J Cancer Res(】 in OncOl(2013)1391901-904

D(D110.1007/s00432-013-1397-1

REVIEW

The eleventh Korea-Japan-Germany joint symposium on cancerand ageing research

Eung-Gook Kim . Iliroyuki Seimiya .

Junho Chung. Jiierg Hoheisel.In Kyoung Lim .

Hirota Fujiki'Sang Chul Park

Received: 6 February 2Ol3l Accepted: 6 February 2013/Published online: 28 February 2013O Springer-Verlag Berlin Heidelberg 2013

Keywords Cancer . Ageing . Angiogenesis . Genomics . organization. Scientists in DKFG are organized into sevenProteomics divisions depending on research programs covering most of

the themes in oncology. Two main bodies, the Manage-ment Board and Board of Trustees, play a key role inDKFZ administration.

Introduction This symposium included diverse types of studies fromindividual to a team-based integrative approach, including

The Eleventh Korea-Japan Joint Symposium on Cancer genomics, proteomics and potential therapeutics. Weand Ageing Research was held along with the first partic- grouped the symposium presentations depending on theiripation of German Cancer Research Center (DKFZ) on July cancer or ageing research theme.5th-5th, 2012, at Gyeongju Hilton Hotel in Gyeongiu,Korea. We greatly appreciate the communication betweenProfessor Hirota Fujiki (Tokushima Bunri University) and Plenary lectures, special lectures and a cancer researchProfessor Otmar Whistler, the director of the DKFZ; three sessionscientists from DKFZ participated in this symposium forthe first time. This symposium was expanded from a Plenary lecture 2: functional genomics and proteomicsbi-national to a tri-nationaljoint meeting in this year. Prof. in cancer researchFujiki delivered an opening address that included a shorthistorical background introduction of this meeting and a Pancreatic adenocarcinoma is one of the most malignantremark on his conversation with Prof. Wiestler. Later, Prof. tumours that show a poor prognosis. Even worse, mostHellmut Augustin kindly introduced DI<FZ and the patients are diagnosed atalate stage. Therefore, early and

E.-G. Kim (E) J. HoheiselDepartment of Biochemisry and Medical Research Center, Division of Functional Genome Analysis, German CancerChungbuk National University College of Medicine, Research Center Heidelberg (DKFZ), Heidelberg, Germany52 Naesoodong-ro, Heungduk-ku, Cheongiu 361-7 63, Korcae-mail: egkim@chungbuk.ac.kr I. K. Lim

Department of Biochemistry and Molecular Biology,H. Seimiya Ajou University School of Medicine, Suwon 443-721, KoreaDivision of Molecular Biotherapy, Cancer ChemotherapyCenter, Japanese Foundation for Cancer Research, H. FujikiTokyo 135-8550, Japan Faculty ofPharmaceutical Sciences, Tokushima Bunri

Univenity, Tokushima 77 A-8514, lapNrJ. ChungDepartment of Biochemistry and Molecular Biology S. C. Parkand Cancer Research Institute, Seoul National University Well Aging Research Center, Samsung Advanced InstituteSchool of Medicine, Seoul 110-799, Korea of Technology, YongSn 446-712, Korea

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J Callccr Res Clin ttcol(2013)139:901-904

accurate diagnosis of pancreatic cancer is critically

required but still renlains a geat challengc. Dr. Jocrg

Hohciscl(DKFZ)addrCSSed this issuc by afnniり _baSCd

quantitattve proteonlc analysis:antibody nlicroarray.The

results were compared to those」lom other analyses,such as

cpigenetic analysis and DNA microaray.Dr.Hohciscl also

introduced a technological development in nucroRNA

diagnosis of blood. It is cxpected that cumulativc data

、vould make it possible to diagnosc pancreatic cancer early

and to idendfy potential therapeudc targets in the near

itwe. NIIore prolnising is that these tools can be easily

adaptcd to analysc other(� seasc entides.

