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Cancerremainstobeoneofthemostdevastatingdiseasesworldwidesincelong
ago. Thepoorprognosisofcancerislargelyduetometastasis.
Metastasisisoften
depictedasamultistageprocessinwhichmalignantcellsspreadfromtheprimary
locustodistantorgansviacirculation.
Whereasgeneticalterationsweresuggested
tobeessentialfortransformationofprimarytumorcellsintometastaticphenotype,
epigeneticeventsareequallyimportant,whichmaybetriggeredbymetastaticf-
torswhereverintheprimarytumorlocus,bloodcirculationandthesecondaryloci.
Signaltransductionsinitiatedbythemetastaticfactorsareresponsibleformediating
themolecularandcellularprocessesleadingtometastasis.
Blockadeoftherelevant
molecularpathwaysisoneofthemosteffectivestrategiesforpreventionoftumor
metastasis. Clinicaltrialsareunderwaywithpromisingoutcome.
Inthisbook, wetakecomprehensive review inregard withthisexciting
eld ofcancerresearch. Chapter1takesabriefoverviewofrecentlyidenti
edsignal
mechanismsforeachstepoftumormetastasisincludingtheinitiationstage,intra-
sation,anti-anoikisinbloodcirculation,homing,extravasationand
nalsurvivalin themetastaticsite.
Chapter2makesacompletedreviewforthemolecularandcel-
lareventsinvolvedininitiationofmetastasis.
Especially,thesignalingmechanisms
formediatingtumorprogressioninducedbysomeimportantmetastaticfactorsare
described.
InChapters3and4,thecentralrolesofMAPKanditsdownstreameff-
torsMAPKAPKplayineachstepoftumormetastasisarewelldelineated.
Chapter5
furtherdescribesdetailedlyabouthowGrb2andotheradaptorproteins,upstreamof
MAPK cascade, contribute tometastasis. InChapter 6, therole
ofreactive o- genspecies(ROS)intumorprogressionarehighlighted.
Moreover,thepotential contribution of ROS to cross talk between
major signaling cascades that lead to
sustainedMAPKactivationareproposedinChapter7.
Chapter8takesaninsight intothesignalingmechanismsfordynamictraf
ckingandturnoveroffocalad-
sionproteinsinregulationoftractionandretractionforces,whichareneededfor
celllocomotionandinvasion.
Chapter9describestheinvolvementofNotchsign-
ingpathwaywhichisnotonlyessentialforembryonicdevelopmentbutalsoplays
importantroleintumorprogression. Chapter10reviewedtherecentlyidenti
ed cancer- and metastasis-initiating cells involved in tumor
progression. Especially, signal pathways that are frequently
deregulated in cancer stem/progenitor cells v vi Preface
duringcancerprogressionarehighlighted.
Chapter11describestheroleoflipid rafts, a special component within
membrane lipid domain, in signal transd- tion triggered by growth
factor receptors leading to tumor metastasis. Finally,
Chapters12,Chapters13,andChapters14presentthesignalingpathwaysresp-
sibleformetastaticprogressionofspeci
ctumorsincludingovariancancer,uveal
melanomaandhepatoma,respectively.
WethankallthecontributorsofeveryChapterinthebookincludingJia-RuWu,
Chi-TanHu,LaureVoisin,StephanieDuhamel,SylvainMeloche,AlexeyShiryaev,
MarijkeVanGhelue,UgoMoens,AlessioGiubellino,PraveenR. Arany,Moulay
A. Alaoui-Jamali, Krikor Bijian, Panagiota Toliopoulos, Pingyu
Zhang, Patrick A. Zweidler-McKay,MurielleMimeault,SurinderK.
Batra,SamirKumarPatra, LydiaW. T. Cheung,CarmanK. M. Ip,AliceS. T.
Wong,CecileLaurent,Jerome
Couturier,XavierSastre-Garau,LaurenceDesjardins,EmmanuelBarillot,Sophie
Piperno-Neumann,SimonSauleandRajagopalN. Aravalli.
Wehopethisbookmightstimulatemorecancerbiologiststoemphasizethis eld
whichbene
tsdevisingmoreeffectivemoleculartargetingstrategiesforprevention
ofcancermetastasis. Hualien,Taiwan Wen-ShengWu Chi-TanHu Contents 1
Overview of Signal Transduction in Tumor Metastasis...1
Wen-ShengWuandJia-RuWu 2 Microenvironment Triggers EMT, Migration
and Invasion of Primary Tumor via Multiple Signal Pathways ...9
Wen-ShengWuandChi-TanHu 3 The ERK1/2 MAP Kinase Signaling Pathway
in Tumor Progression and Metastasis ...25
LaureVoisin,StephanieDuhamel,andSylvainMeloche 4 Mitogen-Activated
Protein Kinase-Activated Protein Kinases and Metastasis...41
AlexeyShiryaev,MarijkeVanGhelue,andUgoMoens 5 Grb2 and Other
Adaptor Proteins in Tumor Metastasis ...77
AlessioGiubellinoandPraveenR. Arany 6 The Role of ROS Signaling in
Tumor Progression...103 Wen-ShengWuandJia-RuWu 7 Signal Cross Talks
for Sustained MAPK Activation and Cell Migration Mediated by
Reactive Oxygen Species: The Involvement in Tumor Progression...
