-270-

:7 Neoplasia -

2,000 ,
." , ,
. , -
. , , . ,
,America Cancer Sodiety 556,000 2003 , 1,500
, 23% " .
, . , ,
.
, ( ,)tumor ( .)cancer
, ,
( .)carcinogenesis , , .
, ,
, ,
.

-Neoplasia .

-Neoplasm .

-Tumor . ) (neoplasm
. ).(neoplasm

)( -(Oncology :=) . .

) -(Cancer . ,
-crab ,
-.

" " , .
" : ,

" . , ,
.
( ) ,
. , ,
(.)clonal

:
, , :
. .
.

 ,
, . ,
. ,
. , ,
. -
( .)desmoplasia , - - (.)scirrhous
, .
)(benign tumors
, oma - .
. , ,
. ,
. , ,
.
) (Adenoma
. ,
,
. + -
( )papillomas -7-1 ,
(.)cystadenomas

-7-1 ( " ,' ,

).

-271-

 -7-2 A . () , -B .
.

) .(papillary cystadenomas , , ( - ,
) (polyp -7-2 ) - .
.polypoid cancers
)(Malignant tumor
, .\
( -=)
( . - , , - ,-
) . - -
( .)carcinomas , ,
.
) (adenocarcinoma
) . (squamous cell carcinoma ( -
) . ,
, ( ).
, ,
. , ,
( . )mixed tumor .
-7--
.3 . ,
( .)pleomorphic adenoma ,
. ( )teratomas
, , . ,
. .

 , - , , ,
- . ( ovarian
(cystic teratoma ,
, ( . )7-4

-7-3 , ,
( . " , ,).
-272 .7-1 ,
, . , ,
- . ( )
. -
.
) -(choristoma -
. , -
.

- ) (hamartoma , , ,
. .
, , ,
. , .
,
. ,
. , .,
. ,
.
, .

 -A 7-4 . , .
-B , , .

: .
4:
. .
.

.
- ,
, , . , ,
. ,
. ,
. ,an .
. innocent face may mask an ugly nature ,
.
() )(anaplasia

,
-.

( . )7-5 ,
. , ( .)7-6
- - ,
.
.one may get so close to the tree that one loses sight of the forest .

-273-

-7-1

Fibrosarcoma

Fibroma

Lipoma

Liposarcoma

Chondrosarcoma

Chondroma

Osteogenic sarcoma

Osteoma

Hemangioma

Lymphangiosarcoma Lymphangioma

Angiosarcoma

Mesothelioma

Synovial sarcoma

Invasive meningioma

Meningioma

Lymphomas

Leukemias

Leiomyosarcoma

Leiomyoma

Rhabdomyosarcoma

Rhabdomyoma

Squamous cell or epidermoid
carcinoma

Squamous cell papilloma

) (

Basal cell carcinoma

Adenocarcinoma

Adenoma

Papillary carcinomas

Papilloma

Cystadenocarcinoma

Cystadenoma

Bronchogenic carcinoma

Bronchial adenoma

Renal cell carcinoma

Renal tubular adenoma

Hepatocellular carcinoma

Liver cell adenoma

Transitional cell papilloma

) (

Hydatidiform mole

cell carcinoma

(transitional)

Choriocarcinoma

) (

Seminoma
Embryonal carcinoma
Malignant melanoma

Nevus

 -7-1

,
(,)mixed tumor
"

Pleomorphic adenoma
(mixed tumor of salivary
)origin

)(renal anlage

Malignant mixed tumor of salivary

gland origin
Wilms tumor

,
-
)(Teratogenous

Mature teratoma, dermoid

cyst

Immature teratoma, teratocarcinoma

, , .
. = , .
,to form backward . ,
,
. ( )7-7
,
.
:

( -(Pleomorphism - (
.)7-8 ,
.
-274-

- , DNA -
. , -
1:1 1:4 - .1:6 ,
" .

- , ,
, .
, .
" rapid turnover ,

- - ,
( . )7-9

- ,
( ) . .

- (, )tumor giant cells

, .

 ,
. , .
,
-275 ,
.

-5-7 ) (leiomyoma . ,
, .

-6-7 () . ( ) colloid filled yhyroid

( .follicles " ," ,).

 -7-7 () .
( ,)6-7
. .
( . " ," ,).

-8-7 () . ,
( . " ," ,).

 -9-7 .
.

-10-7 , .
, ( -)keratin pearls( . " ,
" ,).
, .
, .
, , ,
( .)10-7 ,
, . "
.moderated well differentiated
, ,dysplasia
. ,
.

-A 7-11 . .
. -
-B . .A , ,

 .
.

- ,
. ,
. ,
. , ,
.
. ,
( )surface
.
, , preinvasive neoplasm
( .)7-11
( . )invasive ,
( ,)Barrett esophagus
" .
276

, .
, , .
, ,
. ,
. ,
.
, . ,
, . ,
. ()
. ,
( .)ectopic hormones , ,
, . ,
, .
. ,
.

,
. " :
.
( 10)
30 10 9 ( 1) , .
, 10 10 12 ( 1") , "
( .)7-12

 . " " . ,
: ,
. , ,
.
: ,
( ,)replicative pool .

The rate of growth of a tumor is determined by three main factors: the doubling time
of tumor cells, the fraction of tumor cells that are in the replicative pool, and the rate
at which cells are shed and lost in the growing lesion.
,
. , ,
. ,
. , .
, ) .(growth fraction
, , ,
( .)7-13 ,
, .
.G0 G0 .G1 , ,
. , 20% .
.
, , ,
. ,
( , )small cell carcinoma , . ,
, , 10%
>=. .
:

, cell turnover ,
. , ,
.

.
, 5%

. ( ,
) G0 .
.
. . (
)
.

 : ,
10 ?
, 90.
( 30 , , .)7-12 , ()
, ".

277

-7-12 .
. , ,
.
. ,

( . Tannock IF: Biology of tumor growth.
(Hops pract 18:81, 1983
, ,
. ,

 2-3 .
,
. .
, ,
. , .
. ,
. ,
. , ( )
. , ,
. ,
. " .
. .
,
.
.
"" . ,
, .
278

-7-13 . ,
,G0 .

,
, .
, . ,
( )Tumor initiating cells = T-IC
TIC . 2% , 0.1%-1%
. TIC , ,1BMI
p161Nka - ( p14ARF

 ) . ,
.
. , .
,
. , .
.

-7-14 . ,""
.

, ,
() . ,
( ,)fibrous capsule
.
. ( " ) ,
( 7-14
.) 7-15 ,
. , ( ") -
(" ).
, . ,
, ( 7-16 .) 7-17
, , .
,
, .
, ,
. .
, , .
, ( )invasiveness
.
- . "
, , , "
( .)23 .
. ,
-.

 -7-15 .7-14 ( )
( . " ," ,)
279

-7-16 . , "
.
)(Metastasis
() "" .
. ! .
, , . ,
( ) .
, , .
( rodent ulcers ) ,
. , . , ,
.

 -7-17 7-16
" ( .)7-15
( . " ," ,)
, , ,
, . . ,
. ,
. .
.
30% ( - ) .
. ,
, .
:
.1 : .2
. 3 . , ,
. " .
.1

(-)Seeding of Body Cavities and Surfaces

" " ( .)open fieldnatural
( ,)7-18 - ,,
.
, ,
.
. ,
' (. )pseudomyxoma peritonei

.2

( 7-
,)19 . ,
.

.
. "
, .
.internal mammary arteries
280

-7-18 ( . " ,
,)

-7-19 . ()
. -( . " ,"
,).
, . ,
, .
perihilar tracheobronchial and mediastinal
.nodes , skip metastasis - ,
.
,
."

 . , sentinel
,nodes sentinel nodes .
. , .
.
, .

-7-20 .
, , .
, , . ,
, . , "
.1 .2 ( .)14 ,
.

, . , ,
. ,
- . ,
. ,
. , "
( .)7-21 ,7-20 , "" .

 -7-21 . ( "
," ,).
281

-7-22 () ().
,
" .
. " ,
, .
- .
, .
. ,
, , .
-7-2

/ .
.

"
" ,

.
.

-
.

,

.

 -7-2

.

,
.

, 7-2 .7-22
,
.

, -
. , ,
.
282

,
. ,
,
. , ,
. , ,
,"
.

, . ,
" 1 5 . 556,000 ,2003
23% , .
1 , - - ! ,
100,000 .
.7-23
, , . , ,
. 50% ,
".

 -7-23 .
, ( Jamel A et al:
.) CA cancer J Clin 53:5,2003 .cancer statistics,2003
( 100,00)
( .)7-24 . 50 ,
,
. .
, , -
.
. , 2.5 . ,
,
.
!?!?Papanicolaou (Pap) smear -
-
. , 1930-
,1970 30 .
: , , 1990
2000 . , 1.5%
, 0.6% . ,
. " ,
.
" ,
- , , .
, .
, , 0.3% .

283

-7-24 " 2000

( (Jemal A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5, 2003

. ,
7-8 " . ,
2" , , .
6 ,
. ,
.
" " "
. 7-25
, .
- . :
, , .
UV . , 2
, .7-3
( ) . , " ( 52%
) ( 62% ) .

284

-7-25 "
.
.
. 1 : .
( Cairns J: The cancer problem. In Readings from Scientific AmericanCancer Biology. New York,
)WH Freeman, 1986, p. 13.
14% , 20% .
,
, . , , , ,,
, , , 90% (
.) 9 " .
.
, .
, .
, , ,
.

.
( 55) . 40 79
60 .79 , 7-4 .7-5
60 .79 80
. ,
. 15

 . 10% "
. 60%
. , , ,
,. .10

" : . ?"
, . ,
, . ,
, 4
( ) , (.
) . 10%
, ( )0.1% . ,
. , "
,
. ( .)7-6

.

.
" - .
" .
. 40% . RB
10,000 ," . ,
, Familial adenomatous polyposis .
. -
adenomatous polyposis coli- APC , ,
50% 100% .
285

TABLE 7-3 -- Occupational Cancers

Human Cancer Site
for Which
Reasonable Evidence
Is Available

Agents or Groups of
Agents

Byproduct of metal smelting.

Component of alloys, electrical and
semiconductor devices, medications
and herbicides, fungicides, and
animal dips

Lung, skin,
hemangiosarcoma

Arsenic and arsenic

compounds

Formerly used for many applications

because of fire, heat, and friction
resistance; still found in existing
construction as well as fire-resistant
textiles, friction materials (i.e., brake
linings), underlayment and roofing

;Lung, mesothelioma
gastrointestinal tract
(esophagus, stomach,
)large intestine

Asbestos

Typical Use or Occurrence

TABLE 7-3 -- Occupational Cancers

Agents or Groups of
Agents

Human Cancer Site

for Which
Reasonable Evidence
Is Available

Typical Use or Occurrence

papers, and floor tiles

Benzene

Leukemia, Hodgkin
lymphoma

Principal component of light oil.

Although use as solvent is
discouraged, many applications exist
in printing and lithography, paint,
rubber, dry cleaning, adhesives and
coatings, and detergents. Formerly
widely used as solvent and fumigant

Beryllium and
Lung
beryllium compounds

Missile fuel and space vehicles.

Hardener for lightweight metal
alloys, particularly in aerospace
applications and nuclear reactors

Cadmium and
cadmium compounds

Prostate

Uses include yellow pigments and

phosphors. Found in solders. Used
in batteries and as alloy and in
mental platings and coatings

Chromium
compounds

Lung

Component of metal alloys, paints,

pigments, and preservatives

Ethylene oxide

Leukemia

Ripening agent for fruits and nuts.

