsai, Hui-Yi Lin, Y. Ann Chen,Jill Barnholtz-Sloan, Michael J. Birrer,Gregory Bloom, Stephen J. Chanock,Zhihua Chen, Daniel W. Cramer,Julie M. Cunningham, Getachew Dagne,Judith Ebbert-Syfrett, David Fenstermacher,Brooke L. Fridley, Montserrat Garcia-Closas,Simon A. Gayther, William Ge,Aleksandra Gentry-Maharaj,Jesus Gonzalez-Bosquet, Ellen L. Goode,Edwin Iversen, Heather Jim, William Kong,John McLaughlin, Usha Menon,Alvaro N.A. Monteiro, Steven A. Narod,Paul D.P. Pharoah, Catherine M. Phelan,Xiaotao Qu, Susan J. Ramus, Harvey Risch,Joellen M. Schildkraut, Honglin Song,Heather Stockwell, Rebecca Sutphen,Kathryn L. Terry, Jonathan Tyrer,Robert A. Vierkant, Nicolas Wentzensen,Johnathan M. Lancaster, Jin Q. Cheng, andThomas A. Sellers on behalf of the OvarianCancer Association Consortium (OCAC)

Pr�ecis: Common inherited variants in miRNAbiogenesis genes may be useful to identify high-riskpopulations and to develop novel cancerdiagnostic, prognostic, and therapeutic strategies.

3904 Identification of an UnintendedConsequence of Nrf2-DirectedCytoprotection against a Key TobaccoCarcinogen plus a CounteractingChemopreventive InterventionJoseph D. Paonessa, Yi Ding, Kristen L. Randall,Rex Munday, Dayana Argoti, Paul Vouros, andYuesheng Zhang

Pr�ecis: An important cytoprotective factor is foundto sensitize the bladder to a major tobaccocarcinogen, but a chemopreventive strategy issuggested to limit this pitfall.

THERAPEUTICS, TARGETS, ANDCHEMICAL BIOLOGY

3912 Combining Histone DeacetylaseInhibitor Vorinostat with AuroraKinase Inhibitors EnhancesLymphoma Cell Killing withRepression of c-Myc, hTERT, andmicroRNA LevelsLeo Kretzner, Anna Scuto, Pamela M. Dino,Claudia M. Kowolik, Jun Wu, Patrick Ventura,Richard Jove, Stephen J. Forman, Yun Yen, andMark H. Kirschbaum

Pr�ecis: Proof-of-concept and mechanistic findingsprompt clinical evaluation for a novel drugcombination that could improve cancer treatment.

3921 Histone Methyltransferase KMT1ARestrains Entry of AlveolarRhabdomyosarcoma Cells into aMyogenic Differentiated StateMin-Hyung Lee, Mathivanan Jothi,Andrei V. Gudkov, and Asoke K. Mal

Pr�ecis: Results address the longstanding questionof how an aggressive childhood cancer might beprompted to undergo terminal differentiation,suggesting new strategies to improve therapy.

3932 Erlotinib-Mediated Inhibition of EGFRSignaling Induces Metabolic OxidativeStress through NOX4Kevin P. Orcutt, Arlene D. Parsons,Zita A. Sibenaller, Peter M. Scarbrough,Yueming Zhu, Arya Sobhakumari,Werner W. Wilke, Amanda L. Kalen,Prabhat Goswami, Francis J. Miller Jr.,Douglas R. Spitz, and Andrean L. Simons

Pr�ecis: Findings suggest that the cytotoxicity ofEGFR kinase inhibitors in cancer cells may bebased in large part on induction of oxidative stressvia hydrogen peroxide produced by NOX4signaling.

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3941 ErbB3 Ablation Impairs PI3K/Akt-Dependent Mammary TumorigenesisRebecca S. Cook, Joan T. Garrett,Violeta S�anchez, Jamie C. Stanford,Christian Young, Anindita Chakrabarty,Cammie Rinehart, Yixian Zhang, Yaming Wu,Lee Greenberger, Ivan D. Horak, andCarlos L. Arteaga

Pr�ecis: Findings offer preclinical proof-of-conceptthat ErbB3 disruption may be therapeuticallyeffective in PI3K/Akt-driven breast cancers.

3952 Comparison of Neuropathy-InducingEffects of Eribulin Mesylate, Paclitaxel,and Ixabepilone in MiceKrystyna M. Wozniak, Kenichi Nomoto,Rena G. Lapidus, Ying Wu, Valentina Carozzi,Guido Cavaletti, Kazuhiro Hayakawa,Satoru Hosokawa, Murray J. Towle,Bruce A. Littlefield, and Barbara S. Slusher

Pr�ecis: Compared to taxanes and epothilones, thetwo major classes of antimitotic drugs used incancer treatment, a new FDA approvedantitubulin drug may cause far less debilitatingnerve damage in cancer survivors.

3963 Convection-Enhanced Delivery ofTopotecan into a PDGF-Driven Modelof Glioblastoma Prolongs Survival andAblates Both Tumor-Initiating Cellsand Recruited Glial ProgenitorsKim A. Lopez, Aaron M. Tannenbaum,Marcela C. Assanah, Katy Linskey, Jonathan Yun,Alayar Kangarlu, Orlando D. Gil, Peter Canoll,and Jeffrey N. Bruce

Pr�ecis: The findings of this study suggest thatchemotherapy may prime later recurrence bydecreasing recruitment of normal glial progenitorcells into a brain tumor microenvironment.