Cancerremainstobeoneofthemostdevastatingdiseasesworldwidesincelong
ago. Thepoorprognosisofcancerislargelyduetometastasis.
Metastasisisoften
depictedasamultistageprocessinwhichmalignantcellsspreadfromtheprimary
locustodistantorgansviacirculation.
Whereasgeneticalterationsweresuggested
tobeessentialfortransformationofprimarytumorcellsintometastaticphenotype,
epigeneticeventsareequallyimportant,whichmaybetriggeredbymetastaticf-
torswhereverintheprimarytumorlocus,bloodcirculationandthesecondaryloci.
Signaltransductionsinitiatedbythemetastaticfactorsareresponsibleformediating
themolecularandcellularprocessesleadingtometastasis.
Blockadeoftherelevant
molecularpathwaysisoneofthemosteffectivestrategiesforpreventionoftumor
metastasis. Clinicaltrialsareunderwaywithpromisingoutcome.
Inthisbook, wetakecomprehensive review inregard withthisexciting
eld ofcancerresearch. Chapter1takesabriefoverviewofrecentlyidenti
edsignal
mechanismsforeachstepoftumormetastasisincludingtheinitiationstage,intra-
sation,anti-anoikisinbloodcirculation,homing,extravasationand
nalsurvivalin themetastaticsite.
Chapter2makesacompletedreviewforthemolecularandcel-
lareventsinvolvedininitiationofmetastasis.
Especially,thesignalingmechanisms
formediatingtumorprogressioninducedbysomeimportantmetastaticfactorsare
described.
InChapters3and4,thecentralrolesofMAPKanditsdownstreameff-
torsMAPKAPKplayineachstepoftumormetastasisarewelldelineated.
Chapter5
furtherdescribesdetailedlyabouthowGrb2andotheradaptorproteins,upstreamof
MAPK cascade, contribute tometastasis. InChapter 6, therole
ofreactive o- genspecies(ROS)intumorprogressionarehighlighted.
Moreover,thepotential contribution of ROS to cross talk between
major signaling cascades that lead to
sustainedMAPKactivationareproposedinChapter7.
Chapter8takesaninsight intothesignalingmechanismsfordynamictraf
ckingandturnoveroffocalad-
sionproteinsinregulationoftractionandretractionforces,whichareneededfor
celllocomotionandinvasion.
Chapter9describestheinvolvementofNotchsign-
ingpathwaywhichisnotonlyessentialforembryonicdevelopmentbutalsoplays
importantroleintumorprogression. Chapter10reviewedtherecentlyidenti
ed cancer- and metastasis-initiating cells involved in tumor
progression. Especially, signal pathways that are frequently
deregulated in cancer stem/progenitor cells v vi Preface
duringcancerprogressionarehighlighted.
Chapter11describestheroleoflipid rafts, a special component within
membrane lipid domain, in signal transd- tion triggered by growth
factor receptors leading to tumor metastasis. Finally,
Chapters12,Chapters13,andChapters14presentthesignalingpathwaysresp-
sibleformetastaticprogressionofspeci
ctumorsincludingovariancancer,uveal
melanomaandhepatoma,respectively.
WethankallthecontributorsofeveryChapterinthebookincludingJia-RuWu,
Chi-TanHu,LaureVoisin,StephanieDuhamel,SylvainMeloche,AlexeyShiryaev,
MarijkeVanGhelue,UgoMoens,AlessioGiubellino,PraveenR. Arany,Moulay
A. Alaoui-Jamali, Krikor Bijian, Panagiota Toliopoulos, Pingyu
Zhang, Patrick A. Zweidler-McKay,MurielleMimeault,SurinderK.
Batra,SamirKumarPatra, LydiaW. T. Cheung,CarmanK. M. Ip,AliceS. T.
Wong,CecileLaurent,Jerome
Couturier,XavierSastre-Garau,LaurenceDesjardins,EmmanuelBarillot,Sophie
Piperno-Neumann,SimonSauleandRajagopalN. Aravalli.
Wehopethisbookmightstimulatemorecancerbiologiststoemphasizethis eld
whichbene
tsdevisingmoreeffectivemoleculartargetingstrategiesforprevention
ofcancermetastasis. Hualien,Taiwan Wen-ShengWu Chi-TanHu Contents 1
Overview of Signal Transduction in Tumor Metastasis...1
Wen-ShengWuandJia-RuWu 2 Microenvironment Triggers EMT, Migration
and Invasion of Primary Tumor via Multiple Signal Pathways ...9
Wen-ShengWuandChi-TanHu 3 The ERK1/2 MAP Kinase Signaling Pathway
in Tumor Progression and Metastasis ...25
LaureVoisin,StephanieDuhamel,andSylvainMeloche 4 Mitogen-Activated
Protein Kinase-Activated Protein Kinases and Metastasis...41
AlexeyShiryaev,MarijkeVanGhelue,andUgoMoens 5 Grb2 and Other
Adaptor Proteins in Tumor Metastasis ...77
AlessioGiubellinoandPraveenR. Arany 6 The Role of ROS Signaling in
Tumor Progression...103 Wen-ShengWuandJia-RuWu 7 Signal Cross Talks
for Sustained MAPK Activation and Cell Migration Mediated by
Reactive Oxygen Species: The Involvement in Tumor Progression...
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