Robbins Essential Pathology PDF - Chapter 5 Neoplasia

74 CHAPTER 5 Neoplasia Table 5.6 Important Cancer Genes Cancer Gene Gene Class Function Effect of Mutations...

74 CHAPTER 5 Neoplasia Table 5.6 Important Cancer Genes Cancer Gene Gene Class Function Effect of Mutations Associated Cancers TP53 Tumor suppres- Sensor of cell stress, DNA Loss of function leads to genomic Diverse cancers sor repair instability, resistance to proapoptotic stresses RB Tumor suppres- Negative regulator of cell Loss of function leads to increased Mutated in retinoblastoma, osteo- sor cycle growth, failure to differentiate sarcoma; dysregulated in diverse cancers HER2 Oncogene Growth factor receptor Gain of function leads to growth Amplified in a subset of breast factor–independent signaling cancers and other carcinomas ABL Oncogene Nonreceptor tyrosine kinase Gain of function leads to growth Activated by translocations in factor–independent signaling several leukemias RAS Oncogene Signaling molecule Gain of function leads to growth Diverse cancers factor–independent signaling BRAF Oncogene Signaling molecule Gain of function leads to growth Commonly mutated in melanoma factor–independent signaling Cyclin D Oncogene Cell cycle regulator Gain of function opposes the action of Overexpressed due to transloca- RB, leads to increased proliferation tion or amplification in lym- phoma, breast cancer MYC, NMYC Oncogene Transcription factors Overexpression leads to reprogram- Translocated in Burkitt lymphoma, ming of metabolism amplified in neuroblastoma; dys- regulated in diverse cancers IDH1, IDH2 Oncogene Metabolic enzyme Mutation leads to new enzyme activity Acute myeloid leukemia, glioma, that produces an oncometabolite chondrosarcoma, cholangiocar- cinoma BCL2 Anti-apoptosis Opposes the activity of Overexpression leads to resistance to Translocated in follicular lym- proapoptotic factors apoptosis phoma; dysregulated in diverse cancers PDL1, PDL2 Host/cancer cell Activates immune checkpoint Overexpression leads to immunoeva- Amplified in Hodgkin lymphoma, interactions pathways in T cells sion overexpressed in diverse cancers nlammaon and by genomc nsaby, wc are enabng carac- ceuar componens (e.g., organees, membrane componens, and erscs because ey promoe ceuar ransormaon and subsequen rbosomes) needed or ce dvson umor progresson.    Progresson of te ce troug te ce cyce, resung umaey n Muaons n genes a reguae some or a o ese ceuar ras ce dvson and e “br” o wo dauger ces; s process s are seen n ever y cancer ; accordngy, ese ras orm e bass o e normay reguaed on mupe eves by a baance beween proens oowng dscusson o e moecuar orgns o cancer, durng wc a promoe ce cyce progresson (grow acors, grow acor we w aso dscuss a subse o cancer genes w requen or we- recepors, sgnang moecues, and cycn/cycn-dependen knase dened roes n cancer (summarzed n Tabe 5.6). hrougou e ds- compexes) and ose a oppose  (RB, p53, and cycn-depen- cusson (by convenon) gene symbos are taczed and er proen den knase nbors, descrbed aer) producs are no (e.g., RB gene and RB proen). E ac sep above s suscepbe o corrupon n cancer ces. he mos requeny muaed oncoproens a mpar grow acor Self-Sufficiency in Growth Signals ndependence on cancer ces are varous grow acor recepors, The self-sufciency in growth that characterizes cancer cells most RAS proens, and ceran sgnang acors a ac downsream o often stems from gain-of-function mutations in signaling proteins RAS. S ome o ese same proens are arges o efecve erapeuc that reduce or eliminate growth factor