BREAKING ADVANCES

3113 Highlights from Recent Cancer Literature

CANCER RESEARCH 75th ANNIVERSARYCOMMENTARIES

3115 Adhere, Degrade, and Move: The Three-Step Modelof InvasionLance A. Liotta

3118 Implications of Increase in Vascular Permeability inTumors by VEGF: A Commentary on the PioneeringWork of Harold DvorakMark W. Dewhirst and Kathleen A. Ashcraft

REVIEW

3122 Impact of Pattern Recognition Receptors on thePrognosis of Breast Cancer Patients UndergoingAdjuvant ChemotherapyErika Vacchelli, David P. Enot, Federico Pietrocola,Laurence Zitvogel, and Guido Kroemer

PERSPECTIVE

3127 Toward Value-Based Pricing to Boost CancerResearch and InnovationAlberto Ocana, Eitan Amir, and Ian F. Tannock

PRIORITY REPORT

3130 PTP1B Deficiency Enables the Ability of a High-FatDiet to Drive the Invasive Character of PTEN-Deficient Prostate CancersDavid P. Labb�e, Noriko Uetani, Val�erie Vinette,Laurent Lessard, Isabelle Aubry, Eva Migon, Jacinthe Sirois,Jody J. Haigh, Louis R. B�egin, Lloyd C. Trotman,Maril�ene Paquet, and Michel L. Tremblay

Pr�ecis: These findings suggest a preclinical rationale to explorethe use of small molecule inhibitors of a tyrosine phosphatase,currently in clinical studies for diabetes treatment, as a newmodality to improve management of a certain genetic subtypeof prostate cancers.

INTEGRATED SYSTEMS AND TECHNOLOGIES

3136 Darwinian Dynamics of IntratumoralHeterogeneity: Not Solely Random Mutations butAlso Variable Environmental Selection ForcesMark C. Lloyd, Jessica J. Cunningham, Marilyn M. Bui,Robert J. Gillies, Joel S. Brown, and Robert A. Gatenby

Pr�ecis: Regional heterogeneity of molecular properties of tumorcells is governed by local variation in environmental selectionforces rather than random accumulating mutations

MICROENVIRONMENT AND IMMUNOLOGY

3145 NFAT1 Directly Regulates IL8 and MMP3 toPromote Melanoma Tumor Growth and MetastasisEinav Shoshan, Russell R. Braeuer, Takafumi Kamiya,Aaron K. Mobley, Li Huang, Mayra E. Vasquez,Guermarie Velazquez-Torres,NitinChakravarti, Cristina Ivan,Victor Prieto, Gabriel J. Villares, and Menashe Bar-Eli

Pr�ecis: This study reports a new role for a T-cell transcriptionfactor in melanoma progression and provides mechanisticinsights into the downstream factors endowing cancer cells withmetastatic behaviors.

3156 Myeloid-Derived Suppressor Cells Endow Stem-like Qualities to Breast Cancer Cells throughIL6/STAT3 and NO/NOTCH Cross-talk SignalingDongjun Peng, Takashi Tanikawa, Wei Li, Lili Zhao,Linda Vatan,Wojciech Szeliga, ShanshanWan, ShuangWei,Yin Wang, Yan Liu, Elzbieta Staroslawska,Franciszek Szubstarski, Jacek Rolinski, Ewelina Grywalska,Andrzej Stanisławek,Wojciech Polkowski, Andrzej Kurylcio,Celina Kleer, Alfred E. Chang, Max Wicha, Michael Sabel,Weiping Zou, and Ilona Kryczek

Pr�ecis: This seminal study illuminates an immune-associatedmechanism that extrinsically confers cancer cell stemnessproperties along with immune escape, suggesting theopportunity to therapeutically target a pivotal coupled processin the tumor microenvironment.

