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BREAKING ADVANCES
5647 Highlights from Recent CancerLiterature
REVIEWS
5649 The Kynurenine Pathway in BrainTumor PathogenesisSeray Adams, Nady Braidy, Alban Bessesde,Bruce J. Brew, Ross Grant, Charlie Teo, andGilles J. Guillemin
5658 FoxM1 and Wnt/b-Catenin Signaling inGlioma Stem CellsAihua Gong and Suyun Huang
5663 Realizing the Clinical Potential ofCancer Nanotechnology by MinimizingToxicologic and Targeted DeliveryConcernsSanjay Singh Arati Sharma, andGavin P. Robertson
PRIORITY REPORT
5669 Cytomegalovirus Infection Leads toPleomorphic Rhabdomyosarcomas inTrp53þ/� MiceRichard L. Price, Katherine Bingmer,Lualhati Harkins, O. Hans Iwenofu,Chang-Hyuk Kwon, Charles Cook,Christopher Pelloski, and E. Antonio Chiocca
Pr�ecis: Findings offer perhaps the first causativeevidence that cytomegalovirus infections maycontribute to the development of certain humancancers, where p53 mutation occurs frequently.
CLINICAL STUDIES
5675 Clinicopathological Features ofHomologous Recombination–DeficientEpithelial Ovarian Cancers: Sensitivityto PARP Inhibitors, Platinum, andSurvivalAsima Mukhopadhyay, Elizabeth R. Plummer,Ahmed Elattar, San Soohoo, Bisha Uzir,Jennifer E. Quinn, W. Glenn McCluggage,Perry Maxwell, Harriet Aneke, Nicola J. Curtin,and Richard J. Edmondson
Pr�ecis: Defects in DNA repair mediated by thehomologous recombination machinery define asubset of ovarian cancers that are sensitive to PARPinhibitors and that have favorable survivaloutcomes when cotreated with platinumchemotherapy.
5683 The FGFR4-G388R Single-NucleotidePolymorphism Alters PancreaticNeuroendocrine Tumor Progressionand Response to mTOR InhibitionTherapyStefano Serra, Lei Zheng, Manal Hassan,Alexandria T. Phan, Linda J. Woodhouse,James C. Yao, Shereen Ezzat, and Sylvia L. Asa
Pr�ecis: A coding SNP in the FGFR4 gene correlateswith progression status in pancreaticneuroendocrine tumors and also with the responseto everolimus, an mTOR inhibitor of therapeuticinterest in this setting, potentially offering a simplestratification marker.
5692 DNA Methylation Biomarkers OfferImproved Diagnostic Efficiency in LungCancerGeorgios Nikolaidis, Olaide Y. Raji,Soultana Markopoulou, John R. Gosney,Julie Bryan, Chris Warburton, Martin Walshaw,John Sheard, John K. Field, andTriantafillos Liloglou
Pr�ecis: Determination of a simple DNAmethylation signature in cells obtained frombronchial washings may improve the accuracy ofclinical diagnoses of lung cancer.
INTEGRATED SYSTEMS ANDTECHNOLOGIES
5702 SIRT1 Pathway Dysregulation in theSmoke-Exposed Airway Epithelium andLung Tumor TissueJennifer Beane, Luis Cheng, Raffaella Soldi,Xiaohui Zhang, Gang Liu, Christina Anderlind,Marc E. Lenburg, Avrum Spira, andAndrea H. Bild
Pr�ecis: Gene expression analysis in airwayepithelium exposed to cigarette smoke revealsdysregulation of SIRT1, which is also implicated asa tumor suppressor gene in lung cancer.
5712 Metabolic Associations of ReducedProliferation and Oxidative Stress inAdvanced Breast CancerLivnat Jerby, Lior Wolf, Carsten Denkert,Gideon Y. Stein, Mika Hilvo, Matej Oresic,Tamar Geiger, and Eytan Ruppin
Pr�ecis: This study presents the first genome-scalestudy of the metabolism of breast cancer, providingnew system-level insights into the metabolicprogression of different subsets of this disease.