dependency. drugs. hese muaons conver proooncogenes no oncogenes, wc    Grow t factor receptors and reated protens. One common typ e o encode consuvey acve proens (oncoproens) a ransm pro- oncogenc mutaton c auses growth actor re ceptors or relate d grow sgnas even n e absence o grow acors. To apprecae protens to delver mtogenc sgnals to cells contnuously, e ven ow oncogenes drve napproprae ce grow, reca a grow ac- n the absence o growth actor. Many grow acor recepors or–nduced sgnang can be resoved no e oowng seps: ave an nrnsc yrosne knase acvy a s acvaed by grow    Bndng of a growt factor to ts specc receptor on e ce mem- acors and smuaes downsream sgnang cascades. Oer pro- brane ens w yrosne knase acvy are no surace recepors bu    Transent actvaton of te growt factor receptor, wc n urn ac- s ave e capacy o smuae e same paways wen ac- vaes sgna-ransducng proens vaed. Oncogenc muaons nvovng e genes a encode suc    Transmsson of te transduced sgna across te cytoso to te nuceus proens eer creae a consuvey acvaed yrosne knase or by second messengers or a cascade o sgna ransducon moe- cause e overexpresson o srucuray norma recepors, aow- cues ng sgnang o occur even wen grow acor eves are ver y    Actvaton of transcrpton factors a ncrease e expresson o ow. An exampe o a nonrecepor yrosne knase gene a s genes a reguae DNA repcaon and e bosyness o oer convered o an oncogene by cromosoma ransocaons s ABL,  CHAPTER 5 Neoplasia 75 RAS as an nrnsc guanosne rpospaase (GTPase) acvy Growth factor a ydroyzes GTP o GDP, reurnng e proen o s quescen Growth factor receptor GDP-bound sae. In cancers, s saeguard s oten abrogaed by pon muaons, eadng o amno acd subsuons a nerere Far nesyl membrane anchor w e GTPase acvy : RAS s us rapped n s acvaed, GTP- bound orm and sgnas ncessany.    S g nang fac tors and trans c r pton fac tors dow n stream of R AS. Ac  vae d R AS s mu  aes d ow ns re am regu  aors o pro era - Inactive Active RAS RAS  on by s e vera  nercon ne c e d p a w ay s. Mu a  on o s ome o Activation  es e dow ns re am ac ors m m  c s  e g row   - promo  ng e  e c  s Bridging protein GDP GTP o ac  vae d R AS (e. g. , mu a  ons o BR A F n me anomas and Activates o PI3-k nas e n mu  pe umors). T es e s g na s converge on Inactivation by  e nuceus and upregu  ae  e ex pre ss on o ge ne s  a supp or  NF1 hydrolysis of GTP ce  g row , ncud ng c yc n D, a  ac or re qu re d or c e  c yc e prog resson, and M YC , a  rans c r p on a c or w   w d e-rang ng Active RAS e e c s on anab oc me ab os m and c e  g row   , b o  o w c are ds c uss e d  aer. RAF PI3K PTEN Insensitivity to Growth-Inhibitory Signals Pro-growth MAPK Mutation of oncogenes is not sufcient to produce the unbridled MYC metabolism proliferation that is characteristic of cancer cells; excessive growth Increased protein also requires complementary mutations that inhibit the function synthesis Activation of tumor suppressor genes, which in normal cells apply “brakes” of transcription to cellular proliferation. Many umor suppressor genes ave been descrbed, bu wo are D cyclins p16 parcuary mporan n carcnogeness: RB, a key reguaor o e Cell cycle ce cyce, and TP53, wc eps manan e genomc negry o progression ces. As dscussed beow, a g racon o cancers conan genec aeraons a drecy or ndrecy dsrup e uncon o ese wo crca umor suppressors. CELL GROWTH RB: Governor of Cellular Proliferation Fig. 5.16 Oncogenic growth factor signaling. When a normal cell is stim- ulated through a growth factor receptor with intrinsic tyrosine kinase RB regulates the G1/S checkpont, the