3166 Guidance Molecule SEMA3A Restricts TumorGrowth by Differentially Regulating theProliferation of Tumor-Associated MacrophagesMajken Wallerius, Tatjana Wallmann, Margarita Bartish,

Jeanette €Ostling, Artur Mezheyeuski, Nicholas P. Tobin,Emma Nygren, Pradeepa Pangigadde, Paola Pellegrini,Mario Leonardo Squadrito, Fredrik Pont�en, Johan Hartman,Jonas Bergh, Angelo De Milito, Michele De Palma,

Arne €Ostman, John Andersson, and Charlotte Rolny

Pr�ecis: These results illuminate a mechanism whereby thephenotype of tumor-associated macrophages is controlled andidentify a cell surface tissue guidance molecule as a candidatefor therapeutic targeting in the tumor microenvironment.

June 1, 2016 � Volume 76 � Number 11

Cancer Research

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3179 Membrane IL1a Inhibits the Development ofHepatocellular Carcinoma via Promoting T- andNK-cell ActivationDandan Lin, Lei Lei, Yonghao Liu, Yinsheng Zhang, BoHu,Guangming Bao, Yuan Song, Ziqi Jin, Chunliang Liu,Yu Mei, Dedy Sandikin, Yan Wu, Lixiang Zhao, Xiao Yu,and Haiyan Liu

Pr�ecis: These findings define a new role for IL1a incontrolling liver cancer development.

3189 IL6 Blockade Reprograms the Lung TumorMicroenvironment to Limit the Developmentand Progression of K-ras–Mutant Lung CancerMauricio S. Caetano, Huiyuan Zhang,Amber M. Cumpian, Lei Gong, Nese Unver,Edwin J. Ostrin, Soudabeh Daliri, Seon Hee Chang,Cesar E. Ochoa, Samir Hanash, Carmen Behrens,Ignacio I. Wistuba, Cinthya Sternberg, Humam Kadara,Carlos Gil Ferreira, Stephanie S. Watowich, andSeyed Javad Moghaddam

Pr�ecis: These preclinical findings suggest that IL6 blockadeblocks lung cancer by depriving both tumor cells and thetumor microenvironment of a pivotal oncogenic stimulus.

3200 Endothelial Side Population Cells Contributeto Tumor Angiogenesis and AntiangiogenicDrug ResistanceHisamichi Naito, Taku Wakabayashi, Hiroyasu Kidoya,Fumitaka Muramatsu, Kazuhiro Takara, Daisuke Eino,Keitaro Yamane, Tomohiro Iba, and Nobuyuki Takakura

Pr�ecis: The small population of vascular stem/progenitor-likeendothelial cells identified in this study may have animportant role in tumor neoangiogenesis as well as resistancein the tumor vasculature to antiangiogenic drugs, withimportant clinical implications.

MOLECULAR AND CELLULARPATHOBIOLOGY

3211 Radiation Sensitivity in a Preclinical Mouse Modelof Medulloblastoma Relies on the Function of theIntrinsic Apoptotic PathwayAndrew J. Crowther, Jennifer K. Ocasio, Fang Fang,Jessica Meidinger, Jaclyn Wu, Allison M. Deal,Sha X. Chang, Hong Yuan, Ralf Schmid, Ian Davis, andTimothy R. Gershon

Pr�ecis: While the contributions of apoptotic competence totumor radiosensitivity has been controversial, the findings ofthis study suggest that medulloblasomas—a type of braintumor—which lose the capability for apoptosis, becomeradiation resistant.

3224 Combined Inhibition of DNMT and HDAC Blocksthe Tumorigenicity of Cancer Stem-like Cells andAttenuates Mammary Tumor GrowthRajneesh Pathania, Sabarish Ramachandran,Gurusamy Mariappan, Priyanka Thakur, Huidong Shi,Jeong-Hyeon Choi, Santhakumar Manicassamy,Ravindra Kolhe, Puttur D. Prasad, Suash Sharma,Bal L. Lokeshwar, Vadivel Ganapathy, andMuthusamy Thangaraju

Pr�ecis: These findings demonstrate how combiningepigenetic inhibitors can blunt the tumor-promoting effects ofbreast cancer stem-like cells, suggesting an important new usefor these therapeutics in blocking tumor recurrence andprolonging patient survival.