ContentsCancerResearchNovember 15, 2012 � Volume 72 � Number 22
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MICROENVIRONMENT AND IMMUNOLOGY
5721 NLRP3 Suppresses NK Cell–MediatedResponses to Carcinogen-InducedTumors and MetastasesMelvyn T. Chow, Jaclyn Sceneay,Christophe Paget, Christina S.F. Wong,Helene Duret, J€urg Tschopp, Andreas M€oller,and Mark J. Smyth
Pr�ecis: Findings reveal a proinflammatorypathway that suppresses cancer-controlling NKcells along with a class of suppressor myeloid cellsthat actually promotes the anticancer activity ofNK cells.
5733 Endoneurial Macrophages InducePerineural Invasion of PancreaticCancer Cells by Secretion of GDNF andActivation of RET Tyrosine KinaseReceptorOren Cavel, Olga Shomron, Ayelet Shabtay,Joseph Vital, Leonor Trejo-Leider,Noam Weizman, Yakov Krelin, Yuman Fong,Richard J. Wong, Moran Amit, and Ziv Gil
Pr�ecis: A paracrine response between pancreaticadenocarcinoma cells and macrophages that rovenerve tracks appears to orchestrate nerve invasionby localized tumors, a type of invasion that occursin various types of encapsulated glandular tumors.
5744 Cross-Species Functional Analysis ofCancer-Associated FibroblastsIdentifies a Critical Role for CLCF1 andIL6 in Non–Small Cell Lung CancerIn VivoSilvestre Vicent, Leanne C. Sayles,Dedeepya Vaka, Purvesh Khatri, Olivier Gevaert,Ron Chen, Yanyan Zheng, Anna K. Gillespie,Nicole Clarke, Yue Xu, Joseph Shrager,Chuong D. Hoang, Sylvia Plevritis, Atul J. Butte,and E. Alejandro Sweet-Cordero
Pr�ecis: A cross-species approach identifies 2 IL-6family members as key contributors to paracrinesignaling between cancer cells and cancer-associated fibroblasts in lung adenocarcinoma.
5757 Galectin-3 Contributes to MelanomaGrowth and Metastasis via Regulationof NFAT1 and AutotaxinRussell R. Braeuer, Maya Zigler,Takafumi Kamiya, Andrey S. Dobroff, Li Huang,Woonyoung Choi, David J. McConkey,Einav Shoshan, Aaron K. Mobley, Renduo Song,Avraham Raz, and Menashe Bar-Eli
Pr�ecis: This study elucidates a new mechanism bywhich galectin-3 contributes to tumor growth andmetastasis by regulating the expression ofprotumorigenic genes, such as autotaxin.
MOLECULAR AND CELLULARPATHOBIOLOGY
5767 Differential Effects of PolymorphicAlleles of FGF Receptor 4 on ColonCancer Growth and MetastasisChristine Heinzle, Andrea Gsur,Monika Hunjadi, Zeynep Erdem,Christine Gauglhofer, Stefan St€attner,Josef Karner, Martin Klimpfinger,Friedrich Wrba, Andrea Reti, Balazs Hegedus,Andreas Baierl, Bettina Grasl-Kraupp,Klaus Holzmann, Michael Grusch,Walter Berger, and Brigitte Marian
Pr�ecis: A systematic comparison of 2 commonpolymorphic forms of FGFR4 reveals a higher riskof developing aggressive colorectal cancer forcarriers of the FGFR4arg allele, potentially offeringa simple prognostic marker in this setting.
5778 Prohibitin Attenuates Colitis-Associated Tumorigenesis in Mice byModulating p53 and STAT3 ApoptoticResponsesArwa S. Kathiria, William L. Neumann,Jennifer Rhees, Erin Hotchkiss, Yulan Cheng,Robert M. Genta, Stephen J. Meltzer,Rhonda F. Souza, and Arianne L. Theiss
Pr�ecis: Reduced levels of a mitochondrial proteinduring chronic intestinal inflammation may be anunderlying factor promoting colitis-associatedcancer by acting to modulate epithelial cellapoptosis.