portal through whch cells activity (a so-called receptor tyrosine kinase), inactive (GDP-bound) RAS must pass beore DNA replcaton commences. is activated to a GTP-bound state. Activated RAS transduces prolifer- Norma ceuar proeraon and dferenaon are orcesraed ative signals to the nucleus along two pathways: the so-called RAF/ by members o e renobasoma (RB) amy o proens, reerred ERK/MAP kinase pathway and the PI3 kinase/AKT pathway, which o ere smpy as RB. RB was e rs umor suppressor gene o be upregulate the expression of D cyclins and MYC. The activity of RAS dscovered and s a prooypca represenave. Approxmaey 40% o is normally held in check by GAPs (GTPase-activating proteins) such as renobasomas are ama, w e predsposon o deveop umors NF1, whereas the activity of PI3 kinase is antagonized by PTEN. Factors beng ransmed as an auosoma domnan ra a s caused by shown in green are oncoproteins that are activated by gain-of-function e presence o one deecve copy o e RB gene n e germne o mutations in various cancers, whereas factors shown in red are tumor suppressors that are often missing due to loss-of-function mutations. afeced ndvduas. GDP, Guanosine diphosphate; GTP, guanosine triphosphate; MAP, mito- Renobasomas, weer ama or sporadc, aways sow com- gen-activated protein; PI3K, phosphatidylinositol-3 kinase. pee oss o RB uncon due o nacvaon o bo RB aees, an even a s muc more key n ndvduas wo ner one deecve copy and acqure a somac muaon o e oer aee. RB muaons occur wc s rearranged n ceran eukemas. In conras, e HER2 sporadcay n a specrum o dferen cancers, and many cancers ave gene, wc encodes a recepor yrosne knase, s oten amp- oer aeraons, suc as epgenec modcaons, a mpnge on RB ed n breas cancer. he ne efec o bo ypes o aeraons s ndrecy. As a resu, mos (and peraps a) cancers ave one or more e same: overacvaon o a sgnang cascade nvovng RAS and acqured deecs a ead o oss o RB uncon. acors downsream o RAS. To undersand RB uncon, a bre revew o e ce cyce s   RAS. RAS genes are the most commonly mutated oncogenes n requred. he successve pases o e ce cyce n growng ces are human tumors. Approxmaey 30% o a uman umors ave RAS G , a pase o varabe eng; S, a pase durng wc ces repcae 1 muaons. RAS proens are members o a amy o G proens er DNA; G , a second pase o varabe eng; and M, durng wc 2 a bnd guanosne nuceodes (guanosne rpospae [GTP] ces ener no and compee moss, generang wo dauger ces and guanosne dpospae [GDP]). Normay, RAS lps back a reurn o G. he progresson o ces roug e ce cyce s 1 and or beween an exced (GTP-bound) sgna-ransmng conroed by ree major ses o acors: cycns, proens wose eves sae and a quescen (GDP-bound) sae (Fg. 5.16). Acvaon o oscae up and down dependng on e ce cyce pase; cycn-depen- grow acor recepors (eer by grow acors or, as n cancers, den knases (CDKs), proens wose enzymac acves depend on by muaon o e recepor) eads o e excange o GDP or GTP e bndng o specc cycns; and CDK nbors (CDKIs), proens and subsequen conormaona canges a generae acve RAS. a ac as negave reguaors o cycn/CDK compexes (Fg. 5.17). he hs exced sgna-emng sae s normay sor ved because ranson rom e G pase o e S pase consues an mporan 1 76 CHAPTER 5 Neoplasia K inhibito CD rs C D p21 family K rs Cyclin in o h it ib ib h it in o E p r 2 s K 1 D y fa il C m m fa il y 6 1 p CDK2 Cyclin Cyclin D D Cyclin CDK4 CDK6 C A D K CDK2 i 2 n 1 ih Cyclin f ib P a RB RB m A o li s y CDK1 S G 1 G 2 M Cyclin B CDK1 l i m a f 1 r 2 o p t i i n i K D Fig. 5.17 Cell cycle regulation. The key determinant of cellular proliferation is the G to S phase