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NEOPLASMA 2

(KARSINOGENESIS)

Mata Kuliah :

Basic Mechanism of Disease

Prof. Dr. Syarifuddin Wahid, PhD, SpPA, DFM

Bagian Patologi Anatomi

Fak. Kedokteran Univ. Hasanuddin.

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.

.

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TEORI ASAL NEOPLASIA

tumor

Monoclonal PolyclonalOrigin Origin

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.

.

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Kecepatan Pertumbuhan

Karsinoma LambungJml Sel

10 10cm

0,2cm

10

2 0 !0 P"

1#!t$ 1!#21t$ 1,%#&t$

6

12

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"ou'ling Time o( )uman *a+tric

arcinoma In -io /ulturState of No o( Doubling Re(.

Cancer a+e+ Time

Early 1% 2#yr+ aai,

o$li

Meta+ta+e+ 0,3#2mo 4u5ita,

o$li

A6ance6 ! 2#10mo o$li

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Pemberian awal (Initiator)

karsinogen kimia hidrokarbon

polisiklik pada kulit mencit

Pemberian selanjutnya

(promoter) roton oil. Kankerkulit

.

Pemberian

roton oil

saja

!idak timbul

kanker

Pemberian hidrokarbon polisiklik

dosis tinggi tanpa disusul promoter

(inisiator dapat berperan sebagai

promoter)

Kanker

kulit

L"# !I$% !%&'"I*" K"K%&

.

.

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T

+erangan I

,irus %pstein

-arr (initiasi)In.eksi malaria

(promoter)

Limposit -

+erangan II

,irus %pstein -arr

!ranslokasi /01

"ktipnya onkogen

mycdan salah satu

jenis imunoglobulin

T

TT

T

-urkitt3s lymphoma+el immortal

Proli.erasi sel

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Normal Cell DNA damage

DNA repair No DNA repair

Permanent DNA damage

Mutation in the genome o

!omati" "ells

#nvironmental agents

$Chemi"als%radiation%

viruses&

A"tivation o gro'th(

promoting on"ogenes

)umor suppressor

genesAlteration in gene

*egulate apoptosis

De"reased apoptosisUnregulated "ell prolieration

NEOPLASM

%"!4

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5nkogen

5nkoprotein

1

2

7

Growth factor

Receptor

Growth factor

Signal

" +*!4%+I+

+%L8 +!I$9L"!I5 58 %5PL"+!I %LL P&5LI8%&"!I5

$%I"!% -* 55P&5!%I+:

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Sel Normal $utasi Sel an7er8Muta+i 9 Nonlet$al genetic (")

damage:

8Muta+i 6icega$melalui me7ani+me

;" &epair

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Sel Normal $utasi Sel an7er8Tumor 9 monoclonal origin

8Perlu le'i$ 6ari +atu muta+iuntu7

men5a6i +el 7an7er ar+inogene+i+9

multistep process/leel gen 6an

:enoti:e.

8isebabkanole$ :a:aran

7ar+inogen 7imia atau ra6ia+i 6an

in(e7+i iru+.

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+I8"! +%L K"K%&

/A7i'at mutasi bertahap 8Se6ia7an +en6iri;growth signalygou+ /Normal

muta+i I Rrb $etero>ygou+/N? M

muta+i II

$omo>ygou+;lo++ o(rb rb $etero>ygo+ity

/&etinoblastoma)

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A6enomatou+ Poly:o+i+ oli

("#C!*ene.AP a:c la$ir 6gn ri'uan adeno>

matous polyps6i 7olon

$utasi

a:c a:c adenoma/tumor 5ina7

$utasia:c a:c@ colonic cancers/t.gana+

"P " A "!4%I

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"P " A>"!4%I

No Proliferation Proliferation Proliferation

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TP53#ene (dulu P53)

;stress

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%=ation o. "poptosis8D%" repairgagal sel dieksekusi mati

(apoptosis) ti6a7 ter5a6i muta+i.

