WNTs are soluble factors that bind WNT receptors, which in turn transmit signals that prevent the APC-mediated degradation of β-catenin, allowing it to translocate to the nucleus, where it acts as a transcriptional activator. In quiescent cells that have not been exposed to WNT, cytoplasmic β-catenin is degraded by a destruction complex, of which APC is an integral part. With loss of APC (e.g., in colon cancers), β-catenin degradation is prevented, and the WNT signaling response is inappropriately activated even in the absence of WNT factors. In colonic epithelium this leads to increased transcription of growth-promoting genes, such as cyclin D1 and MYC, as well as transcriptional regulators, such as TWIST and SLUG, which repress Ecadherin expression and thus reduce contact inhibition.
APC behaves as a typical tumor suppressor gene. Individuals born with one mutated allele typically are found to have hundreds to thousands of adenomatous polyps in the colon by their teens or twenties; these polyps show loss of the other APC allele. Almost invariably, one or more polyps undergo malignant transformation, as discussed later. APC mutations are seen in 70% to 80% of sporadic colon cancers. Colonic cancers with normal APC genes sometimes show activating mutations of β-catenin that render them refractory to the degrading action of APC.
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Fig. 6.22 TheroleofAPCinregulatingthestabilityandfunctionofβ-catenin.APCandβ-cateninarecomponentsoftheWNTsignalingpathway.(A)Inrestingcells(notexposedtoWNT),β-cateninformsamacromolecularcomplexcontainingtheAPCprotein.Thiscomplexleadstothedestructionofβ-catenin,andintracellularlevelsofβ-cateninarelow.(B)WhencellsarestimulatedbysecretedWNTmolecules,thedestructioncomplexisdeactivated,β-catenindegradationdoesnotoccur,andcytoplasmiclevelsincrease.β-Catenintranslocatestothenucleus,whereitbindstoTCF,atranscriptionfactorthatactivatesseveralgenesinvolvedinthecellcycle.(C)WhenAPCismutatedorabsent,thedestructionofβ-catenincannotoccur.β-Catenintranslocatestothenucleusandcoactivatesgenesthatpromotethecellcycle,andcellsbehaveasiftheyareunderconstantstimulationbytheWNTpathway.
TGF-β,CONTACTINHIBITION,ANDAPC-βCATENINPATHWAYSRESTING CELL WNT STIMULATION TUMOR CELL WITH RESTING CELL WNT STIMULATION TUMOR CELL WITH
TGF-β inhibitsproliferationofmanycelltypesbyactivationofgrowth-inhibitinggenessuchasCDKIs andsuppressionofgrowth-promotinggenessuchasMYC andthoseencodingcyclins.
TGF-β functioniscompromisedinmanytumorsbymutationsinitsreceptors(colon,stomach,endometrium)orbymutationalinactivationofSMAD genesthattransduceTGF-β signaling(pancreas).
E-cadherinmaintainscontactinhibition,whichislostinmalignantcells.
TheAPC geneexertsanti-proliferativeactionsbyregulatingthedestructionofthecytoplasmicproteinβ-catenin.WithalossofAPC,β-cateninisnotdestroyed,andittranslocatestothenucleus,whereitactsasagrowth-promotingtranscriptionfactor.