3236 DNp63a Silences a miRNA Program to AberrantlyInitiate a Wound-Healing Program ThatPromotes TGFb-Induced MetastasisLidia Rodriguez Calleja, Camille Jacques,Francois Lamoureux, Marc Baud'huin,Marta Tellez Gabriel, Thibaut Quillard, Debashish Sahay,Pierre Perrot, Jerome Amiaud, Celine Charrier, Regis Brion,Fernando Lecanda, Franck Verrecchia,Dominique Heymann, Leif W. Ellisen, and Benjamin Ory

Pr�ecis: This study describes how a wound healing process thatbecomes aberrantly activated during tumorigenesis helpsfacilitate metastatic dissemination, illuminating a newregulatory network that controls metastasis and might betherapeutically exploited.

3252 A CDK4/6-Dependent Epigenetic MechanismProtects Cancer Cells from PML-inducedSenescenceMariana Acevedo, Mathieu Vernier, Lian Mignacca,Fr�ed�eric Lessard, Genevi�eve Huot, Olga Moiseeva,V�eronique Bourdeau, and Gerardo Ferbeyre

Pr�ecis: In addition to triggering cell cycle arrest, CDKinhibitors also impair an epigenetic mechanism that enablescancer cells to evade senescence, thus offering broadertherapeutic applications to faciliate this process in a diversearray of tumors.

3265 Decreased Expression of Fructose-1,6-bisphosphatase Associates with GlucoseMetabolism and Tumor Progression inHepatocellular CarcinomaHidenari Hirata, Keishi Sugimachi, Hisateru Komatsu,Masami Ueda, Takaaki Masuda, Ryutaro Uchi,Shotaro Sakimura, Sho Nambara, Tomoko Saito,Yoshiaki Shinden, Tomohiro Iguchi, Hidetoshi Eguchi,Shuhei Ito, Kotaro Terashima, Katsumi Sakamoto,Masakazu Hirakawa, Hiroshi Honda, and Koshi Mimori

Pr�ecis: These findings establish that FBP1 downregulation inHCC contributes to tumor progression and poor prognosis byaltering glucose metabolism, and they rationalize furtherstudy of FBP1 as a prognostic biomarker and therapeutictarget in HCC patients.

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PREVENTION AND EPIDEMIOLOGY

3277 Genome-Wide Association Study of BladderCancer in a Chinese Cohort Reveals a NewSusceptibility Locus at 5q12.3Meilin Wang, Zhiqiang Li, Haiyan Chu, Qiang Lv,Dingwei Ye, Qiang Ding, Chuanliang Xu, Jianming Guo,Mulong Du, Jianhua Chen, Zhijian Song, Changjun Yin,ChaoQin, ChengyuanGu, Yao Zhu, Guowei Xia, Fang Liu,Zhengsheng Zhang, Lin Yuan, Guangbo Fu, Zhibin Hu,Na Tong, Jiawei Shen, Ke Liu, Jielin Sun, Yinghao Sun,Jue Li, Xingwang Li, Hongbing Shen, Jianfeng Xu,Yongyong Shi, and Zhengdong Zhang

Pr�ecis: This study reveals a previously unidentified risk-associated locus for bladder cancer in a Chinese populationand alludes to a potentially oncogenic role of the resultantgene variant, providing new clues into the genetic etiology ofthis malignancy.

THERAPEUTICS, TARGETS, AND CHEMICALBIOLOGY

3285 Inhibition of PAI-1 Limits Tumor AngiogenesisRegardless of Angiogenic Stimuli in MalignantPleural MesotheliomaYusuke Takayama, Noboru Hattori, Hironobu Hamada,Takeshi Masuda, Keitaro Omori, Shin Akita,Hiroshi Iwamoto, Kazunori Fujitaka, and Nobuoki Kohno

Pr�ecis: This preclinical proof-of-concept study reports a novelbroad-based antiangiogenic therapy that when combinedwith cisplatin exhibits efficacy against malignant pleuralmesothelioma, an aggressive disease yet to benefit fromexisting antiangiogenic therapies.