transition, 1 which is inhibited by RB. This block is released by phosphorylation of RB by cyclin D/CDK4 and cyclin D/ CDK6 complexes. CDK inhibitors of the p16 family provide another level of control by inhibiting cyclin D/CDK4 complexes, whereas CDK inhibitors of the p21 family negatively regulate multiple cyclin/CDK complexes throughout various cell cycle phases. ce cyce ceckpon, because once ces move no e S pase ey are vruses (e.g., HPV) encode oncoproens a nacvae RB. In HPV, commed o compeng e ce cyce and dvdng. he acvy o RB e HPV E7 proen bnds o e ypopospor yaed orm o RB and “governs” G -S pase ranson as oows (Fg. 5.18): prevens E2F nbon. Perssen vra necon and susaned yper- 1    E ary n G , RB s n a ypopospor yaed acve orm a bnds proeraon over years sow e seeds or acquson o addona 1 and nbs ranscrpon acors o e E2F amy, prevenng e muaons and e deveopmen o squamous ce carcnomas a ses expresson o genes a are requred or progresson no S pase. a are suscepbe o HPV necon (e.g., e cer vx and e cr yps o    Sgnas a are normay creaed by acvaed grow acor recep- e oropar yngea onss). ors upreguae e expresson o D cycns, wc orm compexes TP53: Guardian of the Genome w CDK4 and CDK6 a pospor yae and nacvae RB. hs reeases RB rom E2F acors, permng ces o express genes a The TP53 tumor suppressor gene, the most commonly mutated gene in are needed or enr y no S pase. human cancers, functions to protect cells from stress-induced damage.    Subsequeny, ceuar pospaases remove e pospae groups I RB s a “sensor” o exerna sgnas, e proen encoded by TP53, rom RB durng M pase, regenerang e ypopospor yaed p53, can be vewed as a cenra monor o nerna sress. p53 s a ran- orm o RB as e newy dvded ces move back no e G pase. scrpon acor, and s efecs are medaed roug ncreased expres- 1 In cancers with normal RB genes, mutations in other genes that control son o genes a conro ce grow and ce sur vva. Sresses a RB phosphorylation are commonly found; as a result, virtually all can- acvae p53 ncude DNA damage, napproprae progrow smu cer cells show dysregulation of the G1-S check point. (e.g., unbrded RAS acvy), and ypoxa. In nonsressed, eay For e mos par, ese abnormaes ncrease e acvaon o ces, p53 as a sor a-e because o s assocaon w MDM2, cycn D/CDK4 compexes, eadng o nacvaon o RB. he mos a proen a arges p53 or desrucon. In conras, wen e ce common exampes o suc aernave mecansms are muaons a s sressed (e.g., due o DNA damage), “sensor” proens mody and resu n consuve acvaon o grow acor recepors or RAS. sabze p53, enancng s aby o drve e ranscrpon o arge he mporance o RB n e conro o ce grow and n cancer genes. he producs o ese arge genes ac o preven sressed ces was recognzed n par roug e dscover y a ceran oncogenc rom undergong magnan ransormaon.  CHAPTER 5 Neoplasia 77 he acors a deermne weer a ce repars s DNA, becomes GROWTH INHIBITORS GROWTH FACTORS senescen, or undergoes apoposs are unceran; bo e duraon and p53 (EGF, PDGF) e eve o p53 acvaon may be decdng acors. here s s muc o be earned abou e nuances o p53 uncon. Stimulate he mporance o TP53 dysreguaon n cancer s gged by e oowng consderaons: CDK Inhibitors Activate    More tan 70% of uman cancers ave defects n TP53, and oer p16 and p21 cancers oten ave deecs n genes upsream or downsream o TP53. Baec abnormaes o e TP53 gene are ound n vruay Inactivate ever y ype o cancer, ncudng carcnomas o e ung, coon, and breas, e ree eadng causes o cancer deas. Cyclins D/CDK4,6    e ertabe cancer syndrome L-Fraumen syndrome s due to a Cyclins D/CDK4,6 Cyclin E/CDK2 germne mutaton n one TP53 