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2
CancerCellBiology
ViolaHeinzelmann-Schwarz
RosGlasspool
PrimoSchär
Cancer is characterized by dysregulated cellular behavior, which may involve cell
proliferation and death, cell metabolism, cell motility, and interaction with the
microenvironment.Cancersdevelopviadiverseetiologiesandmultiplepathways.Specific
molecularchanges that cause a normalcellto become malignant have beenidentified,but
theirspectrumvariesconsiderablybetweencancertypes.
Themalignantphenotypeischaracterizedbytheabilitytoinvadesurroundingtissues
and to metastasize. The development of a cancer elicits a considerable molecular
responseinthelocalmicroenvironmentthatischaracterizedbyrecruitmentofstromal
elementssuchasnew bloodvessels andbythedevelopmentofanactive immunologic
response.Thesesecondaryeventsplayacriticalroleintheevolutionandprogressionof
cancers.Althoughthemolecularpathogenesisofgynecologiccancershasbeenonlypartially
elucidated,advancesintheunderstandingofthesediseasesareprovidingtheopportunityfor
improvementsindiagnosis,treatment,andprevention.
CellGrowthandProliferation
Thenumberofcellsinnormaltissuesistightlyregulatedbyabalancebetweencellular
proliferation and death. This involves complex molecular mechanisms and a finely
tuned balance between stimulatory and inhibitory growth signals. Physiologically, in
sometissuetypes—such asthebonemarrow,epidermis,andgastrointestinaltract—the life
spanofmaturecellsisrelativelyshort,andhighratesofproliferationbyprogenitorcellsare
requiredtomaintainthepopulation.Inothertissuetypes—suchasliver,muscle,andbrain—
cellsarelonglived,andproliferationrarelyoccurs.
The mitotic cell cycle consists of four discrete phases that comprise the ordered
processesrequiredfortheaccurate division andpartitionofthe genetic materialinto
viabledaughtercells(Fig.2.1).Itinvolvesaseriesofsequentialeventsandisdividedinto
several phases including proteinsynthesisin G1 phase, DNAsynthesis in S phase, cell
growth in G2 phase, chromosomal segregation in mitosis, and cell separation in
cytokinesis. These processes are tightly controlled by cellular machinery, which not only
orchestrates regulation of the various cell-cycle phases, but also integrates environmental
cuestoensurethatproliferationoccursonlywhenconditionsarefavorable.
Regulation of these events depends on a series of phosphorylations and
dephosphorylations of various cell cycle-regulatory proteins. These involve various
regulatory cyclins, cyclin-dependent kinases (CDKs), CDK inhibitors, oncogenes and
tumor-suppressorgenes,andmitoticcheckpointproteins(1–4).
Theintegrityoftheseprocessesisofutmostsignificance.Thederegulationofcell-cycle
regulatorymechanisms,a hallmark of the transformation of normal cells into tumor
cells,cancontributeto tumorigenesis. Mutations of any of these regulatory mechanisms
can,asa consequence, not only contribute to “uncontrolled” proliferationofcellsbut also
lead to reproduction of cells carrying genetic mutations or abnormal numbers of
chromosomes,resultingin genomic instability. Chromosomal instability,contributing to
genomicinstability,referstoabnormalitiesinthenumberofchromosomes,andleadsto
aneuploidy.
Figure2.1Aschematicviewofthecellcycle.Eachphaseinthe cell cycle progression is
regulated by cyclin-dependent kinases (CDKs) and their regulatory partner proteins, the
cyclins, and CDK inhibitors. Reprinted by permission from Bai J, Li Y, Zhang G. Cell cycle
regulationand anticancerdrugdiscovery.CancerBiolMed2017;14:348–362. Copyright 2017
byCancerBiology&Medicine.
Dysregulationofcellularproliferationor“uncontrolled”proliferationisoneofthemain
hallmarks of cancer. Activation of oncogenes and inactivation of tumor suppressor
genes can stimulate cell growth (see Chapter 1). In the past, it was thought that cancer
might arise solely because of more rapid proliferation or a higher fraction of proliferating
cells.Althoughincreasedproliferationisacharacteristicofmanycancersandisanappealing
therapeutictarget(5),thefractionofcancercellsactivelydividing,andthetimerequiredto
transit the cell cycle, is not strikingly different between many cancers and corresponding
normalcells of the same lineage.Altered regulation of proliferationisonly one of several
factorsthatcontributetomalignanttransformation.Ultimately,therelativebalanceofgrowth
stimulatory and inhibitory factors is shifted in malignancy to promote altered cellular
proliferation.
Oncogenes
Alterations in genes that stimulate cellular growth (oncogenes) can cause malignant
transformation(seeChapter 1) (6). Oncogenes can be activated via several mechanisms.