cancer contents researchmediate cancer progression and multiple therapy-resistant phenotypes and...
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BREAKING ADVANCES
2455 Highlights from Recent CancerLiterature
REVIEWS
2457 A Comprehensive Survey of RasMutations in CancerIan A. Prior, Paul D. Lewis, and Carla Mattos
2468 SIRT3 Is a Mitochondrial TumorSuppressor: A Scientific Tale ThatConnects Aberrant Cellular ROS, theWarburg Effect, and CarcinogenesisMarcia C. Haigis, Chu-Xia Deng, LydiaW.S. Finley,Hyun-Seok Kim, and David Gius
MEETING REPORT
2473 Tumor Microenvironment Complexity:Emerging Roles in Cancer TherapyMelody A. Swartz, Noriho Iida,Edward W. Roberts, Sabina Sangaletti,Melissa H. Wong, Fiona E. Yull, Lisa M. Coussens,and Yves A. DeClerck
CLINICAL STUDIES
2481 Identification of Serum BiomarkerSignatures Associated with PancreaticCancerChrister Wingren, Anna Sandstr€om,Ralf Segersv€ard, Anders Carlsson,Roland Andersson, Matthias L€ohr, andCarl A. K. Borrebaeck
Pr�ecis: Pancreatic cancer is deadly in part becauseit is so commonly diagnosed late in developmentdue to the lack of symptoms or diagnostic tools thatcould identify it at earlier stages when it could bemanaged more effectively.
2491 Real-time Raman Spectroscopy for InVivo Skin Cancer DiagnosisHarvey Lui, Jianhua Zhao, David McLean, andHaishan Zeng
Pr�ecis: A rapid, noninvasive technology withpotential for adoption at the clinical point of care isdescribed for ready and accurate diagnosis of skinlesions.
INTEGRATED SYSTEMS ANDTECHNOLOGIES
2501 Phosphoproteomics Identifies DriverTyrosine Kinases in Sarcoma Cell Linesand TumorsYun Bai, Jiannong Li, Bin Fang, Arthur Edwards,Guolin Zhang, Marilyn Bui, Steven Eschrich,Soner Altiok, John Koomen, and Eric B. Haura
Pr�ecis: Global assessment of tyrosinephosphorylation, coupled with functional screens, isused to identify tyrosine kinases driving cell growthand survival in sarcoma, thereby offering insightinto new therapeutic strategies for these deadlytumors.
2512 AMPKa Modulation in CancerProgression: Multilayer IntegrativeAnalysis of the Whole Transcriptome inAsian Gastric CancerYon Hui Kim, Han Liang, Xiuping Liu,Ju-Seog Lee, Jae Yong Cho, Jae-Ho Cheong,Hoguen Kim, Min Li, Thomas J. Downey,Matthew D. Dyer, Yongming Sun, Jingtao Sun,Ellen M. Beasley, Hyun Cheol Chung,Sung Hoon Noh, John N. Weinstein,Chang-Gong Liu, and Garth Powis
Pr�ecis: The requirement for c-Src in tumor invasionevoked by oncogenic Ras has implications for thedevelopment of therapies to target the Ras pathway,long a goal of the field.
MICROENVIRONMENT AND IMMUNOLOGY
2522 Cyclophosphamide Creates a ReceptiveMicroenvironment for Prostate CancerSkeletal MetastasisSerk In Park, Jinhui Liao, Janice E. Berry, Xin Li,Amy J. Koh, Megan E. Michalski, Matthew R. Eber,Fabiana N. Soki, David Sadler, Sudha Sud,Sandra Tisdelle, Stephanie D. Daignault,Jeffrey A. Nemeth, Linda A. Snyder,Thomas J. Wronski, Kenneth J. Pienta, andLaurie K. McCauley
Pr�ecis: The chemotherapeutic drugcyclophosphamide, used in the treatment of manykinds of cancer, is found unexpectedly to exert aprometastatic effect within bone.
ContentsCancerResearchMay 15, 2012 � Volume 72 � Number 10
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2533 Hepatocyte–Stellate Cell Cross-Talk inthe Liver Engenders a PermissiveInflammatory Microenvironment ThatDrives Progression in HepatocellularCarcinomaC�edric Coulouarn, Anne Corlu, Denise Glaise,Isabelle Guénon, Snorri S. Thorgeirsson, andBruno Clément
Pr�ecis: Molecular characterization of the cross-talk between cell types in the liver plays a majorrole in the progression of hepatocellularcarcinoma andmay offer novel therapeutic targetsfor epigenetic modulation.