aee. Paens w s syndrome ave a 25-od greaer cance o deveopng a wde specrum o magnan umors by age 50 compared w e genera popuaon. he mos common ypes o cancers seen are sarcomas, carcnomas Hypophosphorylated Hyperphosphorylated o e breas, and ceran eukemas and bran umors; ese can- RB RB cers oten occur a a young age, and many paens deveop mupe umors o dferen ypes. P P E2F P P    e p53 proten s te target of vra oncoprotens. As w RB, nor- ma p53 s rendered nonuncona by e bndng o ceran DNA P P vruses. he bes caracerzed o ese s E6, a vra oncoproen E2F encoded by HPV, dscussed earer as an mporan cause o cer vca and onsar squamous ce carcnoma. Cell Lineage–Specific Tumor Suppressor Genes Unlike RB and TP53, which are commonly lost in many different human cancers, other tumor suppressor genes are strongly linked to only a few cancer types. A cassc exampe s e APC gene, wc encodes a componen E2F S phase E2F S phase o e Wn sgnang paway. APC s a cyopasmc proen wose site genes site genes domnan uncon s o promoe e degradaon o β-caenn. β-ca- enn s a ranscrpona acvaor, and w oss o APC, β-caenn Transcriptional Transcriptional block activation becomes yperacve. In coonc epeum (unke mos ces o oer neages), yperacvy o β-caenn eads o ncreased ranscrpon Fig. 5.18 RB regulation of G –S phase transition through E2F tran- 1 scription factors. Hypophosphorylated RB in complex with the E2F o grow-promong genes, suc as cycn D and MYC. Indvduas transcription factors binds to DNA and inhibits transcription of genes wo ner one deecve copy o APC deveop adenomatous poyposs whose products are required for the S phase of the cell cycle. When co (rom wc APC akes s name), a dsease caracerzed by e RB is phosphorylated by the cyclin D–CDK4 and cyclin D–CDK6 com- appearance o undreds o coonc poyps by eary aduood and e plexes, it releases E2F, which activates transcription of S-phase genes. deveopmen o coon carcnoma by age 50. hese umors ave somac The phosphorylation of RB is inhibited by CDKIs such as p16, which deeons or muaons a emnae e uncon o e remanng inactivate cyclin–CDK complexes. Virtually all cancer cells show dysreg- norma copy o APC. Smar baec oss o APC s aso seen n a sub- ulation of the G –S checkpoint as a result of a mutation in at least one of 1 se o sporadc coon cancers. Oer exampes o neage-specc umor four genes; RB, CDK4, cyclin D, and/or CDKN2A [p16]. EGF, Epidermal suppressor genes (and oncogenes) are dscussed n aer capers. growth factor; PDGF, platelet-derived growth factor. Altered Cellular Metabolism Even in the presence of ample oxygen, cancer cells demonstrate a    Trggerng ce cyce arrest. p53-medaed ce cyce arres s a pr- distinctive form of cellular metabolism characterized by high lev- morda response o DNA damage (Fg. 5.19). I occurs ae n e els of glucose uptake and increased conversion of glucose to lactose G pase and s caused many by p53-dependen expresson o e 1 (fermentation) via the glycolytic pathway. CDKI p21 By nbng cycn D–CDK4 compexes, p21 prevens hs penomenon, caed e Warburg efect and aso known as RB pospor yaon and ereby arress ces n e G pase. hs 1 aerobc gycoyss, s a caracersc o many rapdy proerang ces, pause n ce cycng provdes me o repar DNA damage (p53 aso ncudng ea ssue, acvaed ympocyes, and umor ces. he “gu- nduces e expresson o DNA damage repar genes). I DNA dam- cose unger” o umors s used o vsuaze umors va posron ems- age s repared successuy, e ce s aowed o proceed roug son omograpy (PET) scannng, n wc paens are njeced w e ce cyce. 18 F-luorodeoxygucose, a gucose dervave a s preerenay aken    