BREAKING ADVANCES

2763 Highlights from Recent Cancer Literature

REVIEWS

2765 Antiangiogenic VEGF-Ax: A New Participantin Tumor AngiogenesisSandeepa M. Eswarappa and Paul L. Fox

2770 Tackling Crizotinib Resistance: The Pathwayfrom Drug Discovery to the Pediatric ClinicElizabeth R. Tucker, Laura S. Danielson, Paolo Innocenti,and Louis Chesler

MICROENVIRONMENT AND IMMUNOLOGY

2775 Breast Cancer Cell–Derived GM-CSF LicensesRegulatory Th2 Induction by PlasmacytoidPredendritic Cells in Aggressive DiseaseSubtypesCristina Ghirelli, Fabien Reyal, Marine Jeanmougin,Rapha€el Zollinger, Phil�emon Sirven, Paula Michea,Christophe Caux, Nathalie Bendriss-Vermare,Marie-H�el�ene Donnadieu, Martial Caly,Virginie Fourchotte, Anne Vincent-Salomon,Brigitte Sigal-Zafrani, Xavier Sastre-Garau, andVassili Soumelis

Pr�ecis: This study describes a mechanism through which anaggressive breast cancer activates pDC to promote aregulatory Th2 response, with implications for therapeutictargeting of a tumor-immune axis of growing recognition inits significance to malignancy.

2788 NOS InhibitionModulates Immune Polarizationand Improves Radiation-Induced Tumor GrowthDelayLisa A. Ridnour, Robert Y.S. Cheng, Jonathan M. Weiss,Sukhbir Kaur, David R. Soto-Pantoja,Debashree Basudhar, Julie L. Heinecke,C. Andrew Stewart, WilliamDeGraff, Anastasia L. Sowers,Angela Thetford, Aparna H. Kesarwala, David D. Roberts,Howard A. Young, James B. Mitchell, Giorgio Trinchieri,Robert H. Wiltrout, and David A. Wink

Pr�ecis: NOS inhibition has long been studied in cancer tolimited impact, but these new preclinical results show howinhibiting NOS in patients after they undergo radiotherapycan relieve immune escape in the tumor microenvironmentand greatly improve treatment responses.

2800 Tumor-Promoting Desmoplasia Is Disruptedby Depleting FAP-Expressing Stromal CellsAlbert Lo, Liang-Chuan S. Wang, John Scholler,James Monslow, Diana Avery, Kheng Newick,Shaun O’Brien, Rebecca A. Evans, David J. Bajor,Cynthia Clendenin, Amy C. Durham, Elizabeth L. Buza,Robert H. Vonderheide, Carl H. June,Steven M. Albelda, and Ellen Pur�e

Pr�ecis: This report identifies a stromal cell populationexpressing the fibroblast activation protein (FAP), whichis required for the desmoplastic response seen in manyhuman carcinomas, also showing how FAP-expressingcells promote tumor growth via immune suppression andimmune-independent remodeling of the stromalmicroenvironment.

2811 Pharmacological Inhibition of b3 IntegrinReduces the Inflammatory Toxicities Caused byOncolytic Adenovirus without CompromisingAnticancer ActivityAshley Browne, Laura A. Tookman,Carin K. Ingemarsdotter, Russell D. Bouwman,Katrina Pirlo, Yaohe Wang, Iain A. McNeish, andMichelle Lockley

Pr�ecis: This work describes a novel and clinically feasiblestrategy to facilitate the safe delivery of systemic viralanticancer therapies by using clinically available b3integrin inhibitors to control the problematic inflammatoryside effects induced by these effective anticancer agents.

2822 Definition of Prostaglandin E2–EP2 Signals inthe Colon Tumor Microenvironment ThatAmplify Inflammation and Tumor GrowthXiaojun Ma, Tomohiro Aoki, Tatsuaki Tsuruyama, andShuh Narumiya

Pr�ecis: These findings show how prostaglandin signaling inneutrophils and cancer-associated fibroblasts in thecolorectal tumor microenvironment shape its inflammatorycharacter, providing a mechanistic rationale to use EP2antagonists as an alternative to aspirin forchemoprevention.