3295 AMPK Activation and Metabolic Reprogrammingby Tamoxifen through Estrogen Receptor–Independent Mechanisms Suggests New Uses forThis Therapeutic Modality in Cancer TreatmentNatalie A. Daurio, Stephen W. Tuttle, Andrew J. Worth,Ethan Y. Song, Julianne M. Davis, Nathaniel W. Snyder,Ian A. Blair, and Constantinos Koumenis

Pr�ecis: The widely used chemotherapeutic agent tamoxifenalters tumor cell metabolism and can be combined with otheragents to increase tumor cell killing.

3307 AZD9496: An Oral Estrogen Receptor InhibitorThat Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical ModelsHazel M. Weir, Robert H. Bradbury, Mandy Lawson,Alfred A. Rabow, David Buttar, Rowena J. Callis,Jon O. Curwen, Camila de Almeida, Peter Ballard,Michael Hulse, Craig S. Donald, Lyman J.L. Feron,Galith Karoutchi, Philip MacFaul, Thomas Moss,Richard A. Norman, Stuart E. Pearson, Michael Tonge,Gareth Davies, Graeme E. Walker, Zena Wilson,Rachel Rowlinson, Steve Powell, Claire Sadler,Graham Richmond, Brendon Ladd, Ermira Pazolli,Anne Marie Mazzola, Celina D'Cruz, and Chris De Savi

Pr�ecis: This article discloses the structure and pharmacologyof an oral nonsteroid small molecule, which is potent againstwild-type and mutant forms of the estrogen receptor,producing antitumor efficacy either as a monotherapy or incombination with PI3K or cell cycle inhibitors in vivo.

3319 Proteasomal Inhibition by Ixazomib InducesCHK1 and MYC-Dependent Cell Death in T-celland Hodgkin LymphomaDashnamoorthy Ravi, Afshin Beheshti, Nass�era Abermil,Frank Passero, Jaya Sharma, Michael Coyle,Athena Kritharis, Irawati Kandela, Lynn Hlatky,Michail V. Sitkovsky, Andrew Mazar,Ronald B. Gartenhaus, and Andrew M. Evens

Pr�ecis: These findings offer a mechanism-based preclinicalproof of concept for an attractive second generationproteasomal inhibitor, which exhibits robust antitumorpotency in preclinical models of lymphoma.

3332 Sustained Accumulation of Microtubule-BindingChemotherapy Drugs in the Peripheral NervousSystem: Correlations with Time Course andNeurotoxic SeverityKrystyna M. Wozniak, James J. Vornov, Ying Wu,Kenichi Nomoto, Bruce A. Littlefield,Christopher DesJardins, Yanke Yu, George Lai,Larisa Reyderman, Nancy Wong, and Barbara S. Slusher

Pr�ecis: While microtubule-binding cancer drugs oftenproduce significant neuropathy in patients, theirneurotoxicity cannot be explained simply by anaccumulation in peripheral nerves, implicating othermechanisms that might be addressed to prevent or relievethis important side-effect.

3340 Novel Protein Disulfide Isomerase Inhibitor withAnticancer Activity in Multiple MyelomaSergei Vatolin, James G. Phillips, Babal K. Jha,Shravya Govindgari, Jennifer Hu, Dale Grabowski,Yvonne Parker, Daniel J. Lindner, Fei Zhong,Clark W. Distelhorst, Mitchell R. Smith, Claudiu Cotta,Yan Xu, Sujatha Chilakala, Rebecca R. Kuang,Samantha Tall, and Frederic J. Reu

Pr�ecis: These results provide an illustration of the utility ofsimple in vivo simulations as part of a drug discovery effort,along with a sound preclinical rationale to develop a newsmall molecule therapeutic for treating multiple myeloma.

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TUMOR AND STEM CELL BIOLOGY

3351 p120 Catenin Suppresses Basal Epithelial CellExtrusion in Invasive Pancreatic NeoplasiaAudrey M. Hendley, Yue J. Wang, Kishore Polireddy,Janivette Alsina, Ishrat Ahmed, Kelly J. Lafaro, Hao Zhang,Nilotpal Roy, Samuel G. Savidge, Yanna Cao,Matthias Hebrok, Anirban Maitra, Albert B. Reynolds,Michael Goggins, Mamoun Younes,Christine A. Iacobuzio-Donahue, Steven D. Leach, andJennifer M. Bailey

Pr�ecis: These results provide insight into mechanismscontrolling early events in the metastatic process, suggestingcancer progression is enhanced by regulating epithelial cellinvasion.