Inducng ceuar senescence. I e DNA damage canno be repared, up no umor ces (as we as norma, acvey dvdng ssues suc as ces w acve p53 may undergo senescence, a orm o perma- e bone marrow). Mos umors are PET-posve, and rapdy growng nen ce cyce arres. he mecansms o senescence are uncear bu ones are markedy so. seem o nvove p21 and epgenec canges a permaneny aer Wy do cancer ces rey on neicen gycoyss (wc generaes e expresson o genes a are requred or grow. wo moecues o ATP per moecue o gucose) nsead o oxdave    Kng stressed ces troug apoptoss. p53 nduces apoposs o ces pospor yaon (wc generaes up o 36 moecues o ATP per mo- w rreversbe DNA damage by upreguang severa proapop- ecue o gucose)? he answer s a aerobc gycoyss provdes rapdy oc genes. 78 CHAPTER 5 Neoplasia Ionizing radiation Carcinogens Mutagens Nor mal cell Cell with (p53 nor mal) mutations or loss of p53 Oncogenic Stress Hypoxia DNA damage DNA damage p53 accumulates and p53-dependent genes binds to DNA not activated No DNA No cell repair, no Transcription dependent and cycle arrest senescence independent effects on targets Mutant cells Expansion p21 GADD45 and Senescence (CDK inhibitor) (DNA repair) additional BAX mutations (apoptosis gene) G1 arrest Successful repair Repair fails Nor mal cells Apoptosis Malignant tumor Fig. 5.19 The role of p53 in maintaining the integrity of the genome. Activation of normal p53 by DNA-dam- aging agents or by hypoxia leads to cell cycle arrest in G and induction of DNA repair, by transcriptional 1 upregulation of the cyclin-dependent kinase inhibitor CDKN1A (p21) and the GADD45 genes. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair fails, p53 triggers either apoptosis or senescence. In cells with loss or mutations of TP53, DNA damage does not induce cell cycle arrest or DNA repair, and genetically damaged cells proliferate, giving rise eventually to malignant neoplasms. dvdng umor ces w meaboc nermedaes a are needed or Beyond e Warburg efec, wo oer nks beween meabosm e syness o ceuar componens, wereas mocondra oxdave and cancer are suiceny mporan o mer bre menon: auop- pospor yaon does no. Durng oxdave pospor yaon, a moe- ag y and “oncomeabosm. ” cue o gucose combnes w O o produce H O and CO , wc s    Autopag y s a sae o severe nuren decency n wc ces can- 2 2 2 os roug respraon. hs yeds abundan ATP, bu  does no yed nbaze er own organees, proens, and membranes o sur vve any o e carbon moees needed o bud e ceuar componens or (see Caper 1). Tumor ces oten grow under margna envron- grow (proens, pds, and nucec acds). In conras, aerobc gyco- mena condons wou rggerng auopag y, suggesng a yss yeds meaboc nermedaes a are useu as ceuar budng e paways a nduce auopag y are deranged. In keepng w bocks. s, severa genes a promoe auopag y are umor suppressors. Metabolic reprogramming is produced by signaling cascades    Oncometabosm. A surprsng group o oncogenc aeraons downstream of growth factor receptors, the same pathways that seen n ceran neopasms consss o muaons n enzymes a are deregulated by mutations in oncogenes and tumor suppressor parcpae n e Krebs c yce. S ome o ese muaons ead o genes in cancers. e oss o enzyme uncon, wereas n oer cases e afeced In c ancer ce s,  s reprog rammng p ersss b e c aus e o  e enzymes acqure new acves aogeer and generae producs ac  ons o mu ae d oncoproens and  e oss o umor suppress or a ave been caed oncomeaboes. In eac nsance,  appears  unc  on. S e vera  mp or  an p ons o cross a  k b e we en prog row  a e ne efec o e muaons s o cause canges n meab- sg na ng ac ors and