8E7+e7u+i +u6a$ 6i:utu+7anole$ TP%teta:i ;algojo< tak mampu melakukan

tugasnya (e=ation):

8)u7uman mati gagal +el 6enganD%"

&amagemito+i+ cikal bakal sel kanker:

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e=elopment o. sustained

angiogensis8Proli(er+i +el mem'entu7 5aringan

tumor memerlu7an ma7anan;O2/memerlukan =askularissi)

8)anya +el tumor yang 6a:at memicu

ter'entu7nya :.6ara$ 'aru

(angiogenesis) dapat berkembang

dan metastases

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"ngiogenesis by !umor ells:

!umor cells

ot$er cell+

Angiogenic (act. Antiangiogenic (act"ngiogenesis

-a+culari>ation En6ot$elial cell+

Nutrient+;O2 grot$ (actor+

proli.eration o. tumor cells

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"ngiogenesis by !umor ells:

!umor cells normal cell+

Angiogenic (act. Antiangiogenic (act"ngiogenesis

-a+culari>ation En6ot$elial cell+

Nutrient+;O2 grot$ (actor+

proli.eration o. tumor cells

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A'ility to Ina6e an6 Meta+ta+e+

E7+tracellular Matri /EM

Bcollagen+, glyco:rotein+ ? :roteoglycan+C

Inter+titiel connectie ti++ue /

'a+ement mem'ran+

/

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Pro+e+ in=asi sel tumor7e 6alam

EM ! +te:+91. Sel tumor mele:a+7an 6iri6ari +el

tumor 6i6e7atnya (loosening of

intracellular 'unctions!.

2. Sel tumor tertanam 6alam 7om:onen

matri7+(attachment!

. EM 6iru+a7/&egra&ation!

!. Sel tumor 'ermigra+i(migration!

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I,"+I dan $%!"+!"+%+In=asi 9 Sel Tumor tem'u+ mem#

'rana 'a+ali+ masuk ke %$:

$etastases9 Sel Tumor +elan5utnya6ari EM menem'u+ 6in6ing

:em'ulu$ lim:e kelenjar limpe,

atau menem'u+ :.6ara$ organlain (hati paru dan otak):

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*enomic In+ta'ility Malignancy

8D%" &amage+etia: +aat 'i+a ter5a6i

(dampak lingkungan):

8D%" &amage muta+i gen+elama

D%" repair'e7er5a 'ai7 (+tabil):

8D%" &amage muta+i gen5i7a

D%" repairgagal (!idak +tabil)

8D%" repairgagal5i7a ter5a6i mutasi

gen pengkode peotein DNA Repair:

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)ere6itary Non:oly:o+i+

olonar+inoma /)NPMi++matc$ re:air gene+

In$erite6 mutation

AcDuire6 mutation

"llowi

Mutation o( T*4#= ? =A gene+

)NP

Permanent" damage

o apoptosis

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In$erite6 Mutation o( "NA

Re:air *ene+ an6 ancer Ri+7In$erite6 Mutation ancer Ri+7

o( "NA Re:air *ene+

"NA mi+matc$ re:air )NP

Nucleoti6 eci+ion S7in ancer

re:air.

=RA1 ? =RA2 =rea+t a.

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Mole7ular =a+i+ o( Multi+te:

ar+inogene+i+

Neo:la+mahasil darimultiple mutations.

8Stu6i e:i6emiologi9 age associate&increase& in cancers

8Tia: :eru'a$an +el /muta+i mela$ir7an

)crucial steps*:rogre+ +el normalmen5a6i +el 7an7er.

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Aenoma of increasin! si"e an

e!ree of #s$lasia

%#$er$roli$erati&e

e$itheli'mIn&asi&e carcinoma

P m'tation

An*or LO%

D+ LO%, LO% of

Other Genes on -./K0ras m'tationAP+ m'tation

DNA meth#lation

a1normalities

Mismatch re$air a1normallities

GASROINESINAL +AN+ER, 23345

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!umor progression and

4eterogenity8Falau:un aalnya$onoclonalteta:i

6alam :er7em'angnya (tumor progression)

+el#+el tumor men5a6i 'er'e6a +atu 6enganyang lain(heterogenity):

8"iantara 5eni+2 muta+i gen yang 6a:at

ter5a6i :a6a 7ar+inogene+i+, urutan muta+iti6a7 +ama :a6a +emua +el sel tumor

heterogen:

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4eterogenitas +el !umor

1. onantigenik?Ti6a7 memili7i antigen6i :ermu7aannya lolo+ 6ari re+:on imun

tu'u$(negative selection!

2. In=asi=e9 Mam:u ina+i. $etastatic9 Mam:u meta+ta+i+

!. Kebutuhan;growth .actor

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transformation

$ro!ression

Proliferation

of !eneticall#

6nsta1le cells

'mor cells

&ariants

hetero!eneit#

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Karyotypic hange in !umors

eru+a7an gen /muta+i 6a:at terli$at

/nyata atau $alu+ :a6a karyotype.

/ara7teri+ti77$romo+om:a6a+elatauin6ii6u.

elainan 'eru:a balanced

translocation deletions6an gene

ampli.ications:

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-alanced !ranslocation

*en 'ertu7aran tem:at 6engan gen lain6ari Chromosome /$ yang 'er'e6a9

1. Tran+lo7a+i$. 226an G

(#hila&elphia Ch!Chronic Myeloenous !eucemia.