Used in rocket propellant and
chemical synthesis, in fumigants for
foodstuffs and textiles, and in
sterilants for hospital equipment

Nickel compounds

Nose, lung

Nickel plating. Component of

ferrous alloys, ceramics, and
batteries. Byproduct of stainless
steel arc welding

Radon and its decay

products

Lung

From decay of minerals containing

uranium. Can be serious hazard in
quarries and underground mines

Vinyl chloride

Angiosarcoma, liver

Refrigerant. Monomer for vinyl

polymers. Adhesive for plastics.
Formerly inert aerosol propellant in
pressurized containers

Modified from Stellman JM, Stellman SD: Cancer and workplace. CA Cancer J Clin
46:70, 1996.

 - ,
multiple endocrine neoplasia types 1 and 2 (MEN-1 and MEN-2), , P53 hereditary -HNPCC
-nonpolyposis colon cancer .mismatch repair gene
:

, ( ).
, MEN-2 RET , .
.

, ,
, .MEN ,
(Lisch nodules and caf-au-lait spots -
-1 .)5

, , .

DNA ()Defective DNA Repair Syndromes.

- ,
DNA .DNA
. ,ataxiatelangectasia -
, .
) -hereditary nonpolypoid colon cancer (HNPCC
HNPCC .DNA nisnatch repair
, ,
( .)17

,
. ,
, . - , , , .
286

TABLE 7-4 -- Reported Deaths for the Five Leading Cancer Types for Males by Age,
US, 2000
Age 80+
All cancers
70,883
Lung and
bronchus
16,626
Prostate
15,630
Colon and

Age 6070
All cancers
158,990
Lung and
bronchus
57,470
Colon and
rectum

Age 4059
All cancers
50,069
Lung and
bronchus

All cancers
4832
Brain and
* ONS

15,827
Colon and
rectum

15,420
Prostate

Age 2039

Leukemia

Pancreas

1298

430
Brain and
* ONS

611
Lung and

All cancers All cancers

Leukemia

626

4801

Under Age
20

All Ages

307
Bones and

286,082
Lung and
bronchus
90,415
Prostate
31,078
Colon and

TABLE 7-4 -- Reported Deaths for the Five Leading Cancer Types for Males by Age,
US, 2000
Age 80+

Age 6070

Age 4059

rectum

Age 2039
bronchus

7821
Urinary
Bladder

14,428
Pancreas

3222
Leukemia

3187

2929
Esophagus

8179

2345

Liver Non-Hodgkin
lymphoma
6107

joints
481

rectum
105

Endocrine Non-Hodgkin
system
lymphoma
444
Colon and
rectum

2308

Under Age
All Ages
20
28,484
Pancreas

104
NonHodgkin
lymphoma

431

14,238
NonHodgkin
lymphoma

79

11,812

"All Cancers" excludes in situ carcinomas except urinary bladder.

Source: US Mortality Public Use Data Tape, 2000, National Center for Health
Statistics, Centers for Disease Control and Prevention, Hyattsville, MD 2002.
*ONS = other nervous system.
,
, . .
, familial adenomatous polyp syndrome
. . , 2-3
. " ,
. ,
. 10%-20%
. -
BRCA1 BRCA2 , 3% . ,
. ,
, . ,
. p16INK4a - , 20% ,
.

? ,
.
.
.
, . ,
BRCA1 BRCA2 3 ,1940
. , .
() - (
" ") .
.P450 - " " ,
P450 . .


. ...
, .
. ,,
.
,
( .)22
.
287

TABLE 7-5 -- Reported Deaths for the Five Leading Cancer Types for Females by
Age, US, 2000
Age 80+

Age 6070

Age 4059

Age 2039

All cancers

All cancers

All cancers

All cancers

131,871

80,697

Lung and
bronchus

Lung and
bronchus
14,693

39,311

Colon and
rectum

Breast

12,379
Breast

11,937

17,842

10,648

Colon and
rectum

Pancreas
7825

5319
Ovary

4039

3033

1871

973

Uterine
cervix
538
Leukemia
452

302

Brain and
* ONS
354

65,016
Breast

238
Endocrine
system

41,872
Colon and
rectum

82
Bones and
joints

397

267,009
Lung and
bronchus

Brain and
* ONS

Lung and
bronchus

Pancreas

7217

1444

3619
Ovary

All cancers All cancers

Leukemia

10,613

12,612

Pancreas

Breast

Lung and
bronchus

Colon and
rectum

NonHodgkin
lymphoma

47,850
Breast

5617

Under Age
20

All Ages

28,950
Pancreas

76
Soft tissue

15,094
Ovary

69

14,060

"All Cancers" excludes in situ carcinomas except urinary bladder.

Source: US Mortality Public Use Data Tape, 2000, National Center for Health
Statistics, Centers for Disease Control and Prevention, Hyattsville, MD, 2002.
*ONS = other nervous system.
80% - , ( .)18

1863 , .
.

TABLE 7-6 -- Inherited Predisposition to Cancer

Inherited Cancer Syndromes (Autosomal Dominant)
Gene

Inherited Predisposition

RB

Retinoblastoma

p53

Li-Fraumeni syndrome (various tumors)

p16INK4A

Melanoma

APC

Familial adenomatous polyposis/colon cancer

NF1, NF2

Neurofibromatosis 1 and 2

BRCA1, BRCA2

Breast and ovarian tumors

MEN1, RET

Multiple endocrine neoplasia 1 and 2

MSH2, MLH1, MSH6

Hereditary nonpolyposis colon cancer

PATCH

Nevoid basal cell carcinoma syndrome

Familial Cancers
Familial clustering of cases, but role of inherited predisposition not clear for each
individual
Breast cancer
Ovarian cancer
Pancreatic cancer
Inherited Autosomal Recessive Syndromes of Defective DNA Repair
Xeroderma pigmentosum
Ataxia-telangiectasia
Bloom syndrome
Fanconi

anemia

,Helicobacter pylori gastritis ,ulcerative colitis ,

. .
, .
. ,
reactive oxygen species-ROS
, . .
) 12 (COX2 cyclooxigenase-2

 . COX2
.

-
the chronic atrophic gastritis of pernicious anemia, solar keratosis of the -
skin, chronic ulcerative colitis, and leukoplakia of the oral cavity, vulva, and penis
.
. , .
- . ,
, 50% . :
? ,
. , , ,
. longstanding pleomorphic adenomas
.
288

,
: , , ,
?

, .
.

. ()
, , . ""
.
, , .
().

(
) . X linked,
6 ) ,(G6PD-2- .
.7-26

) .(HUMARA HUMARA ,90%
.
, ,
. TCR
B .T

4 - ,
, .DNA


. ,
. . ,
,
. .haploinsufficiency
,
.

DNA
, ,
. DNA
.
. mutator phenotype ,
DNA . , DNA
.

.
, , .
, . tumor progression ,
.DNA
289

 -7-26 x-linked isoenzyme cell markers

. ,X ( G6PD
A B ) . X linked ,
X .
.
" ,
. .,
p53 . , c-ABL .
, .
.
(.
. ).

: ,"
.

:
) ,transforming growth facror B (TGF-B
.cyclin dependent kinases

:
p53 .

: DNA DNA
.

: ,
.

: , ,
vascular endothelial growth factor (VEGF).

: ,
.

. ,
, .
DNA . "
DNA ,
.
.7-27
,
.
.
.

,3 G0 G1

( .)3-3
) ,(CDK CDK .
CDK .
.
. CDK ,
.CDK , ( .)7-28 15 .
E D A B .CDK
D RB
,D , G1 S
( .)7-28 3 ,D D1 D2 D3 ,
.D ,D , - ( .)1 G1
, D ,CDK4 ( CDK4 -D .)7-29

 - - . RB on off
. RB ,
E2F( .E2F ) . RB
.E2F , RB
, .
RB , ( G0 ,.)G1 E2F
.DP1 " promoters of E2F-responsive genes
, RB - ,
( 7-29 .)7-30 ,
D E , CDK4 D CDK2 -E
G1 S RB .RB ,
E2F .S DNA ,E , ,
, . M RB ,
.RB

 , 7' - 290-309
' 290

: 7-27

G1/S
S- DNA Replication -
( Cyclin E-CDK2 .)7-29 E2F - Cyclin E
Polymerases ,DNA Replication -" .DNA-
.G2/M
" E2F- ,Cyclin A ,Cyclin A-CDK2-
.

 7-28 )Cyclin-CDK (Cyclin Dependent Kinase .

.

( )Mediator ,Cyclin B-CDK1 -

" ) Protein Phosphatase (Cdc 25 . -
Cyclin B- CDK1 .
CDKs - ( Cyclins A A1 :Cyclin A ,A2- A2
) Cyclins B- ,G2/M :
,Microtubules - Centrosomes - .
.Cyclin B-CDK-1" G1-
, .
, Cyclin E-CDK2
" .Cyclin A2-CDK1 , Cyclin E
( E1 )E2- .

Cyclin-CDK " , .CDK Inhibitors
:CDK Inhibitors
Cip/Kip Family
.1
INK4/ARF
.2
(" 7-29 )7-7

Tumor Suppressors - ( ).

' 291

7-29 ,Cyclins - CDKs - CDK Inhibitors - G1/S

. ,Signal Transduction MYC--
,RAS ( Cyclin D Cyclins ,D , ,
" Cyclin D .)"Cyclin D ,CDK4 - ( Cyclin D ,CDK6 -
.)CDK4 Cyclin D-CDK4 RB -
E2F/DP1/RB ," E2F( E2F ,
,Transcription Factors ,)"E2F",- Cyclin A ,Cyclin E
.G1 - " p21 :Cip/Kip Inhibitors -p27 -
( ?!) " p16INK4A :INK4A/ARF Inhibitors -( p14ARF - ?!) . ,
DNA- , .p53 p53 - " ,MDM2
" .p14ARF

 7-30 " .RB RB , ,E2F/DP1/RB -

" ,Histone Deacetylase "
. RB" Cyclin D-CDK4 Histone Deacetylase - ,"
RB( E2F " .)Cyclin E-CDK2 E2F
Cyclins E Cyclins A - DNA Replication -
. G1

' 292
7-7


)Cyclin-Dependent Kinases( CDK
CDK4
,Cyclin D RB"
.G1
CDK2
Cyclin E ,G1 - .G1/S - ,
Cyclin A ,S- .G2/M
CDK1
Cyclin B .G2/M

Cip/Kip Family: p21, p27

" p21 .Cyclin-CDK Tumor -
p27 .p53 Suppressor Growth Suppressors - .Transforming Growth Factor
p16INK4A INK4/ARF Family: p16INK4A, Cyclin D-CDK4 .RB
p14ARF
p14ARF p53" .MDM2
Checkpoint
p53
, Tumor Suppressor ,
. p21 "
- .BAX p53
MDM2 P53 . G1/S
.G2/M
Telangiectasia Mutated Ataxia " DNA-
)(ATM
. p53 G1/S G2/M
p53 - ,Cdc25 Phosphatase
.Cyclin B-CDK1 , ,
BRCA1 ,BRCA2 - DNA- .

 Cip/Kip - p21, p27 : ,p57 -

Cyclins CDKs . p21
,p53 Tumor Supressor . p53

, .
1INK4a/2ARF - p16INK4a ,p14ARF -
P16INK4a .Tumor Suppressors - Cyclin D -
CDK4 Cyclin D-CDK4 ,RB"
.G1 , P16INK4a , "
- ( ) . INK4a - ( p14ARF ,)p19ARF
p14ARF .p53 (?) INK4a -
(.)providing for an "economical" way to utilize gene-coding sequences
p16INK4a p14ARF , p16INK4a :
,Cyclin D-CDK4 p14ARF - .p53
(")"Checkpoints
, ' ' .
: G1/S - .G2/M -
S- ' -' , , G1/S -
DNA- . ,DNA- DNA-
. .DNA -
DNA - , . , G1/S
,DNA-
. DNA ,
.
G2/M - DNA-
.
. " G2/M .G2 -
.
, ,)Sensors( DNA
( )Signal Transducers . DNA
. RAD
)Ataxia Telangiectasia Mutated( ATM .CHK Kinase -
. G1/S -
" ,p53 .p21
G2/M .p53 -
.
, .