5790 Aryl Hydrocarbon Receptor-InducedAdrenomedullin Mediates CigaretteSmoke Carcinogenicity in Humans andMiceSergio Portal-Nuñez, Uma T. Shankavaram,Mahadev Rao, Nicole Datrice, Scott Atay,Marta Aparicio, Kevin A. Camphausen,Pedro M. Fern�andez-Salguero, Han Chang,Pinpin Lin, David S. Schrump,Stavros Garantziotis, Frank Cuttitta, andEnrique Zudaire
Pr�ecis: Findings suggest that lung cancers arisingin smokers may be susceptible to treatment withtherapeutics that target a proinflammatoryoncogenic pathway known to mediate tumor-immune cell crosstalk, angiogenesis, andmetastasis.
5801 Neuropilin-1–Dependent Regulationof EGF-Receptor SignalingSabrina Rizzolio, Noa Rabinowicz,Elena Rainero, Letizia Lanzetti, Guido Serini,Jim Norman, Gera Neufeld, andLuca Tamagnone
Pr�ecis: Findings reveal a new mechanism forcontrolling EGFR signaling in cancer cells throughclustering and endocytosis of the receptorNeuropilin-1, which highlights its identification asa rational therapeutic target for cancer treatment.
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5812 An Integrated Genomic ScreenIdentifies LDHB as an Essential Genefor Triple-Negative Breast CancerMark L. McCleland, Adam S. Adler,Yonglei Shang, Thomas Hunsaker, Tom Truong,David Peterson, Eric Torres, Li Li,Benjamin Haley, Jean-Philippe Stephan,Marcia Belvin, Georgia Hatzivassiliou,Elizabeth M. Blackwood, Laura Corson,Marie Evangelista, Jiping Zha, and Ron Firestein
Pr�ecis: While the glycolytic regulator lactatedehydrogenase has been studied previously inbreast cancer, this study offers an incisive advanceby defining a crucial specific role for a particularisoform of this enzyme in a breast cancer subtypewith few therapeutic options.
5824 Cancer Cells Cue the p53 Response ofCancer-Associated Fibroblasts toCisplatinJens O. Schmid, Meng Dong, Silke Haubeiss,Godehard Friedel, Sabine Bode,Andreas Grabner, German Ott,Thomas E. M€urdter, Moshe Oren,Walter E. Aulitzky, and Heiko van der Kuip
Pr�ecis: Within the tumor microenvironment, thep53 response of cancer cell determines the p53response within adjacent cancer-associatedfibroblasts, illustrative of the master-slaverelationship that cancer cells enforce on theirneighboring cells.
5833 Lymphatic Reprogramming by KaposiSarcoma Herpes Virus Promotes theOncogenic Activity of the Virus-Encoded G-protein–Coupled ReceptorBerenice Aguilar, Inho Choi, Dongwon Choi,Hee Kyoung Chung, Sunju Lee, Jaehyuk Yoo,Yong Suk Lee, Yong Sun Maeng, Ha Neul Lee,Eunkyung Park, Kyu Eui Kim, Nam Yoon Kim,Jae Myung Baik, Jae U. Jung, Chester J. Koh, andYoung-Kwon Hong
Pr�ecis: Findings resolve long-standing questionsabout the pathological impact of the ability of theKaposi's sarcoma herpes virus to reprogram thetumor microenvironment, explaining why thisprocess favors formation of Kaposi's sarcomas,which are the most common forms of cancer inHIV patients.
5843 FGFR3 Stimulates Stearoyl CoADesaturase 1 Activity to PromoteBladder Tumor GrowthXiangnan Du, Qian-Rena Wang, Emily Chan,Mark Merchant, Jinfeng Liu, Dorothy French,Avi Ashkenazi, and Jing Qing
Pr�ecis: Findings reveal a previously unrecognizedrole for the FGF receptor FGFR3 in regulating lipidmetabolism to maintain tumor growth andsurvival.