Plcnary lecturc 4:bcyond VEGF:status quo

and pcrspcctivcs of anti―angiogenic tumour therapy

Professor Hellmut Augusan(DKFZ)started his tttk with

several unresolved issues in the neld of and― anjogene―

sis tumour therapy. ■ e main stream of angiogenesis

rcscarch and anti―angiogenesis thcrapy has becn focusing

on 電ヽGF/VEGFR signallingo Pron Augustin concen―

trated on the enigmatic role of ANG-2 in promoting

sprOuting anglogenesis and inhibiting vascular mattllration

induced by ANG-1/′ llL2 signallin3・ANG-2 was pro―

angiogenic on IIE-2 negative tip cells, which express

l霞ge alnotlnts of integrins. Interestingly, the ANG-2

cffcct in these cells was mediatcd by ac● vating integrin

signalling,as monitored by activation of the downstream

effectos, FAK and Racl, and sprouting angiogenesis.

This new discovery forIIIs a solid basis for anti一 Ang-2

therapy and thus could facilitate clinical applications in

the ncar futurc.

Plcnary lecture 5:role of CD44 in cancer steln cells

Pl・ofessor Hideyuki Saya(Kelo University)haS been

working on the CD44 adhesion molecule for two decades

to understand the molecular mechanism for its rolc in

cancer.His long jourlley on dcciphering the CD“code

alinost came to an end with qtlitc surpnsing but intriguing

results.Hc found thそ渡CD44,particuLrly va■ ant fonns of

CD44(CD44v),intCracts with xCT,a cystinc transporter,

and promotes cystinc uptakc, which leads to high intra―

cellular GSH levels,「 Fhese elevatcd CSH levels protect

canccr stcm cclls from R《 )S which can bc gcnerated in

large amounts,particularly in the hypoxic tumour mic■ o―

environment. In addtion, CD44 enhanced the glycolytic

phenotype and shifted metabolic aux to the pentose phos―

phate pathway.These results elegantly explaln,in part,the

“Warburg effect''. Finally, his novel andings strongly

suggest CD4躊 、CT as a potential therapeutic target in

diversc typcs of canccr.

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Special lecture 1: low cell stiffness as a malignantindicator of progression

A question was raised a long time ago by Professor HaruoSato and his associates: Is there any relationship betweencancer cell rigidity and its metastatic potential? Recentdevelopments in nanotechnological equipment haveallowed Dr. Masami Suganuma (Saitama Cancer Center) toanswer this question. She measured cell stiffness usingatomic force microscopy (AFM) as monitored by Young'smodulus (Pa). Initial studies were performed with the 816-F10 and 816-F1 breast cancer cell lines and were extendedto oiher cancer cell lines. She found that all lung cancer celllines have significantly lower stiffness than normal cellsand that cell stiffuess decreased when the cells weretransformed. Changes in cell stiffness were also observeddepending on the cell cycle phase. Although these resultssuggest that cell stiffness might represent a discrete featureof cancer cells, a quantitative correlation appears to awaitfurther investigation.

Special lecture 2: diverse functions of the tumoursuppressor TIS2IIBTG2 in normal and cancer cells

TIS21/BTG2 is a primary response gene whose expressionis regulated by stimulation with TPA or other growthfactors. Prof. In Kyung Kim (Ajou University) previouslyreported the diverse role of TIS21/BTG2 in the cell cycle,cell death, maintenance of HSC proliferation and tumoursuppression. This presentation introduced more recentwork on the role of TIS21/BTG2 in cancer invasion andmigration. She found ROS-mediated invasion and migra-tion of breast cancer and A549 lung cancer cells, and thatTIS21/BTG blocked NADPH oxidase (Nox)-dependentROS generation, presumably by downregulating FAK andSrc kinase which function upstream of Racl-Nox. Inaddition, TIS2IiBTG promotes retinoic acid-induced dif-ferentiation of HL-60 cells by downregulating both c-MycnRNA and its protein stability. This TIS2l/BTG2 effect onc-Myc occurred by activating Erkll2 and inhibiting PI3FUAkt. Taken together, cellular context-dependent pleiotropiceffects of TIS2l/BTG2 suggest its importance in themaintenance of in vivo homoeostasis.

Session D: tumorigenesis and genomic stability, chairedby Profs. Hidetoshi Tahara and Eui-Ju Yeo

In this session, four speakers presented their interestingresults on tumorigenesis and genomic stability. Previousstudies have revealed many essential functions of thecondensin complex in mitotic chromosome assembly andsegregation. One of the current issues of this complex isthat the subunit function has not yet been clearly defined.