3364 c-Myb Enhances Breast Cancer Invasion andMetastasis through the Wnt/b-Catenin/Axin2PathwayYihao Li, Ke Jin, GabiW. van Pelt, Hans van Dam, Xiao Yu,Wilma E. Mesker, Peter ten Dijke, Fangfang Zhou, andLong Zhang

Pr�ecis: These results identify a pathway of breast cancerinvasion and metastasis that may provide a general strategyfor therapeutic targeting of aggressive disease.

3376 Ly6E/K Signaling to TGFb Promotes BreastCancer Progression, Immune Escape, and DrugResistanceMidrar AlHossiny, Linlin Luo, William R. Frazier,Noriko Steiner, Yuriy Gusev, Bhaskar Kallakury,Eric Glasgow, Karen Creswell, Subha Madhavan,Rakesh Kumar, and Geeta Upadhyay

Pr�ecis: This seminal study illustrates the deep connectionsbetween the evolution of stem-like cells in cancer andimmune escape, also suggesting a rationale for theireradication by immune checkpoint agents.

3387 Ribosomal Protein Rpl22 Controls theDissemination of T-cell LymphomaShuyun Rao, Kathy Q. Cai, Jason E. Stadanlick,Noa Greenberg-Kushnir, Nehal Solanki-Patel,Sang-Yun Lee, Shawn P. Fahl, Joseph R. Testa, andDavid L. Wiest

Pr�ecis: Varying the copy number of ribosomal protein Rpl22produces unexpectedly divergent effects on how and wherelethal lymphoid tumors develop.

3397 Autophagy Differentially Regulates DistinctBreast Cancer Stem-like Cells in Murine Modelsvia EGFR/Stat3 and Tgfb/Smad SignalingSyn Kok Yeo, Jian Wen, Song Chen, and Jun-Lin Guan

Pr�ecis: These preclinical findings uncover a differentialdependence of heterogeneous breast cancer stem-like cellpopulations on two different signaling pathways, withimplications on how drug combinations might be bettertailored to eradicate these cells and improve therapeuticefficacy.

3411 NOTCH Signaling Regulates AsymmetricCell Fate of Fast- and Slow-Cycling ColonCancer–Initiating CellsTara Srinivasan, Jewell Walters, Pengcheng Bu,Elaine Bich Than, Kuei-Ling Tung, Kai-Yuan Chen,Nicole Panarelli, Jeff Milsom, Leonard Augenlicht,Steven M. Lipkin, and Xiling Shen

Pr�ecis: These results illuminate the basis for cancer stem-likecell heterogeneity and plasticity in colon cancers by definingslow-cycling and fast-cycling cell subpopulations and amechanism of interconversion between each.

3422 Oncogenic Mutation of AIMP2/p38 Inhibits ItsTumor-Suppressive Interaction with Smurf2Dae Gyu Kim, Jin Young Lee, Ji-Hyun Lee, Ha Yeon Cho,Beom Sik Kang, Song-Yee Jang, Myung Hee Kim,Min Guo, Jung Min Han, Seong-Jin Kim, andSunghoon Kim

Pr�ecis: This study provides new insight into the mechanismscontrolling MYC-driven oncogenic transformation,highlighting important contributions of tumor suppressiveTGFb signaling.

CORRECTION

3437 Correction: Delivery of Therapeutics Targetingthe mRNA-Binding Protein HuR Using 3DNANanocarriers Suppresses Ovarian Tumor Growth

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ABOUT THE COVER

Myeloid-derived suppressor cells (MDSC) inhibit tumor immunity, prompt breast cancerstemness, and enhance tumorigenic potential. Mechanistically, MDSC-derived IL6 initiatesSTAT3 phosphorylation, and MDSC-derived nitric oxide activates NOTCH and NOTCHsubsequently and collaboratively acts with IL6 to promote prolonged STAT3 activation. Usingimmunofluorescence, it was found that MDSCs increased ALDH1 expression in tumor cells.For details, see article by Peng and colleagues on page 3156.

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