.
:
,
.
. "
.

INK4A Inhibitor of Kinase 4 (Alternative?).

ARF Alternative Reading Frame.

1
2

' 293
,Oncoproteins
, Oncoproteins .
Growth Factors - .
Oncoproteins - ,
. , :
.1 Growth Factor , .
.2 , Signal Transduction
.
.3 , ( )Second Messengers "
Signal Transduction .
.4 .DNA
.5 , .
, -
. Cascade - Signal
Transduction .Growth Factors - ,
.
, Oncoproteins -
, .
"" "" Acute Transforming Retroviruses"
1989- .-
.
( )Unique Transforming Sequences
( )v-onc - .
, v-onc -
DNA . , , , "
DNA- , .
, .
v-onc " , . ,v- -
onc Feline Sarcome - ,v-FES Simian Sarcoma -
.v-SIS- FES ,SIS ,
."v-"-
RNA .
, , .
- .
" Proviral DNA - -.
Proviral ,"
( c-onc .)onc - Insertional
.Mutagenesis , - -,
.
- -,
, , "
- . : - DNA
? " DNA Transfection DNA
( .)DNA-Mediated Gene Transfer DNA
( )Transfected Fibroblasts ,
. DNA :

 .
.RAS-- v-oncs
Harvey (H) -. Kirsten (K) -
- 20 , .-
.
" - , Growth Factor Ligands or Receptors -
Transcription Factors ,Signal Transduction ( .)7-31
Oncoproteins "
( .)7-8 , Oncoproteins ,
.
,- ( )c-oncs .
)1 : , )2 ?Oncoproteins - -
?
Growth Factors -
"
. ,SIS -Chain - Platelet-Derived ( PDGF-
,)Growth Factor , Astrocytomas -Osteosarcomas -
. , PDGF- ,
. ,
, .
( RAS Signal Transduction)
," , Transforming TGF-
. Growth Factor Epidermal Growth Factor EGF -
" TGF- .EGF Receptor -
Astrocytomas .EGF Receptors

' 294

7-31 .-
, , DNA .

,SIS- Fibroblast Growth ( FGFs

,)Factor HST-1 ,INT-2 - , ,BFGF .
,FGFs - Melanomas - , Melanocytes -Hepatocyte Growth .
Factor c-MET Follicular Carcinomas - ,
Small cell lung carcinomas . bombesin-
)?( like .
,
" . ,
, " .

.
, -
( Tyrosine Kinase .)3
, Kinase - "
, Tyrosine -
Phosphorylation . Signal Transduction -

. , .

" , Gene ,
Rearrangements . ,RET ,Tyrosine Kinase

Glial Cell RET - .Gene Rearrangements -

, Line-Derived Neurotrophic Factor
Parafollicular C ,- RET .
.Parathyroid - , ,
Familial Medullary RET
,MEN 2A - .)24 (MEN 2B - MEN 2A Thyroid Carcinoma
Medullary Thyroid - , RET
,MEN 2B - .Parathyroid - Carcinoma
Tyrosine Kinase - RET
.Parathyroid - ,Adrenal - Thyroid -
295 '
, - 7-8
Mode
Protooncogene Activation

Category

of
Associated Human Tumor

Growth Factors
PDGF- chain

SIS

Overexpression

Astrocytome
Osteosarcoma

Fibroblast growth factors

HST-1

Overexpression

Stomach cancer

INT-2

Amplification

Bladder cancer
Breast cancer
Melanoma

TGF

TGF

Overexpression

Astrocytomas
Hepatocellular carcinomas

HGF

HGF

Overexpression

Thyroid cancer

ERB-B1
(ECFR)

Overexpression

Squamous cell carcinomas of lung, gliomas

ERB-B2

Amplification

Breast and ovarian cancers

FMS

Point mutation

Leukemia

Receptor for neurotrophic RET

factors

Point mutation

Multiple endocrine neoplasia 2A and B,

familial medullary thyroid carcinomas

PDGF receptor

Overexpression

Gliomas

Point mutation

Gastrointestinal stromal tumors and other soft

tissue tumors

K-RAS

Point mutation

Colon, lung, and pancreatic tumors

H-RAS

Point mutation

Bladder and kidney tumors

N-RAS

Point mutation

Melanomas, hematologic malignancies

Translocation

Chronic myeloid leukemia

Growth Factor Receptors

EGF-receptor family

CSF-1 receptor

PDGF-R

Receptor for stem cell KIT

(steel) factor
Proteins Involved
Signal Transduction

in

GTP-binding

Nonreceptor
kinase

tyrosine ABL

Acute lymphoblastic leukemia

RAS signal transduction

BRAF

Point mutation

Melanomas

WNT signal transduction

-catenin

Point mutation

Hepatoblastomas, hepatocellular carcinoma

 - 7-8 ,
of
Associated Human Tumor

Mode
Protooncogene Activation

Category

Overexpression
Regulatory

Nuclear
Proteins

Burkitt lymphoma

Translocation

Transcriptional activators C-MYC

Neuroblastoma, small cell carcinoma of lung

Amplification

N-MYC

Small cell carcinoma of lung

Amplification

L-MYC

Mantle cell lymphoma

Translocation

CYCLIN D

Breast and esophageal cancers

Amplification

Breast cancer

Overexpression

CYCLIN E

Amplification
point mutation

CDK4

Cell-Cycle Regulators

or Glioblastoma, melanoma, sarcoma

Cyclins

Cyclin-dependent kinase

RET ( Hirschsprung ,)17

. , RET--
Somatic
Medullary Carcinomas .Germ Line ,Thyroid - -
Rearrangements ,RET- .MEN 2B -
" .
, c-FMS ,)Colony-Stimulating Factor 1( CSF-1 -
Chronic Myelomonocytic
( .)Myeloid Luekemias
Leukemias ) ,t(12;9 PDGF-
,ETS .PDGF -
.Sporadic -
c-MET ,Papillary Thyroid Carcinomas . ,
c-MET " .
, ,Gene Amplification - ,
.
' 296
EGF Receptor - . ERB
,B1 )EGFR ( EGF - 80%- Squamous Cell Carcinomas -,
50%- Astrocytomas - , ( Glioblastomas ,)2880-100%-
- , , Carcinomas - .
, ( ERB B2 ,)HER 2 / Neu ,EGF-
25%- Human Adenocarcinomas - , ,
. ERB B2 - ,
ERB B2 .
, , .Targeted Therapy
Targeted Therapy Tyrosine -
Kinase c-KIT . , ,c-KIT -
,)Steel Factor ( Stem Cell Factor - Tyrosine
,Kinase .

10

Signal Transducing Proteins

Oncoproteins - -
Signal Transduction . ,
( ," )
.
, Signal Transduction - . -
Oncoprotein Signal Transduction - RAS- Guanine GTP
,Triphosphate .G Proteins :
RAS -
RAS - . RAS
- . 15-20%-
.RAS- RAS
, GTPase - .RAS -
59 ,12 61 HRAS, KRAS .NRAS -
, . 90% ,Pancreatic -
Adenocarcinomas Cholangiocarcinomas - ,RAS- 50%
, 30%- Lung Adenocarcinomas -Myeloid -
.Leukemias , ( ) ,KRAS -
,HRAS - .NRAS -
RAS - , .
RAS Mitogenesis - " .
, RAS" , ,EGF -
PDGF .CSF-1 - RAS ,
, ,Signal Transduction .
Endoplasmic Reticulum - ,Golgi -
" , .
, RAS .)Guanosine Diphosphate( GDP "
- RAS , " GDP( GTP- .)7-32
RAS , , MAP Kinase -" .RAF-1MAP -
Kinases " .Mitogenesis
, Signal Transduction - RAS- ,
,GTPase GTP ,GDP-" ( ).
RAS- GDP( Nucleotide Exchange )1( :" ,)GTP
RAS- ,GTP Hydrolysis )2( - RAS- GTP-RAS-
, .GDP-
. GDP " GTP RAS-
" Guanine Nucleotide-Releasing Proteins
" .Adapter Proteins , GTPase -
RAS " .GTPase Activating Proteins GAPs
RAS- GTPase - ,1000
GTP GDP - .Signal Transduction - GAPs ,
"" RAS . GAPs-
.RAS- RAS ,GAP -
GTPase . , "" ,GTP
. Mitogenic Signaling GTPase -

11

 " "" ,)NF-1( Neurofibromin - ,GTPase

( Tumor Suppressor Genes -).
,RAS- )RAS/RAF/MAP Kinases( RAS Signaling Cascade -
. , ,BRAF - ,RAS -
60%- Melanomas - 80%- . - -
RAS/RAF/MAP Kinases ,Melanomas
.
, Signal Transduction - RAS ,Growth Factors
. , G1 - S -
" Cyclins . CDKs - RAS Cyclins -"
MAP Kinase - . AP-1
RAS - ,
. Anti-RAS .
RAS ," Farnesyl Transferase
( RAS- ) ,
( RAS Signaling - , ,)RAF and MAP Kinases
RAS ,EGF Receptor - .RAS Pathways
' 297

7-32 . RAS RAS , (

RAS ,)GDP RAS .GTP RAF MPA Kinase -
. RAS- ,GTP
, . RAS - " (?) Farnesyl .

12

 , . ,
RAS- RAS- , -
Signaling .
Tyrosine Kinases -
,3 Tyrosine Kinases Signal
Transduction . c-ABL , ,
.
ABL ,Tyrosine Kinase "
. Myeloid Leukemia - Acute Lymphoblastic Leukemias - , ,
c-ABL - 9
( 22 ,)7-33 ( BCR -
, ) . c-ABL , Tyrosine -
Kinase . , ,BCR-ABL - , Tyrosine Kinase
, . Myeloid Leukemia -
,Imatinib Mesylate "" BCR-ABL -
.Tyrosine Kinase .
Transcription Factors
Signal Transduction Transcriptional Regulators
( .)Responder Genes
, DNA Replication - .
DNA .DNA
" ,Leucine Zipper ,Helix-Loop-Helix " .Homeodomains -
DNA
. , ,
.
, FOS ,MYB ,MYC ,JUN
. MYC ,
, , .

13

' 298

7-33 Burkitt Lymphoma -Chronic Myelogenous -

.Leukemia

MYC -
MYC , , Immediate Early -
, Response Genes ( -
.)3 mRNA - ,MYC .
MYC- ,
. MYC - ,
.MAX DNA .

14

 , Ornithine Decarboxylase ,Cyclin D2 - . ,

MYC - : , ,
, Proteinase.
MYC , , (? )in culture
MYC ( ) . MYC
,
" MYC .
MYC , ,
, MYC- .
. MYC
,Burkitt Lymphoma - ( B MYC .)7-33
, , ' ... N-MYCL-MYC -
( Neuroblastomas - )7-34 ,.
Cyclins and Cyclin-Dependent Kinases
Cyclins CDKs - ,
.
Cyclins CDKs - . , Cyclin D
CDK4 . Cyclin D - ,
, ,- ,- Mantle Cell ( Lymphomas
,)Lymphomas Cyclin D1 - " (
).
() CDK4 - Sarcomas - Cyclin E .Glioblastomas -
,
.
- : Tumor Suppressor
" Steady State
( ) .
( . )Carcinogenesis Tumor Suppressor
( Genes .)7-9 , " "Tumor Suppressor Genes
, .
( )
, Tumor Suppressor .
, Tumor Suppressor Genes - " ,
,Retinoblastoma 1 20,000-.