J Canccr Rcs O� Oncol(2013)139:901-904

Dr. Kyungtae Kim (Korean National Cancer Center)sought to identify the function of NCAPG2 subunit and itsmolecular mechanism. Dr. Kim and her associates foundthat NCAPGZ-defective cells show diverse phenotypes:fuzzy chromosome assembly, a significant increase inaneuploidy and cell division without delay under mitoticstress. These cells also showed additional defects inphosphorylation and localization of spindle checkpointregulatory proteins at the kinetochore. The results indicateda dual function for NCAPG2 in chromosome condensationand chromosome-microtubule attachment.

TRF1 is a well-known felomeric protein that regulatesboth length and integrity of telomeres. Dr. Hiroyuki Sei-miya (Japanese Foundation for Cancer Research) presentedan unexpected novel function of TRF1 in the regulation ofchromosome segregation. TRF1 is poly(ADP ribosyl)atedby tankyrase-l, which facilitates proteasomal degradationof TRF1. The finding that forced expression of nucleartankyrase-l, but not cytoplasmic tankyrase-l, interferedwith Aurora A-induced mitotic failure prompted him toexamine the possibility that TRFI might mediate theAurora A-induced phenotype. Indeed, depletion of TRF1suppressed Aurora A-induced mitotic failure. Furtherinvestigation revealed that Aurora A bound and phos-phorylated TRF1. As expected, the unphosphorylatablemutant TRF1 did not mediate the Aurora A-induced phe-notype. Based on these results, Dr. Seimiya proposed thatTRF1 contributes to proper chromosome segregation.

p21-activated kinase (PAK) is a serine/threonine kinasethat regulates a wide range of cellular activities. ProfessorEung-Gook Kim (Chungbuk National University) and hislaboratory members investigated the PAK4 signallingpathway. Interestingly, PAK4 functioned downstream ofprotein kinase A. This provoked the idea that PAK4 mightbe involved in the regulation of the CREB transcriptionfactor. Both CREB transcriptional activity and expressionlevels were regulated by PAK4 activity. Depleting PAK4in prostate cancer cell lines made them susceptible tochemotherapeutic drugs, and forced expression of PAK4into androgen-dependant LNCap-FGC cells made themandrogen independent. The results suggested that PAK4 isa potential therapeutic target in prostate cancerprogression.

Professor Junho Chung (Seoul National University) hasbeen working for over a decade on translational researchinvolving the development of monoclonal antibodies fortherapeutic purposes. In this presentation, he showed us anexample of how to modify peptides for a therapeuticapplication that requires a relatively long half-life in vivo.The conventional PEGylation method requires a peptide-specific optimization process; thus, it is time-consuming.His new idea was to make a hapten-conjugated peptide andthen to use an anti-hapten-specific antibody as a peptide

carrier. To test this idea, he first generated a hapten-WKYMVm-NH2, a synthetic peptide agonist of the formylpeptide receptor family that is effective for treating sepsis.Injection of this hapten-conjugated peptide with the anti-hapten antibody resulted in a significantly improved in vivohalf-life. Easy application of this platform technology toother therapeutic peptides is expected.

Plenary lectures and a session on ageing and senescence

Plenary lecture 1: serendipity in search of longevity-atrivial drug as an elixir

Prof. Sang Chul Park (Gachon University) has been seek-ing modalities to promote functional longevity in humans.Two strategies can be considered for this pu4)ose: behav-ioural correction and biological intervention. An epidemi-ological finding attracted his attention during a survey atSorok Island where Hansen's people lived until recently.Why do Hansen's people live longer than ordinary people?To address this question, he hypothesized that their lifelongdrug 4,4-diaminodiphenylsulfone (DDS) might extendlifespan. It tumed out that DDS had a positive effect onC. elegans lifespan. Moreover, sffuctural analysis revealedpyruvate kinase as its target protein in mammals, sug-gesting that DDS might improve sarcopenic muscleweakness in older people. Thus, DDS holds great promiseas an elixir of life.