July 15, 2015 � Volume 75 � Number 14

Cancer Research

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MOLECULAR AND CELLULARPATHOBIOLOGY

2833 TET2 Mutations Affect Non-CpG Island DNAMethylation at Enhancers and TranscriptionFactor–Binding Sites in ChronicMyelomonocytic LeukemiaJumpei Yamazaki, Jaroslav Jelinek, Yue Lu,Matteo Cesaroni, Jozef Madzo, Frank Neumann,Rong He, Rodolphe Taby, Aparna Vasanthakumar,Trisha Macrae, Kelly R. Ostler, Hagop M. Kantarjian,Shoudan Liang, Marcos R. Estecio, Lucy A. Godley, andJean-Pierre J. Issa

Pr�ecis: Results show how mutations in a leukemia-associated gene act epigenetically by influencing the DNAmethylation of hematopoietic-specific enhancers thataffect leukemia development.

PREVENTION AND EPIDEMIOLOGY

2844 Mitochondrial DNA Copy Number inPeripheral Blood Cells and Risk of DevelopingBreast CancerAlina Lemnrau, Mark N. Brook, Olivia Fletcher,Penny Coulson, Katarzyna Tomczyk, Michael Jones,Alan Ashworth, Anthony Swerdlow, Nick Orr, andMontserrat Garcia-Closas

Pr�ecis: The use of mtDNA copy number measured inblood samples prior to diagnosis is associated withelevated risk of developing breast cancer.

THERAPEUTICS, TARGETS, ANDCHEMICAL BIOLOGY

2851 Enhanced MET Translation and SignalingSustains K-Ras–Driven Proliferation underAnchorage-Independent Growth ConditionsSaori Fujita-Sato, Jacqueline Galeas, Morgan Truitt,Cameron Pitt, Anatoly Urisman,Sourav Bandyopadhyay, Davide Ruggero, andFrank McCormick

Pr�ecis: These results suggest that to drive malignant cellgrowth K-Ras requires the activity of the Met receptorkinase, a therapeutic target already being explored inthe clinic, with implications in addressing the long-standing challenge of how to attack K-Ras–driven humantumors.

2863 Vacuolar-ATPase Inhibition Blocks IronMetabolism to Mediate Therapeutic Effects inBreast CancerLina S. Schneider, Karin von Schwarzenberg,Thorsten Lehr, Melanie Ulrich,Rebekka Kubisch-Dohmen, Johanna Liebl,Dirk Trauner, Dirk Menche, and Angelika M. Vollmar

Pr�ecis: Inhibition of a vacuolar ATPase that functions asan ion pump in maintaining cellular pathophysiology incancer appears to selectively disturb iron metabolicpathways, thereby blocking tumor growth.

2875 An In VivoMethod to IdentifymicroRNA TargetsNot Predicted by Computation Algorithms: p21Targeting by miR-92a in CancerXiaoping Su, Huaming Wang, Wei Ge, Mingjin Yang,Jin Hou, Taoyong Chen, Nan Li, and Xuetao Cao

Pr�ecis: This study describes a new method for in vivomiRNA precipitation (miRIP), which can identify target-specific miRNAs for an mRNA not otherwise identified bycurrent in silico methods.

2886 Secalonic Acid-D Represses HIF1a/VEGF-Mediated Angiogenesis by Regulating theAkt/mTOR/p70S6K Signaling CascadeSantosh Kumar Guru, Anup Singh Pathania,Suresh Kumar, Deshidi Ramesh, Manjeet Kumar,Satiander Rana, Ajay Kumar, Fayaz Malik, P.R. Sharma,B.K. Chandan, Sundeep Jaglan, J.P. Sharma,Bhahwal Ali Shah, Sheikh Abdullah Tasduq,Surrinder K. Lattoo, Abdul Faruk, A.K. Saxena,R.A. Vishwakarma, and Shashi Bhushan

Pr�ecis: These findings offer a preclinical validation of theantiangiogenic uses for a novel mycotoxin in thegeneralized treatment of solid tumors.

2897 KRASGenomic Status Predicts the Sensitivity ofOvarian Cancer Cells to DecitabineMichelle L. Stewart, Pablo Tamayo, Andrew J. Wilson,Stephanie Wang, Yun Min Chang, Jong W. Kim,DineoKhabele,Alykhan F. Shamji, andStuart L. Schreiber

Pr�ecis: These findings define a mechanistic basis and abiomarker to predict the sensitivity of ovarian cancer cells toa cytotoxic DNA methyltransferase inhibitor, withpotentially generalizable applications.