15

' 299

:7-34 N-MYC - Neuroblastomas - . ,N-MYC -

,2p Extra Chromosomal Double Minutes - Chromosomally integrated, homogeneous -
( staining region , . )... Autosomes , 4,9 .13

60% Retinoblastomas - , 40%- ,

. -
Knudson , ."Two-Hit" :
, (" )"First Hit ,
, (" )"Second Hit
( ) . - , , ()hits
, .
Retinoblastoma " "Two-Hit Oncogenesis -
Kundson " Tumor
Suppressor Genes , -
Retinoblastoma:
Retinoblastoma ,RB -
.13q14 , Deletion
.13q14
RB- ( )Two Hits
( Retinoblastoma - .)7-35 ,
.RB - -
Retinoblasts ( , (?)
,13q14 13 ) . ,
RB " .Retinoblasts - :
Retina RB- .

16

Retinoblastoma Osteosarcoma
( ) . , RB-
, Adenocarcinoma Small Cell Carcinoma ,
. , ,RB -
Cyclin D-Dependent Kinases ,INK4a ,RB
.

, . RB
( ) . RB-
RB - .
, , RB
( ,LOH ) . RB-
, .
RB - . ,
11 Hepatoblastoma , Wilms-
. Rhabdomysarcoma )Von Hippel Lindau( VHL - Tumor Suppressor Gene Clear
Cell Renal Carcinomas LOH .
. Tumor Suppressor Genes
Tumor Suppressor Genes ,
. , ,
,Signal Transduction , .DNA-
Tumor Suppressor Genes .7-9 -
Tumor Suppressor Genes ,
(.)Carcinogenesis
RB-
RB - Tumor Suppressor Gene - . ,RB-
,RB- ( Phosphoprotein ) .
. RB ,
G1/S - ( .)7-36
' 300
TABLE 7-9 -- Selected Tumor Suppressor Genes Involved in Human Neoplasms
with

Tumors
Tumors
Associated
Associated
with Inherited
Somatic Mutations Mutations
of Unknown

gastric

of Familial
cancer

Neurofibromatosis
type
1
and
sarcomas

Function

Gene

Growth inhibition Carcinomas

colon

TGF-
receptor

Carcinoma
stomach

Subcellular
Location
Cell surface

E-cadherin Cell adhesion

Inhibition of RAS Neuroblastomas

signal
transduction and
of p21 cell-cycle

17

Inner aspect of NF-1

plasma membrane

TABLE 7-9 -- Selected Tumor Suppressor Genes Involved in Human Neoplasms

Subcellular
Location

Gene

Tumors
Tumors
Associated
Associated
with Inherited
Somatic Mutations Mutations

Function

with

inhibitor
Cytoskeleton

NF-2

Cytoskeletal
stability

Schwannomas and Neurofibromatosis

meningiomas
type 2, acoustic
schwannomas and
meningiomas

Cytosol

APC/catenin

Inhibition
signal
transduction

of Carcinomas
of Familial
stomach,
colon, adenomatous
pancreas;
polyposis coli/colon
melanoma
cancer

PTEN

PI-3 kinase signal Endometrial

and Unknown
transduction
prostate cancers

SMAD
2 TGF-
signal Colon,
and SMAD transduction
tumors
4
Nucleus

pancreas Unknown

RB

Regulation of cell Retinoblastoma;

Retinoblastomas,
cycle
osteosarcoma
osteosarcoma
carcinomas
of
breast, colon, lung

p53

Cell-cycle arrest Most

and apoptosis in cancers
response to DNA
damage

WT-1

Nuclear
transcription

p16
(INK4a)

Regulation of cell Pancreatic, breast, Malignant

cycle
by and
esophageal melanoma
inhibition
of cancers
cyclin-dependent
kinases

Wilms tumor

human Li-Fraumeni
syndrome; multiple
carcinomas
and
sarcomas
Wilms tumor

BRCA-1
DNA repair
and BRCA2

Unknown

Carcinomas
of
female breast and
ovary; carcinomas
of male breast

KLF6

Prostate

Unknown

Transcription
factor

. ,S
) Gene Deletions - ( RB
,S- , , E2F

18

 . RB- ,RB-
" ,"RB Pocket . E2F -
Germ-Line RB- Retinoblasts
.Osteosarcomas , Small ,Glioblastomas -
Cell Carcinomas , . RB
, : Germ-Line RB-
?Retinoblastomas RB
?
Retina- , RB
, .RB-,
RB- Retinoblastomas
.
( RB ) ,
: RB ,RB
RB . , ,
Cyclin D CDK4 " .RB Cyclin D ,
.
CDK " Cyclins .CDKs - ,

( )RB ,CDK4 ,Cyclin D ,p16INK4a -
. , RB- RB-
.
' 301-302
, , RB -
( :)7-36
TGF- . TGF- , ,"
( p27 .)CDK
, , DNA ,
, ," RB . , RB
" Simian .
Virus 40 :Polymavirus Large T Adenoviruses EIA - -
,Human Papillomavirus (HPV) E7 - .RB
RB Pocket - .E2F ,HPV
, ,HPV 16
. , ,RB- ,E2F
, .
P53 Tumor Suppressor Gene - "
,CDK-( p21 - 7-29 .)7-36

19

 : 7-35 .Retinoblastoma RB- 13q14

. Retinal - , RB .
RB- Retina - . - , ,
RB- " Retina .

20

 :7-36 RB . .Cyclin-D-CDK4 -
( )Cyclin E-CDK2 ,RB ( ) - ().
RB . G1/S , p53 , TGF-( Cip/Kip -
, )p57 , p21 p16INK4a( INK4a - )p19ARF - . RB , ,
, RB- . ,
" .

:p53
p53 - ,17p13.1
. 50%- .
p53 , , , ,
. , p53
( .)Germ Line - ,
.p53 ,RB -
" "Hit
. , ,Li-Fraumeni
25 ,50 .
, RB Li-
Fraumeni . ,Sarcomas ,Leukemia ,
. ,
Li-Fraumeni ,
(?).
p53 - p53 - "-
" . , p53 - " "
.
p53 - DNA (?) . ,
" . 80% p53
DNA- p53 .
,DNA ( )Missense Mutation .
, p53 " . ,RB -
, DNA , E6 - ,HPV
p53 - .
21

 p53 ,MDM2 p53"

. MDM2 - 33%- 50%- ,Leukemias -"
p53 .
p53 -
p53 .DNA- DNA " , -
- ,Hypoxia ,
DNA-.
,DNA- .p53 - , DNA-Dependent Protein
Kinase )Ataxia-Telangectasia Mutated( ATM - .DNA-
,p53 , ,DNA- Transcription -
Factor ( p53 .)7-37
. p53 G1 - "
p53- :CDK - . p21 -
DNA- . ,
p53 ( 20-) . Ubiquitin , ,RB -
P53 . "
,)Growth Arrest and DNA Damage( GADD45
.DNA DNA - , p53 , ,MDM2 p53 -
," ( .)7-29
DNA- , p53 - , ,
( , ) " ,
,BAX . BAX , BCL-2 : .
BAX , .
' 303
p53 , ,DNA . -
,DNA " p53 .DNA DNA"
G1 .DNA DNA " p53
( .)7-37 p53 , " " .
,p53 DNA- , ,
.
p53 DNA- .
, , (?) " -
DNA . p53
. Testicular Teratocarcinomas
Lymphoblastic Leukemias ( ) . ,
, ,p53 -
.

22

 :7-37 p53 . p53 - " DNA- " ,

G1 - ,DNA-" ,CDK- ,p21- ,GADD45 -
. DNA , DNA- , BAX-
p53 . ,p53 - DNA ,DNA
.

p53 -
. p53
.MDM2 Adenoviruses - p53
. p14ARF
,p53 - p53 . Multigene - ( p73 -
,)p53 - , 1p36 60% -
. p53 .

23

 .p63 - , p53 "

.
' 304
APC/-Catenin
Down-Regulation Tumor
Suppressor Genes . APC - NF-1 - .
Germ Line )5q21( APC )17q11.2( NF-1 -
.
,APC -
( )Adenomatous (,familial adenomatous polyposis
.) 17 , ,
.
Tumor Suppressor Genes - , APC -
. , . Adenomas "
Adenomas APC - .
, 70-80% ,
Adenomas ,APC -
APC .
APC Tumor Suppressor -
" "Drosophila- ( Xenopus APC .)7-38
, WNT , .
WNT WNT .
)FRZ( Frizzled ,
-Catenin. APC -

A :7-38 APC- APC . -Catenin -Catenin -

. WNT- ( -Catenin ,)WNT - -
.APC - -Catenin - -Catenins B .

24

 " ,WNT , -Catenin

- -Catenin . , ,RCF -
C . APC , -Catenin - -Catenins .
( ) Coactivates ,
.WNT -

APC- Down-Regulation . -Catenin

APC ,WNT ,-Catenin . "
- ,-Catenin . -Catenin APC-
- , -Catenin
. , APC WNT
-Catenin . -Catenin , ,TCF
" Cyclin D1 ,c-MYC .
APC/-Catenin ( )Tumorgenesis "
APC . -Catenin -- -
Catenin " APC .
APC/-Catenin - , -Catenins -
50%- Hepatoblastomas - 20%- . Hepatocellular Carcinomas -
-Catenin ,3 E-Cadherin - ,
-.
' 305
.Cadherin-Catenin -
-Catenin .
Tumor Suppressors -
Tumor Suppressor Genes . ,
Chromosomal Deletions -
.LOH Tumor Suppressor Genes -
( :)7-9
INK4a/ARF - 20%- Melanomas - .
Pancreatic
, p16INK4a - 50%--
Adenocarcinomas Squamous Cell Carcinomas - ,
, .Cholangiocarcinomas - p16INK4a
Cyclin D-CDK4
RB . , p16INK4a ,
" , (
).
TGF- - Type 2 TGF- - 70%-
,HNPCC
- ( Microsatellite ,)DNA
, SMAD4 . HNPCC -
Signal Transduction " ,TGF- 50%-
, ,SMAD2 - ,
. SMAD4 , Deleted In Pancreatic ( DPC4 -
.)Cancer
NF-1 - NF-1 -
Neurofibromas .
( Neurofibromatosis Type 1 .)5 Neurofibromas - -
.Neurofibrosarcomas Neurofibromas Type 1
Gliomas ,Neurofibromin . Optic Nerve - ,NF-1 -
25

Signal Transduction .RAS - RAS -

( GDP-) ( GTP) Neurofibromin .
,GTPase-Activating RAS -.
RAS ,NF-1 .
NF-2 - Germ-Line NF-2 -
.Neurofibromatosis Type 2 ,5 NF-2
Schwannomas- .Acoustic Nerve - ,
NF-2 Meningiomas - . Ependymomas -
,NF-2 - ,Merlin
( 4.1 ,)13 )Ezrin, Radixin & Moesin( ERM-
Merlin . , , Actin - , ,CD44 -
- ( .)3 NF-2 -
, Merlin -
-.
VHL Germ Line )Von Hippel Lindau( VHL - 3p
Hemangioblastomas ,Phechromocytomas ,
, ( Retina - ) .
VHL- ( .)20 VHL-
.Ubiquitin Ligases - HIF-1
( ,)Hypoxia Inducible Transcription Factor 1 , VEGF.PDGF -
VHL Ubiquitination HIF-1
. Angiogenic
PTEN , Phosphatase and Tensin )PTEN( 10
,10q23 Deletion
. Glioblastomas - PTEN
, . PTEN "
p27 Cip/Kip .
,PTEN , .
WT-1 ,WT-1 - ,11p13 ,Wilms Tumor
. - Wilms Tumor,
WT-1 - . WT-1 -
.
Mesenchyme - . ,
WT-1 -
. Wilms ,WT-2 , ,11p15
( Beckwith-Wiedeman .)10
Cadherins Glycoproteins ( .)3 -
Cadherins ,
. E-Cadherins
, , , , . Germ-line
E-Cadherin - , E-
Cadherin .
E-Cadherin . , E-Cadherin -
( .)16q , E-Cadherin -
,-Catenins . -Catenin , - Cadherins
.