Plenary lecture 3: genetic risk factors in cancerand ageing

This lecture started with a description of accumulatedepidemiological and biological data supporting the closecorrelation between cancer and ageing. Dr. Daniel Campa(DKFZ) addressed this issue with a genome-wide associ-ation study (GWAS). A previous GWAS identified anassociation between the rs401681 locus and pancrcaticcancer risk, which was replicated in a recent study. Arecent review on TERT locus polymorphisms and cancerrevealed a statistically significant association between thers2736100 polymorphism and risks for diverse types ofcancer, including pancreatic cancer. Surprisingly, bothrs4975605 and rs2736100 variations were present in theoldest group. The genetic evidence in this presentationsupported that these two phenofypes are closely linked.

Session A: senescence and ageing, chaired byDr. Hiroyuki Seimiya and Prof. Jeong A Han.

In this session, four speakers presented their interestingresults on diverse aspects of ageing and an improvementstrategy. Prof. Kyung A Cho (Chonnam Universiry)addressed the specific question of how to improve response

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904 J Canccr Res Clin Oncol(2013)139:901-904

to vaccines which frequently decrease in older people. In

contrast to previous studies focusing on Toll-like receptor 4(TLR4), she paid a great attention to the role of TLR5,which is related to the innate immune response during

ageing. Flagellin is a specific agonist of TLR5. Prof. Chofound that aged mice showed a greater protective effectfrom streptococcus pneumonia infection when vaccinated

with a flagellin-linked bacterial epitope. Accumulatingevidence supports the role for flagellin as an effectiveadjuvant in various pathophysiologies. Thus, it is expectedthat Prof. Cho's proposal will be helpful to older people

who need protection from bacterial infections.Prof. Hidetoshi Tahara (Hiroshima University) pre-

sented a new discovery on the role for miRNAs in theregulation of cellular senescence. Senescence may act as a

tumour suppressive mechanism, and his previous studyidentified miR-22, which represses cancer progression byinducing senescence. Further screening newly identifiedseveral senescence-associated (SA) miRNAs. One of thefeatures was that senescent cells show a senescence-associated secretory phenotype (SASP). As expected,miR-22 activated SASP. Exosome-miRNA profiling wasperformed. In contrast to his expectation, exosomes con-taining fi11?-22 were seldom secreted. Although theimmunological functions of exosomes have been describedfor immune cells, their pathophysiological functions in

senescent cells await furthsr investigation.Professor Yeo Eui-Ju (Gachon University) described the

positive effects of lysophosphatidic acid (I-PA) and/or anadenylate cyclase inhibitor (ACI) on wound healing andtissue regeneration in aged animals. She hypothesized thatreactivation of senescent cells in aged animals mightexplain this phenomenon. She found that LPA and/or ACIstimulated expression of several Wnt signalling-related

stem cell markers, such as B-catenin, TCF-4, c-myc and

cyclin D1. Moreover, expression of other stem cell markers

such as integrin o6 and CD34 was up-regulated in response

to these chemicals. Therefore, stem cell activation mayplay a key role in LPA and/or ACi-stimulated woundhealing and regeneration.

An intriguing talk on the cause and a potential thera-peutic modality for myasthenia gravis was delivered byProfessor Yuji Yamanashi (The University of Tokyo).Motor neurons control skeletal muscle contraction, whichrequire proper signal transmission through neuromuscularjunctions (NMJ). Thus, defective neuromuscular kans-

mission causes muscular weakness or so-called myasthe-nia. Dok-7 is considered an adaptor-like protein, but it isactually a cytoplasmic activator of the receptor protein

tyrosine kinase (PTK) MUSK, which controls neuromus-cular synaptogenesis. Because impaired Dok-7 signallingcauses NMJ synaptopathy, Dok-7 has emerged as apotential therapeutic target in myasthenia.

Short talks and poster presentations

The goals of this symposium have been to practice pre-

sentation of their own project in English and to encourageparticipation of young scientists and graduate students in ascientific discussion in the more intimate environment.Thus, five short talks and 2l poster presentations wereallocated to young scientists and graduate students on awide range of cancer and ageing topics. Their hot discus-sion in a quiet room in the museum made a truly joyful

atmosphere.

Conflict of interest Here, I declare no conflict of interest.

O SPringer