Cancer Biology: How Science Works

179 Pages·2021·6.957 MB·English

by  Carsten Carlberg, Eunike Velleuer

Carsten Carlberg
Eunike Velleuer
Cancer Biology:
How Science
Works
Cancer Biology: How Science Works
·
Carsten Carlberg Eunike Velleuer
Cancer Biology: How
Science Works
CarstenCarlberg EunikeVelleuer
InstituteofBiomedicine DepartmentforPediatricHemato-Oncology
UniversityofEasternFinland Children’sHospital
Kuopio,Finland Krefeld,Nordrhein-Westfalen,Germany
ISBN978-3-030-75698-7 ISBN978-3-030-75699-4 (eBook)
https://doi.org/10.1007/978-3-030-75699-4
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Preface
This book starts with bad news: one in two of us will face during our lifespan the
diagnosis of cancer, i.e., the detection of a malignant tumor. However, the good
newsarethatlessthanhalfofallcancerpatientsdiefromthediseaseandthatevery
second cancer death is preventable. Cancer is a collection of diseases that can
affectbasicallyeveryorganofourbody,allofwhichhaveincommonuncontrolled
cellulargrowth.Behindeverynewlydiagnosedmalignanttumorinadulthoodthere
isanindividualhistoryofprobably20ormoreyearsoftumorigenesis.Cancer
is typically considered as a disease of our genome caused by the accumulation of
DNApointmutationsaswellastranslocations,deletionsandamplificationsoflarger
genomic regions. However, tumorigenesis also comes along with abnormalities in
cellularidentity,differentresponsivenesstointernalandexternalstimuliandmajor
changesinthetranscriptome,allofwhicharebasedonchangesofourepigenome.
Infact,mosttypesofcancercarrymutationsbothinthegenomeandepigenome.
The cells forming our body have the potential to grow in the context of wound
healingorfortheconstantreplacementofcellsinourblood,skinorintestine.Malig-
nanttumorformationoftentakestimemakingcancerinmostcasestoanage-related
diseasethatweseemnottobeabletoevade.However,tumorigenesisisdependenton
multipleenvironmentalinfluences,includingthesurveillanceoftheimmunesystem
forcancercells.Manypro-andanti-cancereffectsoftheenvironmentwehaveunder
controlbylifestyledecisions,suchasretainingfromsmoking,selectinghealthyfood
and being physically active. Thus, cancer preventive interventions are the most
effectivewaytofightagainstcancer.
We should try to understand ourselves in detail as well as in a global setting.
Basicbiologyexplainscellularmechanisms,suchasgrowth,differentiationandcell
death, which make life as a whole possible. Every (human) organism represents a
complex interplay between hundreds of different cell types forming distinctive
tissuesandorganswithspecializedtasks.Theseprocessesneedtobehighlyorches-
tratedespeciallyduringembryogenesisandlateroninmaintaininghomeostasisof
theadultbody.Studyingthecellularandmolecularbasisofthesemechanismsisone
ofthemostfascinatingareasbutalsoagreatchallenge.Nevertheless,researchmade
the biggest steps in elucidating biological processes via studying malfunctions of
normalmechanismsleadingtodifferentdiseases.Therefore,thistextbookwantsnot
v
vi Preface
onlytodescribebasicmechanismleadingtocancerbutalsotoprovidethereaders
withamoreholisticviewandplacingtheseinsightsinthecontextofthepersonal
consequencesofeveryone’slifestyledecisions.
The content of the book is linked to the lecture course in “Cancer Biology”,
whichispartofaseriestogetherwithcoursesin“MolecularMedicineandGenet-
ics”, “Molecular Immunology” and “Nutrigenomics”, that is given by one of us
(C.Carlberg)indifferentformssince2005attheUniversityofEasternFinlandin
Kuopio.Moreover,biologicalprocessesexplainedinthisbookwillbesetintoaclin-
icalcontextusingtheexperienceofthedailycareinoncology.Thisbookalsorelates
to the textbooks “Mechanisms of Gene Regulation: How Science Works” (ISBN
978-3-030-52321-3),“HumanEpigenetics:HowScienceWorks”(ISBN978-3-030-
22907-8) and “Nutrigenomics: How Science Works” (ISBN 978-3-030-36948-4),
the studying of which may be interesting to readers who like to get more detailed
information. The clinical impact of the book is based on personal experience in
detecting,treatingandpreventingcancerbyoneofus(E.Velleuer).
Chapter1ofthisbookwillprovideageneraloverviewoncancer.Chapters2–6
focusonthemolecularbasisofthedisease,whileChaps.7–9willdiscussthecellular
aspectsofcancer.Finally,Chaps.10and11willexplaintheconceptsofanefficient
therapyagainstcancer.Bycombiningbasicunderstandingofcellularmechanismof
cancerwithclinicalexamples,wehopetomakethistextbookapersonalexperience.
Aglossaryintheappendixwillexplainthemajorspecialist’sterms.
Wehopethatreaderswillenjoythisrathervisualbookandgetasenthusiasticas
theauthorsaboutlifeanditsmalfunctioncounterpartreflectedincancerbiology.
Kuopio,Finland CarstenCarlberg
Düsseldorf,Germany EunikeVelleuer
March2021
Acknowledgements
The authors would like to dedicate this book to all victims of cancer, whom they
knowinperson.Somemanagedtosurviveandenrichtheworldwiththeirpresence.
Othersarenotanymorewithusbutwillneverbeforgotten.
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Contents
1 IntroductiontoCancer ........................................ 1
1.1 TheGlobalBurdenofCancer .............................. 1
1.2 CategorizationandDiagnosisofTumors ..................... 4