26

' 306
KLF6 KLF6 , TGF- -
KLF6 . TGF- 70%- . KLF6
" ,p21 Cip/Kip
. p53 - " . p21
PTCH )PTCH( Patched Tumor Suppressor Gene
( ,)PATCHED .Hedgehog -
Hedgehog/PATCHED , TGF- . PDGF - -
PTCH ,Gorlin Nevoid Basal Cell
( Carcinoma .)26 PTCH -
20% 50% . Basal Cell Carcinoma
" .UV-

" ,
. , "
,Tumor Suppressor Genes "
.
.
.1 BCL-2
.
,BCL-2 - , 85%B-Cell Lymphomas -
( )14 ) , t(14;18)(q32:q21 BCL-2 --
18q21 ( 14q32
MYC -Burkitt -
.)Lymphoma BCL-2
. BCL-2 - BCL-2 ,1
. , ( B Lymphocytes
[?]) , Lymphadenopathy -Marrow -
. Infiltration Lymphomas - BCL-2
, , Lymphomas -
. BCL-2
BCL-2 . B-Cell Lymphomas BCL-2
,
.
p53 : . MYC -
" . BCL-2 p53 ,
- .BAX ,p53 " p53 -
INK4a - ,MDM2- - ,BAX ,
. BAX
" ,BID . p53 - ,BCL-2 -
" p53 MYC . BCL-2 - ,
MYC : BCL-2- ,
.
. , , ,
, PI-3 Kinase/AKT .
, " " . AKT
AKT - PTEN Tumor Suppressor Gene -
. .
27

 DNA -
" " . ,DNA-
, , ROS- ,
, . -
DNA- .
DNA- , DNA-
.DNA- ,
, .
DNA "
DNA .
DNA
. . ,
. DNA ,
.
, . ,
. Tumor Suppressor Genes - DNA
Nucleotide Excision Repair ,Mismatch Repair ,Recombination Repair - .
Nonpolyposis Cancer
Mismatch Repair " . HNPCC
" , Cecum - -
( Proximal Colon .)17 Mismatch DNA
, Proximal Colon - .HNPCC
' 307
, , ,
. Germ Line , APC - ,
HNPCC- .
DNA , - ( )Mismatch " " .,
, G ,T A ,T -
. Proofreaders , , -
. Tumor Suppressor Genes- DNA-
( ,)Replication Error Phenotype "
- DNA- .
- 1-6 ( .)5
- .
, ,
. -
Mismatch Repair -.
,DNA- 4 ,HNPCC Germ-
Line )2p16( MSH2 - )3p21( MLH1 - 30% - ( Each account for
.)approximately 30% of cases PMS2 ,PMS -
.Mismatch ,DNA Mismatch
"Second Hit" - . , DNA -
Tumor Suppressor Genes , , Tumor Suppressor Genes -,
.
,HNPCC
, ( 50-
) .DNA-

28

 HNPCC - 2-4% - , -
15%- .
HNPCC ,Type II TGF- -
TCF , BAX ,-Catenin - .Tumor Suppressor Genes -
, TGF- - ,TGF- -
BAX .
Xeroderma Pigmentosum
,Xeroderma Pigmentosum , DNA
UV .
UV Cross-Linking - ,Pyrimidine" DNA .
DNA- " , Nucleotide Excision Repair NER -
" .UV ,NER-
. Xeroderma Pigmentosum -
DNA" -
, ,Ataxia-Telangiectasia BloomFanconi -
,Anemia " ,DNA- (Ataxia-
Telangiectasia ,)Bloom Cross-Linking .)Fanconi Anemia( DNA-
, , (,)Ataxia-Telangiectasia
( )Fanconi Anemia ( .)Bloom
Bloom .
15 ,)BLM Helicase( Helicase - DNA" - .
Ataxia-Telangiectasia , "
Purkinje ( )Cerebellum ( Cerebellar Ataxia - "
) . ,
, . ,ATM-
.
ATM Kinase DNA-- ,
. , Kinase - ATM ATM . ,p53
G1 - . ,ATM
" p53 , DNA
. ATM- 1%-
, . ,
DNA- " .

.
BRCA-1BRCA-2 -
,BRCA-1 ,17q21 ,BRCA-2 - ,13q12-13
( .)24 ,Tumor Suppressor Genes -
BRCA-1 - BRCA-2 - .
Germ-Line ,BRCA-1 -
.
, BRCA-2 - ( -
)BRCA-1 (?) Melanomas .
10-20%- . BRCA-1 - BRCA-2 - 80%-
, 3%- .
, Tumor Suppressor Genes - ( )RB, p53, NF-1, VHL
, BRCA
29

( ) . , BRCA-1 -BRCA-2 -
-.
BRCA-1 BRCA-2 - .
.
' 308
BRCA-1 Estrogen - Co-Activator
( ) . BRCA-1 BRCA-2 - -
.DNA ,RAD51 - DNA--,
( Chromatin Remodeling BRCA- .)23
1 BRCA-2 - , G1/S
.DNA- BRCA-1 ,BRCA-2 -
,
.
, ,
DNA-- " - ( .)7-39
ATM( CHEK2 - Protein Kinase " )DNA- BRCA-1
,RAD51 .DNA- Fanconi Anemia
, BRCA-2 - ,FANCD-1 -
. Fanconi Anemia -

30

 :7-39 )Ataxia-Telangiectasia Mutated( ATM .DNA

- ,DNA- " ATM . CHEK2 - ,BRCA-1
. ( Fanconi Anemia ) A, C, E, F, G Ubiquitination -
Fanconi Protein D2 BRCA-1 BRCA-2 . ,RAD51
DNA" - BRCA-2 ,BRCA-1 . RAD51 - DNA-" -
RAD51 . .

:7-40 . ,
.

31

 , BRCA- Fanconi Anemia - ,

" DNA" -
.
DNA
ATM- .
-Telomerase :
( ,)1 ,
- " " ( .)Replicative Senescence
"" ,
( ,)Telomeres .
, ,p53 -
( .)7-40 ,
. ( , )Germ Cells "
, Telomerase .
' 309
, .
Telomerase ,
Telomerase .
Telomerase - ,
?
, .Telomerase - ,
Telomerase 90% - .
Telomerase ( )Tumorgenesis"
. , Telomerase
.
, ,
. ,
, ( allowing for
. )??critical telomere shortening in dividing cells
( .)7-40 Telomerase
.
( )Angiogenesis
, ,Angiogensis
.
, 1-2 mm - ,
. , 1-2 mm -
. ,
.
,
" -
Insulin-Like Growth Factor Angiogenesis .PDGF - ,
( Metastasis - ) . ,
.
?
( Angiogenesis .)3
" " ,
Angiogenesis - . ,
( 7-41 ) .
.VEGF , ,
32

 . , ,
, " " . Vasculogenic Mimicry
"
( ) .
, VEGF.Basic Fibroblast Growth Factor bFGF -
VEGF " " ( ) .
bFGF VEGF - Angiogenesis .3
,
.
,
.Angiogenesis ,
. ."Angiogenic Switch"-
Angiogenic Switch -
.Angiogenesis , p53 - ( )wild type
Angiogenesis" Thrombospondin-1 -.
VEGF )Hypoxia Inducible Factor( HIF-1-
.VEGD ( p53- ),
Thrombospondin-1 - , VEGF , HIF-1 "
, .
, - .
" . Angiogenesis
- , ,Thrombospondin-1 " ,
, Endostatin ,Angiostatin ,Tumstatin - . -
Angiogenesis )Angiostatin( Plasminogen
(.)Endostatin, Tumstatin
Angiogenesis - ,
Angiogenesis .
" Endostatin - Endostatin . Tumstatin -
. - VEGF --
,VEGF-R2 Signal Transduction . VEGF-R2
()Metastasis
.
.
, ,
( .)7-42 . ,
, .

33

" 309

Invasion and Metastasis

( )Invasion ( )Metastasis .
. ,
,
( .) 7-42
.

Figure 7-42 The metastatic cascade. Schematic illustration of the sequential steps involved in the
hematogenous spread of a tumor.

" 310
,
. ?
( )7-43A
.
( .)7-43C
- "
" . ,
, ,
( .) 7-43D
.
)1( : )2( ECM .

Invasion of Extracellular Matrix

ECM .
3 :ECM
( )interstitial connective tissue
ECM , , . ,7-42
ECM .
"
.
.

Figure 7-43 Mechanisms of metastasis development within a primary tumor. A nonmetastatic primary
tumor is shown (light blue) on the left side of all diagrams. Four models are presented: A, Metastasis is
caused by rare variant clones that develop in the primary tumor; B, Metastasis is caused by the gene
expression pattern of most cells of the primary tumor, referred to as a metastatic signature; C, A
combination of A and B, in which metastatic variants appear in a tumor with a metastatic gene
signature; D, Metastasis development is greatly influenced by the tumor stroma, which may regulate
angiogenesis, local invasiveness and resistance to immune elimination, allowing cells of the primary
tumor, as in C, to become metastatic.

" 311
ECM ( :)7-44

ECM

. ,
, E .
,
. , ,
E .
E .
, ( .)7-38
E . , E
, .
,ECM .
. ,
, . ,

.
.

Figure 7-44 AD, Schematic illustration of the sequence of events in the invasion of epithelial
basement membranes by tumor cells. Tumor cells detach from each other because of reduced
adhesiveness, and cells then attach to the basement membrane via the laminin receptors and secrete
proteolytic enzymes, including type IV collagenase and plasminogen activator. Degradation of the
basement membrane and tumor cell migration follow.

" 312
(
) , ,
( ) . ,
. ,
.
ECM
, , .
. ,
.
ECM , ( .)7-44
ECM
.ECM
( )
.
.
. : , ,
( MMP9 .)MMP MMP2 4
. MMP
:

, , .

.
MMP.

MMP
. , MMP

.
.
,
,
.
MMPs . , ,
MMP9 . MMP2 4
VEGF .

" 313
4
.
.,
MMP ECM , ,
. ,
.

Vascular Dissemination and Homing of Tumor cells

,
. .

, ( .)7-42
. ,
,
. ( )
CD44 . T,
.
CD44 )High Endotelial Venules( HEV
. ,
.

.
. ,
,
. :

,
.
.

. ,
CXCR4 .CCR7,
,
.
. chemoattractants
. .Insulin-like growth factor I or II

, .,

.
,
.

Molecular Genetics of Metastasis Development

?

.
. ,
EZRIN ,
.
KAI-1 ,NM23 .KISS

Stromal Microenviroment and Carcinogenesis

ECM . ,
4 ,VEGF 5-
MMP-2 . ECM GF
( ) , .
,TGF ,PDGF ,b-FGF .
,
ECM .
. , ,"
, ""carcinoma associated fibroblast
( , )CAF .
. , CAF
immortalized but non-tumorigenic
, poorly differentiated
.
, .
.
.