MOLECULAR AND CELLULARPATHOBIOLOGY
2543 Parkin Pathway Activation MitigatesGlioma Cell Proliferation and PredictsPatient SurvivalCalvin W.S. Yeo, Felicia S.L. Ng, Chou Chai,Jeanne M.M. Tan, Geraldene R.H. Koh,Yuk Kien Chong, Lynnette W.H. Koh,Charlene S.F. Foong, Edwin Sandanaraj,Joanna D. Holbrook, Beng-Ti Ang,Ryosuke Takahashi, Carol Tang, andKah-Leong Lim
Pr�ecis: This study provides mechanistic insightinto the tumor suppressor function of parkin, agene that is often mutated in genetic Parkinsondisease, but is shown here to play a role in thepathogenesis of gliomas.
2554 KRas Induces a Src/PEAK1/ErbB2Kinase Amplification Loop That DrivesMetastatic Growth and TherapyResistance in Pancreatic CancerJonathan A. Kelber, Theresa Reno,Sharmeela Kaushal, Cristina Metildi,Tracy Wright, Konstantin Stoletov,Jessica M. Weems, Frederick D. Park,Evangeline Mose, Yingchun Wang,Robert M. Hoffman, Andrew M. Lowy,Michael Bouvet, and Richard L. Klemke
Pr�ecis: In serving as a novel diagnostic andprognostic biomarker in pancreatic ductalcarcinoma, the novel tyrosine kinase PEAK1 maymediate cancer progression and multiple therapy-resistant phenotypes and thus represents animportant new therapeutic target.
2565 Mitochondrial Bcl-2 Family DynamicsDefine Therapy Response andResistance in NeuroblastomaKelly C. Goldsmith, Michelle Gross, Susan Peirce,Dema Luyindula, Xueyuan Liu, Annette Vu,Michael Sliozberg, Rong Guo, Huaqing Zhao,C. Patrick Reynolds, and Michael D. Hogarty
Pr�ecis: Mitochondrial profiling reveals thatacquired therapy resistance in neuroblastoma isdue to repression at the level of Bak/Bax-mediatedapoptosis, and this may offer a basis to stratifypatients who could benefit most from treatmentwith Bcl-2/Bcl-xL antagonists.
2578 Loss of Cell-Surface LamininAnchoring Promotes Tumor Growthand Is Associated with Poor ClinicalOutcomesArmin Akhavan, Obi L. Griffith,Liliana Soroceanu, Dmitri Leonoudakis,Maria Gloria Luciani-Torres, Anneleen Daemen,Joe W. Gray, and John L. Muschler
Pr�ecis: Defects in the cell surface anchoring oflaminin in cancer cells of diverse origin is commonand strongly associated with aggressivephenotypes, suggesting a common tethering pointto understand how laminins in the tumormicroenvironment direct malignant progression,as well as how novel generalized therapies mightbe directed to this aspect.
2589 Interleukin-17 Promotes Formationand Growth of ProstateAdenocarcinoma in Mouse ModelsQiuyang Zhang, Sen Liu, Dongxia Ge,Qingsong Zhang, Yun Xue, Zhenggang Xiong,Asim B. Abdel-Mageed, Leann Myers,Steven M. Hill, Brian G. Rowan, Oliver Sartor,Jonathan Melamed, Zhenbang Chen, andZongbing You
Pr�ecis: Findings in a mouse model of prostatecancer indicate that proinflammatory cytokine IL-17 drives the transition of premalignant lesions tofrank adenocarcinoma, suggesting a molecularmechanism to underpin the concept that reducingprostate inflammation could help preventemergence of this disease.
THERAPEUTICS, TARGETS, ANDCHEMICAL BIOLOGY
2600 Dinitroazetidines Are a Novel Class ofAnticancer Agents and Hypoxia-Activated Radiation SensitizersDeveloped from Highly EnergeticMaterialsShoucheng Ning, Mark Bednarski,Bryan Oronsky, Jan Scicinski, Gordon Saul, andSusan J. Knox
Pr�ecis: Findings characterize a novel compoundbased on a highly energetic chemical scaffold thatselectively targets hypoxic tumors and enhancesthe effects of radiotherapy.