5856 Basal but not Luminal MammaryEpithelial Cells Require PI3K/mTORSignaling for Ras-Driven OvergrowthKristin A. Plichta, Jessica L. Mathers,Shelley A. Gestl, Adam B. Glick, andEdward J. Gunther
Pr�ecis: Oncogenic Ras uses distinct effectorpathways to drive dysregulated proliferation of thecells derived from different layers of a stratifiedepithelium.
5867 DDX31 Regulates the p53-HDM2Pathway and rRNA Gene Transcriptionthrough Its Interaction with NPM1 inRenal Cell CarcinomasTomoya Fukawa, Masaya Ono, Taisuke Matsuo,Hisanori Uehara, Tsuneharu Miki,Yusuke Nakamura, Hiro-omi Kanayama, andToyomasa Katagiri
Pr�ecis: Findings offer potentially seminal insightsinto the origins of renal cell cancer, addressinglong standing questions about how sporadic formsof this cancer develop.
5878 The Metabolomic Signature ofMalignant Glioma Reflects AcceleratedAnabolic MetabolismPrakash Chinnaiyan, Elizabeth Kensicki,Gregory Bloom, Antony Prabhu,Bhaswati Sarcar, Soumen Kahali,Steven Eschrich, Xiaotao Qu, Peter Forsyth, andRobert Gillies
Pr�ecis: Global metabolomic analysis identifies keyfeatures underlying the aggressive phenotype ofmalignant glioma, providing novel strategies fortherapeutic intervention.
5889 Identification of FoxM1/Bub1bSignaling Pathway as a RequiredComponent for Growth and Survival ofRhabdomyosarcomaXiaolin Wan, Choh Yeung, Su Young Kim,Joseph G. Dolan, Vu N. Ngo, Sandra Burkett,Javed Khan, Louis M. Staudt, and Lee J. Helman
Pr�ecis: Dysregulation of a mitotic checkpointsignaling pathway has a critical role in the growthof pediatric tumors, defining direct interactionsbetween the oncogenic transcription factor,FoxM1, and the key mitotic checkpoint protein,Bub1B.
5900 Inactivation of the Dlc1 GeneCooperates with Downregulation ofp15INK4b and p16Ink4a, Leading toNeoplastic Transformation and PoorPrognosis in Human CancerXiaolan Qian, Marian E. Durkin, Dunrui Wang,Brajendra K. Tripathi, Lyra Olson, Xu-Yu Yang,William C. Vass, Nicholas C. Popescu, andDouglas R. Lowy
Pr�ecis: Diminished expression of a RhoGAP tumorsuppressor along with the Cdk inhibitors p15 andp16 drives cell transformation in mouse cells andconfers poor prognosis in clinical cases of lung andcolon cancer.
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5912 Hedgehog Signaling Blockade DelaysHepatocarcinogenesis Induced byHepatitis B Virus X ProteinAlla Arzumanyan, Vaishnavi Sambandam,Marcia M. Clayton, Steve S. Choi, Guanhua Xie,Anna Mae Diehl, Dae-Yeul Yu, andMark A. Feitelson
Pr�ecis: Hedgehog signaling is emerging as a majordriver in the development and progression of livercancer.
THERAPEUTICS, TARGETS, ANDCHEMICAL BIOLOGY
5921 Temporal Molecular and BiologicalAssessment of an Erlotinib-ResistantLung Adenocarcinoma Model RevealsMarkers of Tumor Progression andTreatment ResponseZo€e Weaver, Simone Difilippantonio,Julian Carretero, Philip L. Martin,Rajaa El Meskini, Anthony J. Iacovelli,Michelle Gumprecht, Alan Kulaga,Theresa Guerin, Jerome Schlomer,Maureen Baran, Serguei Kozlov,Thomas McCann, Salvador Mena,Fatima Al-Shahrour, Danny Alexander,Kwok-Kin Wong, and Terry Van Dyke
Pr�ecis: This study illustrates the importance oflongitudinal therapeutic studies in preclinicalassessment of drug principles by offering in vivoevidence that tyrosine kinase inhibitors can exerta strong, unexpected impact on specific metaboliccontrols.