" 314

Dysregulation of Cancer-Associated Genes

( )
( ) .
"genetic profile" - "signature"/

Chromosomal Changes
.
.,
.
()

.
. ,
(-2
)ABL ,BCL ( .)RB,APC ,
.
ABL chronic myeloid leukemia c-MYC Burkitt
lymphoma ( .)7-32
.
( .)7-10
:

( )Burkitt
. 3 ,8q24
MYC
. , MYC
. ,
MYC 14q 8 32

 ( IgH .)7-33
) .t(8:14)(q24;q32 , ,MYC
. ,
.MYC
.
.
MYC .
, ,
. Mantle cell Cyclin D1 11q13
IgH .14q32 ,
) ,t(14;18)(q32;q21 , .BCL-2
.B ,
T
.T ,
MYC .
, chronic myeloid leukemia
,
. , 9 22
(c-ABL )9 )break point cluster region( BCR
( 22 .)7-33

TABLE 7-10 -- Selected Examples of Oncogenes Activated by Translocation

Affected Genes

Translocation

Malignancy

Ab1 9q34

)(9;22)(q34;q11

Chronic myeloid leukemia

bcr 22q11
AF4 4q21

)(4;11)(q21;q23

)Acute leukemias (AML and ALL

MLL 11q23
AF6 6q27

)(6;11)(q27;q23

MLL 11q23
c-myc 8q24

)(8;14)(q24;q32

Burkitt lymphoma

IgH 14q32
Cyclin D 11q13
IgH 14q32

)(11;14)(q13;q32

Mantle cell lymphoma

TABLE 7-10 -- Selected Examples of Oncogenes Activated by Translocation

Affected Genes

Translocation

Malignancy

IgH 14q32

)(14;18)(q32;q21

Follicular lymphoma

bcl-2 18q21
c-myc 8q24

)(8;14)(q24;q11

lymphoblastic
leukemia

acute

T-cell

TCR- 14q11
Hox 11 10q24

)(10;14)(q24;q11

TCR- 14q11
Fl-1 11q24

)(11;22)(q24;q12

Ewing sarcoma

EWS 22q12
Underlined genes are involved in multiple translocations.
AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia.
" 315
ABL-BCR .
ABL-BCR .
, .
,chronic myeloid leukemia KD 210
.KD190 BCR-ABL-
. , ,
, ,RAS
PI-3 kinase ( STATs ABL -BCR .)3 ..
, .
. , MLL
( )Myeloid,lymphoid leukemia 11q23 25
( .)7-10 )EWS( Ewing Sarcoma
22q12 ) t(11;22)(q24;12
( Ewing Sarcoma .)26
EWS . ,
. Ewing tumor , EWS
,FLI 1 ETS .transforming ability

Gene Amplification

.. .
.
.. . ,
. :
Chromosome like structure

).double minutes (dms

).homogeneous staining regions (HSRs

,
,normal banding pattern G-band
( .)7-34 N-MYC
B2 ERB N-MYC . 25% 30% B2 ERB
, dms .HSRs ERB B2 20%
. C-MYC, L-MYC and N-MYC
.small cell cancer of the lung
( D1 CYCLIN , ,
).

Epigenetic Changes


.. . .
CpG... ,. - .
. p14ARF p16INK4a ,
BRCA1 , VHL , ( MLH1
' ) . genomic imprinting
..
. ,
.
.
,
.

Molecular Profiles of Cancer Cells

.
.. () ( .)7-1 ,
.. ( .)7-45 .. :
.Gene expression signature or molecular profiles
( .)7-1
molecular signatures
( 23-1 .)23 acute
lymphoblastic leukemia .. molecular signature
.

Molecular Basis of Multistep Carcinogenesis

, .

Box 7-1. Gene Expression Profiles of Human Cancers. Microarrays

and Proteomics
, .
.
,microarray (cDNA
-) .
' - ()
, "."gene chips
' 20,000-
. ( )cDNA
. '
( ,)probes cDNA . -
( , ) . '
:

/

. .hierarchical clustering
.
.,
,
. laser capture
microdissection .
:
.1
.2
.3
.4
.5

.
70 . )1( :
( )2 5 ()3


.

, ,
.

protenomics-

 , .
' - .
)isotope-coding affinity tags( ICAT , .

.
,
- . ,
.
.

Figure 7-45 Schematic representation of the steps required for the analysis of global gene expression
by DNA microarray. RNA is extracted from tumor and normal tissue. cDNA synthesized from each
preparation is labeled with fluorescent dyes (in the example shown, normal tissue cDNA is labeled
with a green dye; tumor cDNA is labeled with a red dye). The array consists of a solid support in which
DNA fragments from many thousands of genes are spotted. The labeled cDNAs from tumor and
normal tissue are combined and hybridized to the genes contained in the array. Hybridization signals
are detected using a confocal laser scanner and downloaded to a computer for analysis (red squares,
expression of the gene is higher in tumor; green square, expression of the gene is higher in normal
tissue; black squares, no difference in the expression of the gene between tumor and normal tissue). In
the display, the horizontal rows correspond to each gene contained in the array; each ventrical row
corresponds to single samples.

 .
, ,
.
: ( )initiation ( .)promotion
-
.

"
.
. , RAS

. MYC
- .
.

.
.
.
, ,
.
:7-46
.1 APC
.2 RAS
.3 SMAD2 ( 18q)SMAD4-
.4 p53 .TGF Receptor II-

Figure 7-46 (Figure Not Available) Molecular model for the evolution of colorectal cancers through the adenoma-carcinoma
sequence. Although APC mutation is an early event and loss of p53 occurs late in the process of tumorigenesis, the timing for the
other changes may show variations. Note also that individual tumors may not have all of the changes listed. (Adapted from
Vogelstein B, Kinzler KW: Colorectal tumors. In Vogelstein B, Kinzler KW: The Genetic Basis of Human Cancer. New York,
)McGraw-Hill, 2002, p. 583.

, ? ,
APC
. COX-2 EGF-
. APC ,
p53 .
APC- ,
. .

Gatekeeper and Caretaker Genes

. ( gatekeeper")
.
( )cancer susceptibility syndromes . ,
:
.1 RB- ,INK4 D RB-
( )RB-
.2 p53- HDM2 ,p14ARF .p53
caretaker
.genes DNA .mismatch
,
.gatekeeper , '-
,caretaker .
caretaker gatekeeper ,
.gatekeeper
-
.

Figure 7-47 Schematic illustration of the pathways of malignancy initated by mutation of the gatekeeper genes (e.g., APC, NF-1,
RB) or caretaker genes (e.g., hMSH2, BRCA-1, BRCA-2).

Mutator Phenotype
DNA .
" "mutator phenotype .
, ( )
.
.

Tumor progression and heterogeneity

.
( ) ( preneoplastic --
) , . "."tumor progression
.tumor progression
( , , )

 .
, , , ,
, . ,
, . ,
. -
. tumor progression ,

, . "
. "" ( )transformed cells
. , p53
" .) DNA repair( .
,
. , "
. "
. ,
, , .
, (
) ( )fig 7-12
.

Carcinogenic Agents and Their Cellular Interactions

.
:
.1

.2

radiant energy

.3

Chemical Carcinogenesis
.Sir Percival Pott - 18-
.

" . (

the polycyclic aromatic

)hydrocarbons , ,
.
.

Steps involved in Chemical Carcinogenesis

.7-48 .

-initiation

( ,)initiator .
( 2 )3- initiation ( 1)
initiatin " () ,
" " . 3
( .
)

promptors initiated cells -

( .nontumorigenic .)5 ,
) )promoting agents initiators -
( . )4
, ,initiators -
"
( -6 .) initiated cells -
,initiated cells -
.

 7-48

Figure 7-48 Experiments demonstrating the initiation and promotion phases of

carcinogenesis in mice. Group 2: application of promoter repeated at twice-weekly
intervals for several months. Group 3: application of promoter delayed for several
months and then applied twice weekly. Group 6: promoter applied at monthly
intervals.
initiation - promotion -
, , , . 2
( )7-49
Initiation of Chemical Carcinogenesis

( .)7-11 2-:
-direct acting compounds .1 .
indirect-acting compounds .2 -procarcinogens in vivo
.
direct - :highly reactive -
( electrophiles )
(.)nucleophilic=electron rich
" .

 , " ,"
. initiated cells - ,
" .
Metabolic Activation of Carcinogens
direct acting alkylating and acylating agents
- ,
( . .)7-49
( ) detoxification . ,
,
.
" P-450 -
) .(metabolized by cytochrome p-450 dependent mono oxygenases
.
, "
. : CYP1A1 - p-450
polycyclic aromatic hydrocarbons . 10%
" " ,
. 7
. ,glutathione S transferase
.polycyclic aromatic hydrocarbons .
50% ,
.
. ,
.
Molecular Targets of Chemical Carcinogens
,
, " , -
initiating chemicals . .Ames Test -
, 70%-90% .
. in vitro in vivo.
" .
"
" . " initiation - "

 " . " "

. .
" xeroderma pigmentosum
"
UV .
"
. , , RAS -
. "
. ""fingerprint
. P53- .
)HBV( B
.aflatoxin B1
B C .
, P53 90% transversion C:G-
T:A .249 ,
249 . " "
.initiating agents -
Initiated Cells
" .initiation -" ( )heritable
" . ," initiation
" . ,
,reactive electrophiles
72-96 " .
"" ( ,)quiescent "

.
, .

:7-49

Figure 7-49 General schema of events in chemical carcinogenesis. Note that

promoters cause clonal expansion of the initiated cell, thus producing a preneoplastic
clone. Further proliferation induced by the promoter or other factors causes
accumulation of additional mutations and emergence of a malignant tumor.

7-11
TABLE 7-11 -- Major Chemical Carcinogens
Direct-Acting Carcinogens
Alkylating Agents
-Propiolactone
Dimethyl sulfate
Diepoxybutane
Anticancer

drugs

(cyclophosphamide,

chlorambucil,

nitrosoureas, and others)

Acylating Agents
1-Acetyl-imidazole
Dimethylcarbamyl chloride
Procarcinogens That Require Metabolic Activation
Polycyclic and Heterocyclic Aromatic Hydrocarbons
Benz(a)anthracene
Benzo(a)pyrene
Dibenz(a,h)anthracene
3-Methylcholanthrene
7,12-Dimethylbenz(a)anthracene
Aromatic Amines, Amides, Azo Dyes
2-Naphthylamine (-naphthylamine)
Benzidine
2-Acetylaminofluorene
Dimethylaminoazobenzene (butter yellow)
Natural Plant and Microbial Products
Aflatoxin B1

Griseofulvin
Cycasin
Safrole
Betel nuts
Others
Nitrosamine and amides
Vinyl chloride, nickel, chromium
Insecticides, fungicides
Polychlorinated biphenyls

Promotion of Chemical Carcinogenesis

initiation - ( . .)7-49
( ,phorbol esters , )
.nontumorigenic
( )clonal expansion initiated -
initiated cells .cells. ,
. ( )RAS
.
initiated cells -
. , :
,preneoplastic ,tumor progression
.
initiation-promotiom - :
( ) ,
( ?)tumorigenesis
( )pleiotropic TPA .tumor promotion
( ,)tetradecanoyl phorbol-13 acetate ,phorbol ester tumor
,)PKC( C
, " .

 ( )the promoting effect

.TGF-B
( neoplastic
)transformation .
,
.
Carcinogenic Chemicals
7-11 initiators promoters -
.
-Direct Acting Alkylating Agents
.
. - -,
lymphoid neoplasms . ,Alkylating agents - -

.Wegener granulomatosis ,rheumatoid arthritis -
, .
Alkylating Agents - " " ,
.
-Polycyclic Aromatic Hydrocarbons
.
( .)species ,
, .
polycyclic hydrocarbons - ,
.bladder -

Polycyclic Aromatic

Hydrocarbons " .
-Aromatic Amines and Azo Dyes ,
" " " .P450
( .)gastrointestinal tract -
B- naphthylamine .
50% .aniline dye -
" -

) (detoxification" . , -
" glucuronidase
. .
-Azo Dyes - . ".
-Naturally Ocurring Carcinogns "
. aflatoxin B1
. " Aspergillus flavus
, .
" .
, " aflatoxin - HBV - .
-Nitrosamines and Amides
gastrointestinal tract , gastric
.carcinoma nitrostable amines nitrate - nitrites -"
. .
)(preservatives nitrate
-Miscellaneous Agents . .7-3
. ,
. .
,Vinyl chloride polyvinyl ".
hemangiosarcoma -
. nickel , ,
. arsenic - . insecticide
" ( )9
-Promptors of Chemical Carcinogenesis
.
initiating chemicals , initiated cells -

. exogenous agents -
, .
- .

, " .

diethyl-stilbestrol -
.

.

.

Larynx ,Pharynx , 10 ,

.
Radiation Carcinogenesis
, UV ,
neoplasms - " .
UV ,
neoplasia .

.
. 1988-1992
.1993-1997
UV- " .
-Ulteaviolet Rays
UV basal cells ,squamous cells
. ,UV-
.