1.3 CrucialTransitionsinCancer .............................. 7
1.4 CausesofCancer ......................................... 10
1.5 CancerPrevention ........................................ 12
FurtherReading ................................................ 16
2 OncogenesandSignalTransduction ............................ 17
2.1 CellularTransformation ................................... 17
2.2 ActivatingOncogenesinSignalTransductionPathways ........ 19
2.3 OncogenicTranslocationsandAmplifications ................ 23
2.4 TheHallmarksofCancerConcept .......................... 26
FurtherReading ................................................ 28
3 TumorSuppressorGenesandCellFateControl .................. 29
3.1 p53-AMasterExample .................................. 29
3.2 TumorSuppressorsandOncogenesinCellCycleControl ...... 33
3.3 TumorSuppressorInhibitionandCancerOnset ............... 35
FurtherReading ................................................ 40
4 Multi-stepTumorigenesisandGenomeInstability ................ 41
4.1 CharacteristicsofTumorGrowth ........................... 41
4.2 Multi-stepTumorigenesis ................................. 44
4.3 GenomeInstability ....................................... 47
4.4 CancerDriverMutationsandGenes ......................... 50
FurtherReading ................................................ 53
5 CancerGenomics ............................................. 55
5.1 HumanGeneticVariationandCancerSusceptibility ........... 55
5.2 TheCancerGenome ...................................... 59
5.3 CancerGenomeProjects .................................. 62
FurtherReading ................................................ 66
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x Contents
6 CancerEpigenomics ........................................... 67
6.1 EpigeneticMechanismsofCancer .......................... 67
6.2 DNAMethylationandCancer .............................. 72
6.3 ChromatinChangesandCancer ............................ 76
6.4 EpigeneticReprogramminginCancer ....................... 81
FurtherReading ................................................ 85
7 AgingandCancer ............................................. 87
7.1 CentralRoleofAgingDuringChronicDiseases .............. 87
7.2 TheHallmarksofAging ................................... 89
7.3 EpigeneticsofAging ..................................... 93
7.4 TelomeresandReplicativeImmortality ...................... 96
FurtherReading ................................................ 98
8 TumorMicroenvironment ...................................... 101
8.1 TheImpactoftheWoundHealingProgramforCancer ........ 101
8.2 CellTypesoftheTumorMicroenvironment .................. 104
8.3 InducingAngiogenesis .................................... 108
8.4 Tumor-PromotingInflammation ............................ 110
8.5 DeregulatingCellularEnergetics ........................... 111
FurtherReading ................................................ 114
9 MetastasisandCachexia ....................................... 115
9.1 TheMetastaticCascade ................................... 115
9.2 Epithelial-MesenchymalTransition ......................... 118
9.3 MetastaticColonization ................................... 121
9.4 Cachexia ................................................ 123
FurtherReading ................................................ 128
10 CancerImmunity ............................................. 129
10.1 OutlineofCancerImmunity ............................... 129
10.2 RecognitionofTumorAntigens ............................ 135
10.3 MonoclonalAntibodiesinCancerImmunotherapy ............ 138
10.4 ImmuneCellTherapies ................................... 141
FurtherReading ................................................ 145
11 ArchitectureofCancerTherapies ............................... 147
11.1 ClassicalCancerTreatments ............................... 147
11.2 TargetedTherapies ....................................... 152
11.3 PrecisionOncology ....................................... 156
FurtherReading ................................................ 160
Glossary ......................................................... 163
Abbreviations
3C Chromosomeconformationcapture
3D 3-dimensional
5hmC 5-hydroxymethylcytosine
5hmU 5-hydroxyuracil
5mC 5-methylcytosine
A Adenine
ABL1 ABLproto-oncogene1,non-receptortyrosinekinase
ADAMTS13 ADAMmetallopeptidasewiththrombospondintype1motif13
AIDS Acquiredimmunedeficiencysyndrome
AKT Aktmurinethymomaviraloncogenehomolog
ALK Anaplasticlymphomakinase
ALL Acutelymphoidleukemia
AML Acutemyeloidleukemia
AMPK AMP-activatedproteinkinase
AP-1 Activatingprotein1
APC APCregulatorofWNTsignalingpathway
APAF1 Apoptoticpeptidaseactivatingfactor1
APOBEC ApolipoproteinBmRNAeditingcatalyticsubunit
APR Acuteproteinresponse
ARID AT-richinteractiondomain
AR Androgenreceptor
ASNS Asparaginesynthetase(glutamine-hydrolyzing)
ATAC-seq Assayfortransposase-accessiblechromatinusingsequencing
ATM ATMserine/threoninekinase
ATR ATRserine/threoninekinase
ATRX ATRXchromatinremodeler
BAX BCL2associatedX,apoptosisregulator
BCL2 BCL2apoptosisregulator
BCL2L BCL2like
BCR Bcellreceptor
BER Baseexcisionrepair
BID BH3interactingdomaindeathagonist
xi