5934 Genetic Screening for Synthetic LethalPartners of Polynucleotide Kinase/Phosphatase: Potential for TargetingSHP-1–Depleted CancersTodd R. Mereniuk, Robert A. Maranchuk,Anja Schindler, Jonathan Penner-Chea,Gary K. Freschauf, Samar Hegazy, Raymond Lai,Edan Foley, and Michael Weinfeld
Pr�ecis: This paper elucidates a synthetic lethalcombination of target inactivation events that canincrease levels of DNA damage that escape repair,suggesting an effective killing paradigm to exploittherapeutically.
5945 Cisplatin Sensitivity Mediated byWEE1and CHK1 Is Mediated by miR-155 andthe miR-15 FamilyLynn M. Pouliot, Yu-Chi Chen, Jennifer Bai,Rajarshi Guha, Scott E. Martin,Michael M. Gottesman, and Matthew D. Hall
Pr�ecis: Defeating acquired resistance to platindrugs remains a major goal in the oncology clinic,given the large and diverse number of cancers thatuse these chemotherapeutic agents in treatment.
5956 Brachytherapy Using Injectable SeedsThat Are Self-Assembled fromGenetically Encoded PolypeptidesIn SituWenge Liu, Jonathan McDaniel, Xinghai Li,Daisuke Asai, Felipe Garcia Quiroz,Jeffery Schaal, Ji Sun Park, Michael Zalutsky, andAshutosh Chilkoti
Pr�ecis: A novel injectable modality that can self-assemble a polypeptide-based radionuclide seedat tumor sites could radically improve treatmentof prostate cancers that are presently treated bybrachytherapy, an invasive radiotherapeuticprocedure.
5966 p21-Activated Kinase 1 Is Required forEfficient Tumor Formation andProgression in a Ras-Mediated SkinCancer ModelHoi Yee Chow, Adrian M. Jubb, Jennifer N. Koch,Zahara M. Jaffer, Dina Stepanova,David A. Campbell, Sergio G. Duron,Marie O'Farrell, Kathy Q. Cai,Andres J.P. Klein-Szanto, J. Silvio Gutkind,Klaus P. Hoeflich, and Jonathan Chernoff
Pr�ecis: Findings offer preclinical proof-of-conceptfor a functionally pleiotropic kinase as atherapeutic target in KRAS-driven tumors,illustrating a key mechanism for its action throughsignaling by Erk but not Akt.
5976 The V-ATPase-Inhibitor ArchazolidAbrogates Tumor Metastasis viaInhibition of Endocytic Activation ofthe Rho-GTPase Rac1RominaM.Wiedmann, Karin V. Schwarzenberg,Andrea Palamidessi, Laura Schreiner,Rebekka Kubisch, Johanna Liebl,Christina Schempp, Dirk Trauner, Gyorgy Vereb,Stefan Zahler, Ernst Wagner, Rolf M€uller,Giorgio Scita, and Angelika M. Vollmar
Pr�ecis: Findings reveal insights into how a vacularproton pump drives tumor dissemination andmetastasis, with implications for how to applytherapeutics that can target this pump.
TUMOR AND STEM CELL BIOLOGY
5988 OTX2 Represses Myogenic andNeuronal Differentiation inMedulloblastoma CellsRen-Yuan Bai, Verena Staedtke, Hart G. Lidov,Charles G. Eberhart, and Gregory J. Riggins
Pr�ecis: Findings may hold the key tounderstanding the etiology of medullo-myoblastoma, a subtype of the common pediatricbrain tumor medulloblastoma that is marked bythe presence of differentiated muscle cells.
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6002 Rat Mcs1b Is Concordant to theGenome-Wide Association-IdentifiedBreast Cancer Risk Locus at Human5q11.2 and MIER3 Is a CandidateCancer Susceptibility GeneAaron D. denDekker, Xin Xu, M. Derek Vaughn,Aaron H. Puckett, Louis L. Gardner,Courtney J. Lambring, Lucas Deschenes, andDavid J. Samuelson
Pr�ecis: Genetic studies in the rat suggest a goodcandidate for a breast cancer susceptibility genethat has been mapped previously to humanchromosome 5q11.2.