.
:UV
320-400( UVA)
280-320( UVB)
200-280( UVC)
UVB UVC , "
.
UV , ,
, UVB .
" . " " .)nucleotide excision repair( NER
" :NER . "
. " , .

 .
.
. ,.
30- . NER- "
. ,.
NER-
.xeroderma pigmentosum
2000 .
" -
NER " xeroderma pigmentosum . 7
( NER- UVB .)NER-
. RAS-P53-
UVB- .
-.
-Ionizing Radiation
( )x-rays, gama-rays "" ( particulate= alfa particles,
)beta particles, protons, neutrons . x-rays
. " 10 .
-
, 7 . ,
( , ,,
)

90% . 10 15 5%
.
( .)fallouts"
.1986 30-
2000- .

.
, , ,
- .
. 9%-
.
. ,

 , , .
, .salivary glands , , ,

.
,
.
" 324-330

Microbial Carcinogenesis
DNA RNA
- .
.
, , ,
Helicobacter pylori .

Oncogenic DNA Viruses

DNA .
- , , boving
,papillomaviruses , .
- DNA :
Papillomaviruses -HPV
Hepatitis B virus -HBV
Epstein Barr virus -EBV
Kaposi Sarcoma herpesvirus -KSHV

.
( KSHV 6 .)11
, Hepatitis C virus- HCV DNA
.
,
:DNA

.

 , DNA .
.
, (, )early genes
, .
Human Papillomavirus
70- .HPV ( )1,2,4,7,
( Squamous Papillomas : ) , . HPV
, -
,Squamous cell carcinoma - ,
.

, HPV . DNA HPV ,18 , 16 HPV 31, ,
,33,35, 51 85% - Squamous cell carcinoma,
( ).
, , ,
, HPV HPV 6 .)"low- risk" type( HPV 11
HPV ,
.
- , HPV ,
, DNA . ,
, .
, , ( DNA
) ,
. . HPV
"" . , DNA
, .
,E1/E2 .
E2 , ( E6 E7
,)early genes E6 , E7 HPV 16 .HPV 18
HPV 16
,HPV 18 ,
.

 DNA , , E6 E7
E6 . , P53 E7 ,RB
. E7 , P53
.P21
E7 ,E6 , P53 .RB
, ,Tumor Suppressor
.HPV
: E6
, E6 HPV ,) HPV 16 ,18 &31 ( ,
,P53 .
,E6 HPV ( , ) HPV 6 & 11 p53
.

:E7
, E7 HPV , , RB
, RB/ E2F .RB E7
HPV , , RB
.
, , E7 & E6 HPV , tumor
,suppressor .
, HPV P53 ,
,P53 - . E6
P53 ,
P53 . DNA , DNA
.
, , E6 - , ,P53
, .
,E6-P53 ,
.

 P53 - , , 72 ,
. P53 , ,72 .E6
, P53 ,
, .

Figure 7-50 Effect of HPV proteins E6 and E7 on the cell cycle. E6 and E7 enhance p53 degradation,
causing a block in apoptosis and decreased activity of the p21 cell cycle inhibitor. E7 associates with
p21 and prevents its inhibition of the Cyclin/CDK4 complex; E7 can bind to RB, removing cell cycle
restriction. The net effect of HPV E6 and E7 proteins is to block apoptosis and remove the restrains to
cell proliferation (see Fig. 7-29 ). (Modified from Mnger K, Howley PM: Human papillomavirus
)immortalization and transformation functions. Virus Research 89:213228, 2002.

HPV
, DNA ,HPV 16 ,18, 31
, -Vitro - , .
( mRAS- RAS ) ,
.
, , HPV ,
, .
,
, , . -
.
, HPV ,
.

Epstein- Barr Virus- EBV

, EBV , :
.1 Burkitt Lymphoma
.2 , B (
,
- )
.3 '
.4 '
( ) EBV
EBV , . B
B , CD21 .B B
, EBV ( DNA DNA) .
B , , .
, B , -
.Vitro B . , HPV
Tumor Suppressors .EBV
, ,
, .
)Latent membrane protein 1( LMP-1 ,
CD40 .B

,T-Helper - ( B .)6
LMP-1 , CD40 -NFB -JAK/STAT
.B
, T Helper
( T ) , B .
, B .
, LMP-1 EBV ,
( " ) , , LMP-1
, .B
EBV ,EBNA-2 - ,
, Cyclin D , SRC B , G0
EBNA-2 .G1 ,LMP-1

 . , B -
.
Burkitt Lymphoma
B , .
, ,
,African Burkitt Lymphoma EBV :
.1 90 EBV
.2 100- , ( Capsid-
. .
.3 , Caspid -

EBV African
,Burkitt Lymphoma ,
:
.1 EBV , EBV . Burkitt Lymphoma
, - .
EBV .2 ( , )8 B
.3 EBV 15%-20% ,Burkitt Lymphoma
. ,Burkitt Lymphoma
)( t(8;14 )8,14 ( )
- .c-MYC
.4 EBV ,In Vitro B
In vivo
.5 ,EBV B
( ) , .Burkitt Lymphoma ,
, T
.

Figure 7-51 Schema depicting the possible evolution of Epstein-Barr virus (EBV)-induced Burkitt
lymphoma.

, EBV Burkitt Lymphoma

.) Figure 7-51( .
, EBV ,
,
, .

 Burkitt Lymphoma ( ,
) ,- ( ),
B - .EBV
B , ,
)( ,t(8;14 8 ,) 14
MYC . ,
. MYC
,80% ,Burkitt Lymphoma " ,
, .MYC
MYC , ,
.
EBV , (
) , , B
) ,t(8,14 , .
, T
, . , p53
,p14ARF/MDM2/p53 - ,p16INK4a
-
B
, EBV , B
. ,AIDS -
, , B
, . ,
.
LMP-1 ,
In vivo B ,
,EBV . In vitro
, EBV ,
, , .
Nasopharyngeal Carcinoma

 ' , .EBV
, ,
.
,Burkitt Lymphoma 100 ',
, DNA .EBV
, , EBV .
, ( ,)Caspid
IgA .

100% EBV ' ,

EBV , ( , ) Burkitt Lymphoma
, - ,
, .
EBV ' , 14
HBV - Hepatitis B Virus
, HBV
( HBV .)18 .
- . ,
HBV 200 ,
HBV .
HBV .
HBV , , hepadnavirus
.
, , HBV
, . , HBV DNA
, , HPV
.DNA
HBV , -
.

 ,
, ,
.
HBV :
.1 , HBV ,
..
, ,
, .Dietary aflatoxins
HBV .2 , HBx protein

. ILGF-II -
( )Insulin like growth factor II .)Insulin like growth factor I ( IGF-I
HBx , p53 .
, )Hepatitis C virus ( HCV , DNA
. ,HBV
, HCV.
, .
, ,
.
Oncogenic RNA Viruses
-
, - ,)HTLV-1( Human T-Cell leukemia virus type 1 ,
.
Human T-Cell leukemia virus type 1
, HTLV-1 / T
, , ".
, HTLV-1 - T , CD4 T
.
T , ,
. ,3%-5% ,
40-60.
HTLV-1 , , Tropical
,spastic paraparesis

(" ,) 28 ( uveeitis ) ,
.
HTLV-1 , T ,
, . -
HTLV-1, .
, .
HTLV-1 gag, pol, env - LTR- long terminal -
,repeats - . HTLV-1 ,
. tax , .TAX
" , mRNA
, .5'LTR TAX
, .T
,c-FOS , IL-2 ,
, GM-CSF

( Granulocyte-

.)macrophage colony stimulating factor

TAX , , p16INK4a
, D - .
TAX , .
TAX , DNA
, ATM .DNA
/ T ,
:
, HTLV-1
,
TAX . T ,
, .TAX T -
.
, IL-2 .

"
. ,
, " "

 . ,
. 90%-
. , .
, 20%-30% , ,
. "
" (
) ( CagA- ) ,
CagA . ,VacA
.
( )17 ,
( ) ,-
, .
- ( ;)MALT
. B " '
; , ' ( .)14
B
- , ).a t (11;18
" ,
.

"
, ( )
. ,
" " " ,
. "
;
, ;
; T .

. ,
.

.
"
. "- "

 ""
.
:
? ? -
?
?

.
: ,
; ,
.
.
.

.
" T
( ,)CTLs - .
CTLs
) major histocompatability complex (MHC ( I .)6
( .)7-52
-
, , ,
- "
. -
, ,
MHC I " T .CD8 ,
II ,
" T CD4 .
, . T
CD4 T CD8
p53 ,RAS .BCR-ABL - ,

 RAS p53 - CTLs

. , CTLs
.

, ,
.
.
" ,
,
MHC- I .CTLs

MHC I
.
,
.
Overexpressed or Aberrantly Expressed Cellular Proteins
, -
, .
, , ,
, ,
. , Tyrosinase -
. T
, .
, .
.
, , ,
.

Figure 7-52 Tumor antigens recognized by CD8+ T cells. (Modified from Abbas AK, Lichtman AH:
)Cellular and Molecular Immunology, 5th ed. Philadelphia, WB Saunders, 2003.

, ,
( )
. , ,
, .
( , )MAGE , ,
T , . MAGE
, , ,, ,
. , MAGE . , 25
MAGE ,Xq . MAGE
, - . , MAGE
, ,
T . BAGE ,GAGE .RAGE -
MAGE , , ,
. ,
"cancer-testis antigen" -

 .
, . ,
. ,
, , DNA .
HPV .EBV ( CTLs T) ,
,
, .
, ,
, DNA .
.Oncofetal Antigens.
- , , ,
, () .
, , - (
) . -
,
.
,
, . ,
, . -
, , . -
,carcinoembryonic antigen (CEA) -
- .alpha-fetoprotein (AFP). -
.
, .
, ,/
, .
, , (.)mucins
,
. ,
, , .

 .
, GM2, -
.GD2, & GD3
, GM2- ,GD3 - GM2
.
( , )Mucins ,
.

,
= , ,
, - .
, CA-125 , CA-19-9
, , , MUC-1 .
MUC-1 ,
, , .
, ,
, .
T ,
.

Cell Type-Specific Differentiation Antigens.

.
,differentiation antigens
. ,
. ,
B , , ("
") , ( CD10 common acute lymphoblastic leukemia antigen,
,) or CALLA .CD20 -
. B
, B B .,
B
. ,
.


-,
CD8CTL -
(.)Cytotoxic T Lymphocytes
,6 :
Cytotoxic T Lymphocytes
CTL -
. , CTL -
( : Burkitt EBV -
,Lymphoma HPV -)
. Tumor-specific T lymphocytes -
. .
Natural killer cells
NK - (/)
. MHC class 1 -
. ,6 NK -
.MHC
, ,IL-2 NK - ()
. NK -
. NK -
,
.

. T
NK .
,INF- - T ,NK -
.
(,)microbes
.

.
antibody
,dependent cell-mediated cytotoxicity FC -
NK . ,
, .
Immune Surveillance
,
?
( immunodeficient
.)hosts
5% - 200
.
, ( ) (
.)immunoblastic B-cell lymphoma X-linked recessive immunodeficiency -
disorder .)x- linked lymphoproliferative syndrome( XLP

 SAP
( .)lymphocyte signaling pathway XLP ,EBV
( ,)self limited form of infectious mononucleosis
. 25% - XLP -
.B
.
,
( .)7-53

Figure 7-53 Mechanisms by which tumors evade the immune system. (Reprinted
from Abbas AK, Lichtman AH: Cellular and Molecular Immunology, 5th ed.
)Philadelphia, WB Saunders, 2003.