3972 6-Bromoindirubin-30-Oxime InhibitsJAK/STAT3 Signaling and InducesApoptosis of Human Melanoma CellsLucy Liu, Sangkil Nam, Yan Tian, Fan Yang,Jun Wu, Yan Wang, Anna Scuto,Panos Polychronopoulos, Prokopios Magiatis,Leandros Skaltsounis, and Richard Jove

Pr�ecis: Inhibitors of the JAK/STAT3 signalingpathway represent a very appealing therapeuticdirection because of the central importance of thispathway in tumor cells and the tumormicroenvironment in sustaining malignant growthand progression.

TUMOR AND STEM CELL BIOLOGY

3980 Phosphorylation of Serine 68 of Twist1by MAPKs Stabilizes Twist1 Proteinand Promotes Breast Cancer CellInvasivenessJun Hong, Jian Zhou, Junjiang Fu, Tao He,Jun Qin, Li Wang, Lan Liao, and Jianming Xu

Pr�ecis: Ras-activated MAP kinases promoteinvasion and metastasis by stabililizing a masterregulator of epithelial-mesenchymal transition.

3991 Aldehyde Dehydrogenase inCombination with CD133 DefinesAngiogenic Ovarian Cancer Stem CellsThat Portend Poor Patient SurvivalInes A. Silva, Shoumei Bai, Karen McLean,Kun Yang, Kent Griffith, Dafydd Thomas,Christophe Ginestier, Carolyn Johnston,Angela Kueck, R. Kevin Reynolds, Max S. Wicha,and Ronald J. Buckanovich

Pr�ecis: This report identifies a pair of ovariancancer stem cell markers that may be functionallycritical for stem cell differentiation in cancers.

4002 Hedgehog Overexpression IsAssociated with Stromal Interactionsand Predicts for Poor Outcome inBreast CancerSandra A. O'Toole, Dorothy A. Machalek,Robert F. Shearer, Ewan K.A. Millar,Radhika Nair, Peter Schofield, Duncan McLeod,Caroline L. Cooper, Catriona M. McNeil,Andrea McFarland, Akira Nguyen,Christopher J. Ormandy, Min Ru Qiu,Brian Rabinovich, Luciano G. Martelotto,Duc Vu, Gregory E. Hannigan,Elizabeth A. Musgrove, Daniel Christ,Robert L. Sutherland, D. Neil Watkins, andAlexander Swarbrick

Pr�ecis: This study identifies an importantprognostic role of Hedgehog pathway in breastcancer and highlights its potential as a noveltherapeutic target in metastatic carcinoma.

4015 The Hypoxia-Associated FactorSwitches Cells from HIF-1a– to HIF-2a–Dependent Signaling PromotingStem Cell Characteristics, AggressiveTumor Growth and InvasionMei Yee Koh, Robert Lemos, Jr., Xiuping Liu, andGarth Powis

Pr�ecis: This study shows how tumor cells exposedto more intense periods of hypoxia in themicroenvironment will respond to improve theirlikelihood of survival and progression, withimplications for therapeutic targeting.

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4028 EZH2-Mediated ConcordantRepression of Wnt AntagonistsPromotes b-Catenin–DependentHepatocarcinogenesisAlfred S.L. Cheng, Suki S. Lau, Yangchao Chen,Yutaka Kondo, May S. Li, Hai Feng,Arthur K. Ching, Kin F. Cheung, Hoi K. Wong,Joanna H. Tong, Hongchuan Jin,Kwong W. Choy, Jun Yu, Ka F. To,Nathalie Wong, Tim H.-M. Huang, andJoseph J.Y. Sung

Pr�ecis: Mechanistic results reveal how theprometastatic transcription repressor EZH2coordinately blocks Wnt antagonists, therebypromoting Wnt/ß-catenin signaling in cancer.

4040 Uncoupling Cancer Mutations RevealsCritical Timing of p53 Loss inSarcomagenesisNathan P. Young, Denise Crowley, andTyler Jacks

Pr�ecis: Altering the sequence of mutations in amouse model of sarcomagenesis shows thatmutation order dictates tumor phenotype.

CORRECTION

4048 Correction: Peptide Vaccination afterT-Cell Transfer Causes Massive ClonalExpansion, Tumor Eradication, andManageable Cytokine Storm

4049 Correction: FLT3-Mediated p38–MAPKActivation Participates in the Controlof Megakaryopoiesis in PrimaryMyelofibrosis

4051 Correction: Functional Cooperation ofRKTG with p53 in Tumorigenesis andEpithelial-Mesenchymal Transition

ABOUT THE COVER

Melanoma exosomes home to sentinel lymph nodes and inducemicroenvironmental responses that permit metastasis of melanoma cells.The figure demonstrates an increase in the number of melanoma cells (green)infiltrating a sentinel node (blue) for the larger melanoma exosome–inducedsentinel node (bottom) in contrast to the smaller control liposome node (top)following serial injections of melanoma exosomes or control liposomes. Fordetails, see the article by Hood and colleagues on page 3792 of this issue.

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