6013 A Synthetic Matrix with IndependentlyTunable Biochemistry and MechanicalProperties to Study EpithelialMorphogenesis and EMT in a LungAdenocarcinoma ModelBartley J. Gill, Don L. Gibbons, Laila C. Roudsari,Jennifer E. Saik, Zain H. Rizvi,Jonathon D. Roybal, Jonathan M. Kurie, andJennifer L. West
Pr�ecis: Findings illuminate the extracellular cuesthat influence epithelial morphogenesis byshowing how a synthetic ECM mimetic can affectmetastatic properties.
6024 Rab25 Is a Tumor Suppressor Genewith Antiangiogenic and Anti-InvasiveActivities in Esophageal SquamousCell CarcinomaMan Tong, Kwok Wah Chan, Jessie Y.J. Bao,Kai Yau Wong, Jin-Na Chen, Pak Shing Kwan,Kwan Ho Tang, Li Fu, Yan-Ru Qin, Si Lok,Xin-Yuan Guan, and Stephanie Ma
Pr�ecis: This study advances progress in the acuteneed for identifying biomarkers that can assist thediagnosis, prognosis, and treatment of esophagealcancer, a deadly disease with a rising incidence.
6036 Loss of SNAIL Regulated miR-128-2 onChromosome 3p22.3 Targets MultipleStem Cell Factors to PromoteTransformation of MammaryEpithelial CellsPengXu Qian, Arindam Banerjee,Zheng-Sheng Wu, Xiao Zhang, Hong Wang,Vijay Pandey, Wei-Jie Zhang, Xue-Fei Lv,Sheng Tan, Peter E. Lobie, and Tao Zhu
Pr�ecis: Results elucidate a signaling axis thatdrives mesenchymal character and stem cell-liketraits in malignantly transformed epithelial cells.
6051 Oncostatin M Modulates theMesenchymal–Epithelial Transition ofLung Adenocarcinoma Cells by aMesenchymal Stem Cell-MediatedParacrine EffectMong-Lien Wang, Chih-Ming Pan,Shih-Hwa Chiou, Wen-Hsin Chen,Hsiang-Yi Chang, Oscar Kuang-Sheng Lee,Han-Sui Hsu, and Cheng-Wen Wu
Pr�ecis: A molecule secreted by mesenchymal stemcells attracted to tumors is found to exert ananticancer effect in lung cancer, with potentialimplications for cancer therapy.
6065 Gliomagenesis Arising from Pten- andInk4a/Arf-Deficient Neural ProgenitorCells Is Mediated by the p53-Fbxw7/Cdc4 Pathway, Which Controls c-MycHong Sug Kim, Kevin Woolard, Chen Lai,Peter O. Bauer, Dragan Maric, Hua Song,Aiguo Li, Svetlana Kotliarova, Wei Zhang, andHoward A. Fine
Pr�ecis: A sophisticated genetically engineeredmouse model confirms that p53 mutationscontribute to formation of aggressive brain tumorsby supporting c-Myc overexpression but also byprotecting cells against c-Myc-induced apoptosis.
ABOUT THE COVER
Perineural invasion of cancer cells is found in most patients withpancreatic adenocarcinoma and is common in other tumors as well.Immunohistochemical analysis of specimens excised from patients withpancreatic cancer showed a significant increase in the number of endoneurialmacrophages around nerves invaded by cancer. Using animal models andtime-lapse analysis, we noticed that these endoneurial macrophagesfacilitated cancer cells dissociation from tumors and the formation of cellclusters that migrated in a unidirectional fashion along the nerve toward theganglion. The study identified a paracrine response between endoneurialmacrophages and cancer cells, which orchestrates the formation of nerveinvasion. For details, see article by Cavel and colleagues on page 5733.
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2012;72:5647-6075. Cancer Res 72 (22)
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