2907 Targeting Pancreatic Cancer Metastasis byInhibition of Vav1, a Driver of Tumor CellInvasionGina L. Razidlo, Christopher Magnine,Arthur C. Sletten, Rachel M. Hurley, Luciana L. Almada,Martin E. Fernandez-Zapico, Baoan Ji, andMark A. McNiven

Pr�ecis: These findings offer a preclinical rationale forrepositioning the well-established drug azathioprine toinhibit metastasis of deadly pancreatic cancers.

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2916 Evidence Suggesting That DiscontinuousDosing of ALK Kinase Inhibitors May ProlongControl of ALKþ TumorsAmit Dipak Amin, Soumya S. Rajan, Winnie S. Liang,Praechompoo Pongtornpipat, Matthew J. Groysman,Edgar O. Tapia, Tara L. Peters, Lori Cuyugan,Jonathan Adkins, Lisa M. Rimsza, Yves A. Lussier,Soham D. Puvvada, and Jonathan H. Schatz

Pr�ecis: This important study shows how kinaseupregulation in cancer cells can foster resistance to akinase inhibitory drug, but that this upregulation alsosensitizes cells to kinase-mediated toxicities that can beexploited by altering the drug dosing schedule, as a strategyto defeat the drug resistance.

2928 Noninvasive Imaging of Tumor PD-L1Expression Using Radiolabeled Anti–PD-L1AntibodiesSandra Heskamp, Willemijn Hobo,Janneke D.M. Molkenboer-Kuenen, Daniel Olive,Wim J.G. Oyen, Harry Dolstra, and Otto C. Boerman

Pr�ecis: PD-L1 expression in tumors is important forPD-1/PD-L1–based therapeutics and can bemonitored noninvasively using SPECT/CT imaging,which may more readily enable patient selection fortrials of this type of antibody-based immune checkpointtherapy.

TUMOR AND STEM CELL BIOLOGY

2937 Genetic Identification of SEMA3F as anAntilymphangiogenic Metastasis SuppressorGene in Head and Neck Squamous CarcinomaColleen L. Doci, Constantinos M. Mikelis,Michail S. Lionakis, Alfredo A. Molinolo, andJ. Silvio Gutkind

Pr�ecis: By focusing on recurrent 3p21 deletions in headand neck cancers, this study identifies a novel metastasissuppressor gene that offers an appealing prognosticbiomarker and therapeutic target in this setting.

2949 Androgen-Induced TMPRSS2 ActivatesMatriptase and Promotes Extracellular MatrixDegradation, Prostate Cancer Cell Invasion,Tumor Growth, and MetastasisChun-Jung Ko, Cheng-Chung Huang, Hsin-Ying Lin,Chun-Pai Juan, Shao-Wei Lan, Hsin-Yi Shyu,Shang-Ru Wu, Pei-Wen Hsiao, Hsiang-Po Huang,Chia-Tung Shun, and Ming-Shyue Lee

Pr�ecis: This important study shows how the serineprotease TMPRSS2 promotes the growth, invasion, andmetastasis of prostate cancer cells via activation of thematrix protease matriptase, with implications thattargeting these two proteases may offer new options totreat advanced prostate cancer.

ABOUT THE COVER

In normal epithelial cells, there is a balance of pro- and antiangiogenic and lymphangiogenicfactors maintaining proper tissue homeostasis. During malignant transformation, early loss ofone such factor, the lymphatic endothelial cell inhibitor SEMA3F, is necessary to enablepathologic lymphangiogenesis. As the squamous cell carcinoma cells develop amore aggressivephenotype, acquired expression of surface receptors like neuropilin 2 (NRP2), a receptortypically expressed at high levels on lymphatic endothelial cells, further facilitate tumorvascularity, expansion, and metastatic spread. Thus, expression of SEMA3F may function inboth an autocrine and paracrine fashion through NRP2 to inhibit tumor growth, lymphaticinvasion, and metastasis. For details, see article by Doçi and colleagues on page 2937.

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2015;75:2763-2960. Cancer Res     75 (14)

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