2. Tran+lo7a+i $ & 6an 1!

"urkitt lymphoma

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"eletion

/+e'agianchromosome$ilang1. "eletion o( c$ 1D1!9

&etinoblastoma

2. "eletion o( c$ 1H:, %D, 1&D9

olorectal ancers:

. "eletion o( c$. :9

Small ell Lung arcinoma

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*ene Am:li(ication

aryoty:ing9

8)omogenou+#Staining Region /)SR

8"ou'le Minute+

Am:li(ication o( %+$,C gene

:a6a $. 2:9

Neuro'la+toma

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4%$I"L "&I5#%+8 Sangat 'eraria+i /natural atau +inteti78 A6a yang 'e7er5a lang+ung (&irect acting!

a6a yang :erlu 6i meta'oli+me 6ulu 'aru

a7ti: +e'agai 7ar+inogen (In&irect acting!8 Direct acting carsinogen ele7tro:ili7

yang +angat rea7ti( 'erea7+i 6engan atomyang 7aya ele7tron :a6a "NA, RNA, 6an

:rotein +eluler

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4%$I"L "&I5#%+

8 E(e7 7ar+inogen +e5umla$ 'a$an

7imia 6i:er$e'at ole$ 'a$an 7imia lain

yang +e'enarnya ti6a7 memili7i e(e77ar+inogen (promoters!

8 =e'era:a 7ar+inogen 7imia 'e7er5a

'er+ama 6enga 7ar+inogen lain /iru+atau ra6ia+i.

Pemberian awal (Initiator)

karsinogen kimia hidrokarbon

L"# !I$% !%&'"I*" K"K%&

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karsinogen kimia hidrokarbon

polisiklik pada kulit mencit

Pemberian selanjutnya

(promoter) roton oil

. Kanker

kulit

.

Pemberian

roton oil

saja

!idak timbul

kanker

Pemberian hidrokarbon polisiklik

dosis tinggi tanpa disusul promoter

(inisiator dapat berperan sebagai

promoter)

Kanker

kulit

.

.

Karsinogen kimia masuk tubuh

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g

A7ti:a+i meta'oli7 6alam tu'u$

Interme6iat ele7tro:ili7

Mengi7at 7e "NA +el

Kerusakan "

Per'ai7an "NA 'er$a+il

+el ormal

Per'ai7an "NA *agal

A::o:to+i+ 'er$a+il

+el $ati

A:o:to+i+ *agal

eolasma

Kerusakan permanen "

(mutasi)

Proli(era+i

I

I!

"

+

I

P

&

5$

5

+

I

)e:ato+it Normal

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D%" &amage(lesi biokimiawi) D%" repair

Paparan karsinogen

Initiate& hepatocyte(8iksasi lesi biokimiawi)

Promoter

No6ul $i:er:la+ti7 ar+inoma )e:ato+eluler

Promoter

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7IRAL +AR+INOGEN7IRAL +AR+INOGEN

! #%%+

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%LL !&"+85&$"!I5%LL KILLI#

%LL %"!4 !&"885&$% %LL

55#%I

" ,I&9+

I8%!% %LL

9L%"& "

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,>onc

,>onc

#onc

,>onc

#onc

Integration

Integrated =iral oncogene

%5PL"+!I %LL

Trans#ormation

$n#ection

" =irus

4ost ell

4ost ell "cti=ated =iral oncogene

55#%I " ,I&9+

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,>prom

#onc

>onc

Integration

Integrated =iral promoter gene

(&" transcript " transcript)

%5PL"+!I %LL

Trans#ormation

$n#ection

&" =irus

4ost ell

4ost ell "cti=ated cellular oncogene

,>prom

,>prom

(&" transcript)

%n@yme re=erse

transcriptase

+L5B !&"+85&$I# 55#%I ,I&9+ &"

&" =irus "9!% !&"+85&$I#

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>onc

>onc

#onc

>onc

#onc

$nteration

$nterate% cellular oncoene

(&" transcript " transcript)

%5PL"+!I %LL

Trans#ormation

$n#ection

&" =irus

2nd4ost ell

2nd4ost ell Acti&ate% &iral oncoene

>onc

Trans%uction

1st

4ost ell

Incorporated >onc

into =iral genome

&" !ranscript

En>yme reer+e

tran+cri:ta+e

55#%I &" ,I&9+

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6MOR IMM6NOLOG86MOR IMM6NOLOG8

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+el !umor