2609 Coxsackievirus B3 Is an OncolyticVirus with ImmunostimulatoryProperties That Is Active against LungAdenocarcinomaShohei Miyamoto, Hiroyuki Inoue,Takafumi Nakamura, Meiko Yamada,Chika Sakamoto, YasuoUrata, ToshihikoOkazaki,Tomotoshi Marumoto, Atsushi Takahashi,Koichi Takayama, Yoichi Nakanishi,Hiroyuki Shimizu, and Kenzaburo Tani
Pr�ecis:While oncolytic viruses have failed as yet torealize clinical potential, this study defines a potentvirus that by exerting adjuvant immunostimulatoryproperties may yield a unique and more effectiveantitumor activity.
iv Cancer Research
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2622 Activation of Ras/PI3K/ERK PathwayInduces c-Myc Stabilization toUpregulate ArgininosuccinateSynthetase, Leading to ArginineDeiminase Resistance in MelanomaCellsWen-Bin Tsai, Isamu Aiba, Yan Long,Hui-Kuan Lin, Lynn Feun, Niramol Savaraj, andMacus Tien Kuo
Pr�ecis: Findings offer mechanistic insight into howresistance emerges to arginine deprivation therapyand how inhibitors of the Ras/ERK and PI3K/AKTpathways might restore therapeutic responses.
2634 Mitochondria-Targeted DrugsSynergize with 2-Deoxyglucose toTrigger Breast Cancer Cell DeathGang Cheng, Jacek Zielonka, Brian P. Dranka,Donna McAllister, A. Craig Mackinnon Jr,Joy Joseph, and Balaraman Kalyanaraman
Pr�ecis: This important study may crack the long-standing challenge of how to employ the glycolyticinhibitor 2-deoxyglucose for generalized anticancertherapy, by combining it with mitochondria-targeted cationic compounds that can improvecancer cell cytotoxicity without toxic liabilities tonormal tissue.
2645 SmacMimetic LBW242 Sensitizes XIAP-Overexpressing Neuroblastoma Cellsfor TNF-a–Independent ApoptosisGeorg Eschenburg, Angelika Eggert,Alexander Schramm, Holger N. Lode, andPatrick Hundsdoerfer
Pr�ecis: Smac mimetics offer a potential adjuvantapproach to sensitize or resensitize tumors tochemotherapy, as illustrated by this preclinicalproof-of-concept study in a commonly deadly typeof pediatric cancer.
TUMOR AND STEM CELL BIOLOGY
2657 Epidermal Growth Factor ReceptorVariant III Contributes to Cancer StemCell Phenotypes in Invasive BreastCarcinomaCatherine A. Del Vecchio, Kristin C. Jensen,Ryan T. Nitta, A. Hunter Shain,Craig P. Giacomini, and Albert J. Wong
Pr�ecis: By identifying breast cancer stem cells thatexpress a variant EGFR receptor, this study hasimplications for how to improve treatment forpatients who harbor this variant receptor.
2672 HER3 is Required for HER2-InducedPreneoplastic Changes to the BreastEpithelium and Tumor FormationDavid B. Vaught, Jamie C. Stanford,Christian Young, Donna J. Hicks, FrankWheeler,Cammie Rinehart, Violeta S�anchez, John Koland,William J. Muller, Carlos L. Arteaga, andRebecca S. Cook
Pr�ecis: Findings offer a preclinical proof-of-concept for a new strategy to treat or preventHER2-amplified breast cancers, which representnearly 30% of all breast cancers, by targeting animportant heterodimeric partner of HER2.
2683 Real-Time Monitoring of RareCirculating Hepatocellular CarcinomaCells in an Orthotopic Model by In VivoFlow Cytometry Assesses Resection onMetastasisZhi-Chao Fan, Jun Yan, Guang-Da Liu,Xiao-Ying Tan, Xiao-Fu Weng, Wei-Zhong Wu,Jian Zhou, and Xun-Bin Wei
Pr�ecis: In vivo flow cytometry may offer abreakthrough technology to elucidate mechanismsof hematogenous metastasis and to monitor theefficacy of cancer therapy.
ABOUT THE COVER
Interleukin-17 (IL-17) is a key proinflammatory cytokine involved in manyinflammatory and autoimmune diseases. Mice with conditional knockout ofPTEN tumor suppressor gene developed invasive prostate adenocarcinomasat ages of 9 to 30 weeks. When IL-17 signaling was blocked by knockoutIL-17 receptor C (IL-17RC) in the PTEN-null mice, the number and size ofprostate tumors were reduced compared to mice that expressed IL-17RC,because IL-17RC knockout reduced cellular proliferation, increasedapoptosis, inhibited inflammatory infiltration, and diminished expression ofmatrix metalloproteinase 7 in the mouse prostates. For details, see article byZhang and colleagues on page 2589 of this issue.
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2012;72:2455-2691. Cancer Res 72 (10)
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