Selective outgrowth of antigen-negative variants
, (=
).
MHC -
,HLA class 1
T . ,
.NK -
-
, T 2
,MHC - ( .)6

 MHC -
,class 1 - . ,
, ( )anergy
.
( )autoloous - .B7-1
,
. - ,
.anti-tumor T cells -
Immunosupression
( )
. , .
,TGF- , , .
, tumor -
.immunity
Antigen masking

glycocalyx
.mucopolysacchaides glycocalycs -
( ).
T
- .FAS ligand
T FAS , tumor -
.specific T cells

"" .
-
,immune surveillance .
,
,B -
EBV .
( , ())gastrointestinal
, .
tumor -
,immunity ,
.
( ,)MMPs
.

.

, . ,
. , , ( )morbidity .
, , .

 .
. ,
.
,
.
. ,
. , , .
, , "
.
: , / ( )masses .
, .
3:
.1 .
.2 grading - staging - .
.3 .
.1
.
, , /:
.
.
.
.
.
( )cachexia .

.pituitary adenoma
, ,
(.)endocrinopathy

.
, , . ,
(
.)17
.
,
.
- cell adenoma 1 -"
. ,
( )hormone-like - ( ).

( , ) , .
( Melena ) ( ) , .
,
( )cachexia .
Cancer Cachexia

 ,
. cachexia - .wasting syndrome -
cachexia - . , -
cachexia ,
.
, ,
.gastrointestinal tumors - -
, ,
cachexia - .
cachexia :
, ,
.
, ,
.
cachexia - ,
.
- " . -
,cachexia , tumor ( TNF
)necrosis factor . TNF
wasting syndrome - .
IL-1, IFN- leukemia inhibitory factor - .TNF
,
( ,)proteolysis-inducing factor PIF :
.
,
. cachexia .
-
- ,
( ) .
10% .
, , :
.
.
, .
- .7-12
.
TABLE 7-12 -- Paraneoplastic Syndromes
Causal Mechanism

Major Forms of
Underlying Cancer

Clinical Syndromes
Endocrinopathies

ACTH or ACTH-like
substance

Small cell carcinoma of

lung

Cushing syndrome

TABLE 7-12 -- Paraneoplastic Syndromes

Clinical Syndromes

Major Forms of
Underlying Cancer

Causal Mechanism

Pancreatic carcinoma
Neural tumors
Syndrome of
inappropriate antidiuretic
hormone secretion
Hypercalcemia

Small cell carcinoma of Antidiuretic hormone or atrial

lung; intracranial
natriuretic hormones
neoplasms
Squamous cell carcinoma
of lung

Parathyroid hormone-related
protein (PTHRP), TGF-,
TNF, IL-1

Breast carcinoma
Renal carcinoma
Adult T-cell
leukemia/lymphoma
Ovarian carcinoma
Hypoglycemia

Fibrosarcoma

Insulin or insulin-like
substance

Other mesenchymal
sarcomas
Hepatocellular carcinoma
Carcinoid syndrome

Bronchial adenoma
(carcinoid)

Serotonin, bradykinin

Pancreatic carcinoma
Gastric carcinoma
Polycythemia

Renal carcinoma

Erythropoietin

Cerebellar hemangioma
Hepatocellular carcinoma
Nerve and Muscle
Syndromes
Myasthenia

Bronchogenic carcinoma

Disorders of the central

and peripheral nervous
systems

Breast carcinoma

Immunologic

Dermatologic Disorders
Acanthosis nigricans

Gastric carcinoma
Lung carcinoma
Uterine carcinoma

Immunologic; secretion of
epidermal growth factor

TABLE 7-12 -- Paraneoplastic Syndromes

Clinical Syndromes
Dermatomyositis

Major Forms of
Underlying Cancer

Causal Mechanism

Bronchogenic, breast
carcinoma

Immunologic

Bronchogenic carcinoma

Unknown

Pancreatic carcinoma

Tumor products (mucins that

activate clotting)

Osseous, Articular, and

Soft Tissue Changes
Hypertrophic
osteoarthropathy and
clubbing of the fingers
Vascular and
Hematologic Changes
Venous thrombosis
(Trousseau phenomenon)

Bronchogenic carcinoma
Other cancers
Nonbacterial thrombotic
endocarditis

Advanced cancers

Hypercoagulability

Anemia

Thymic neoplasms

Unknown

Various cancers

Tumor antigens, immune

complexes

Others
Nephrotic syndrome

ACTH, adrenocorticotropic hormone; TGF, transforming growth factor; TNF, tumor

necrosis factor; IL, interleukin.
.)endocrinopathies(
,
.
Cushing Syndrome
50% - .
corticotropin .small cell type ,
.corticotropin-like peptides
.)pro-opiomelanocortin( POMC - corticotropin
- POMC Cushing Syndrome -
corticotrophin . corticotrophin
.POMC

. -
.
: 2
) (osteolysis( .1
. multiple myeloma )

 .2 ( )calcemic humeral substances

(.)extrossous
( )skeletal metastases -
.
- .
,PTH - PTHRP -
(.)Parathyroid hormone related protein
PTHRP - (.)amino terminous
PTHRP - ,PTH -
( )GPCR PTH-R( PTH / PTHRP receptor - .)PTHRP-R
PTHRP ,PTH - , ,
. , .
PTHRP - lactating brest - .
- , , .
, PTHRP - ,
.
,squamous cell bronchogenic - -
small cell cancer of the lung
(.)endocrinopathies
TNF ,TGF- ,IL-1 dihidroxyvitamin D -
.
( Neuromyopathic Paraneoplastic syndrome
).
.:
( peripheral neuropathy o )
cortical cerebellar degeneration o
( polymyositis o ,
).
( Myasthenic syndrome o .)myasthenia gravis -
.
,
. .
,
.
Acanthosis nigricans
- hyperkeratosis verrucous .
.
50% - ( ,)40
. .
( Hypertrophic osteoarthropathy ).
1%-10% - bronchogenic carcinoma (
).
:
( ,)periosteal
,metatarsal ,metacarpal ,.proximal phalanges -
.

 ( .)digits
, ,
, ( )cyanotic , .
Hypertrophic osteoarthropathy - .
Vascular and hematologic manifestations
. ( ,)4
)Trousseau Syndrom( migratory thrombophlebitis
, .
- ( .)13
- promyelocytic leukemia-
.prostatic adenocarcinoma
( )fibrinous vegetation , -
( ) ,
( mucin ).
,nonbacterial thrombotic endocarditis .12
.
Grading and staging of tumors
.
( )grade ()stage
.
Grading
. I IV- .
, .
, ,
, well-differentiated, mucin-secreting
adenocarcinoma of the stomach highly undifferentiated, retroperitoneal malignant
(.tumor )probably sarcoma
, ( ) , grading-
.staging-
- Staging ,
(.)blood-borne metastases
:
.1 )Union Internationale Contre Cancer ( UICC- T :TNM
N , ( )region M- .
TNM , :
T1 ,T4 T0 .in situ
N0 N1- N3 .
M0 M1- M2
.
.2 )American Joint Committee( AJC- 0 ,IV
, .
Staging , .
.
, staging , , positron
.emission tomography


, . .
( ... !) ...
, .

.
. .
.

. .
. ,
. ( ,)adequate
.
)1( : ( )excision ( )2 " ( )3
( )smears . ,
, .
(
) , (
)glutaraldehyde
, .
" "quick-frozen section ,
.
. ,
. .
, .
" ( )Fine-needle aspiration .
( )small-bore needle
. ,
. ,
.
. , .
.Cytologic (Pap) smears
, ,in situ , ,
( ,)bronchogenic , ,
, , .
.

Figure 7-54 A normal cervicovaginal

smear shows large, flattened squamous
;cells and groups of metaplastic cells
interspersed are some neutrophils.
There are no malignant cells. (Courtesy
of Dr. P.K. Gupta, University of
)Pennsylvania, Philadelphia, PA.

 ,
. , ,
. ,
,
. , .
.in situ
.
,
. , , .
, , . :

.
:
( )undifferentiated ,
.
.H&E- ,
,
. intermediate filaments
, IF .
, , ()
.
( )
, T B- .
.14
.
. ,

. ( prostate-specific
)antigen .

(/) ,
( .)23 , ,
, . , ERBB2
" . ERBB2
.

Figure 7-55 An abnormal

cervicovaginal smear shows
numerous malignant cells that have
;pleomorphic, hyperchromatic nuclei
interspersed are some normal
polymorphonuclear leukocytes.
(Courtesy of Dr. P.K. Gupta,
University of Pennsylvania,
)Philadelphia, PA.

 ()molecular diagnosis
, ,
.

Figure 7-56 Anticytokeratin

immunoperoxidase stain of a
tumor of epithelial origin
(carcinoma). (Courtesy of Dr.
Melissa Upton, University of
)Washington, Seattle, WA.

,

.
() T B
() . ,6 T B-
. (
) , .
, " ( FISH ,)5
.
rearrangements , " .
BCR-ABL" PCR
( )chronic myeloid leukemia .
(
)26 . , ,
( round blue cell tumors ,)10 .
,Ewing sarcoma [t(11;22)(q24;q12)] , " PCR
. ()spectral karyotyping
. ,
24- ( ,)fluorochromes
rearrangements- ,
( ,5
.)5-25 ,
, . comparative
,genomic hybridization .
.
.

. N-MYC
1p . "
" PCR .FISH ,
1p 19q- ,
.EGF-
minimal residual disease ,
, ,PCR
" . BCR-ABL" PCR
.

 , K-RAS -
. , " PCR
, .
,
, BRCA2 ,BRCA1 ,RET
.
.
( )RET ,
. ,
- .
DNA microarray proteomics-
( ) ( .)7-1 microarray
RNA- 30,000 ' .
,
( 23 .)7-1
Proteomics .
. , 3000-
.
DNA .
, .tissue arrays
( )core ,
.
" .
Flow cytometry
,
DNA .
( .)14 ( )ploidy ,
( ) , ( )effusion
, .
DNA . ,
, , ,
.
()tumor markers
. ,
, . ,
.
. .
.
. .
, ,7-13 ,
:
,CEA , , ,
. , 60% 90%- ,
50% 80%- 25%- 50% CEA .
. CEA ,
( ,)alcoholic cirrhosis ,ulcerative colitis , .
. CEA

 . CEA .
, ( Dukes grading system- .)17
CEA , CEA
. CEA ,
CEA . .
AFP ( ,18 .)21
, GIT- .
. AFP
, . ,CEA- ,
, , ( ) ,
AFP . , AFP
. AFP
.
( AFP )human chorionic gonadotropin
.
PSAprostate-specific antigen and prostate ( PSMA-
)specific membrane antigen human chorionic gonadotropin ,
CA125- .
.
APC ,p53 , RAS- , p53
( )hypermethylated
p53 .
TABLE 7-13 -- Selected Tumor Markers
Associated Cancers

Markers

Hormones
Human chorionic gonadotropin Trophoblastic tumors, nonseminomatous
testicular tumors
Medullary carcinoma of thyroid

Calcitonin

Pheochromocytoma and related tumors

Catecholamine and metabolites

See Paraneoplastic Syndromes in Table

7-12

Ectopic hormones

Oncofetal Antigens
Liver cell cancer, nonseminomatous
germ cell tumors of testis

-Fetoprotein

Carcinoembryonic antigen Carcinomas of the colon, pancreas, lung,

stomach, and heart
Isoenzymes
Prostate cancer

Prostatic acid phosphatase

Neuron-specific enolase Small cell cancer of lung, neuroblastoma

Specific Proteins
Multiple myeloma and other

Immunoglobulins

TABLE 7-13 -- Selected Tumor Markers

Markers

Associated Cancers
gammopathies

Prostate-specific antigen and prostatespecific membrane antigen

Prostate cancer
Mucins and Other Glycoproteins

CA-125

Ovarian cancer

CA-19-9

Colon cancer, pancreatic cancer

CA-15-3

Breast cancer
New Molecular Markers

p53, APC, RAS mutations in stool and

serum

Colon cancer

p53 and RAS mutations in stool and serum

Pancreatic cancer

p53 and RAS mutations in sputum and

serum

Lung cancer

p53 mutations in urine

Bladder cancer