肿瘤的生物学特性

肿瘤的生物化学特性物质代谢及酶的变化肿瘤细胞的分化肿

瘤

细

胞的

生

长肿瘤细胞扩散的过程机制肿瘤侵袭和转移相关基因An

inflammetorymkrcenrpnmentTissue

irva

sion&metastaslsSustainedangioEeneslsUmitle

atential

plicatSeM-sufticieney

incnewthsienalsEvationof

PaPtoEiPireenitlvttygrewtntoinnibtors物质代谢及酶的变化核

酸

代

谢核酸增多是肿瘤迅速生长的物质基础DNA

拓扑异构酶>端粒酶物

质

代

谢

及

酶

的

变

化核

酸

代

谢DNA

拓扑异构酶存在于细胞核内的一类酶，他们能够催化DNA链的

断裂和结合，从而控制DNA的拓扑状态。·DNA拓扑异构酶通过形成短暂的单链裂解-结合循环，

催化DNA复制的拓扑异构状态的变化(A)Classification

of

human

DNA

topoisomerases.Type

IB

are

the

only

enzymes(C)Noncovalent

binding

of

type

IB

enzymes.(D)Scheme

of

the

30phosphotyrosine

covalent

bond

in

the

Top1cc.The

arrow

indicates

thereversible(religation)reaction,which

is

favored

under

normal

conditions.G)that

form

cleavage

complexes

(cc)with

30-phosphotyrosyl

(30-P-Y)Scheme

of

the

50-phosphotyrosine

covalent

bond

in

the

Top2cc.intermediates.Type

IAType

IBType

IIATopo

1

Topo

lGyraseTopo

ivkDa987497(x2)90(x2)

0(x

)x2)784Type

IAoliType

ATop2a

170(x2)

Top2β

180(x2)Top3a

Top3βTop1Top1mtALk+1+1土1土1±2±2△Lk十

1±2±2kDa1129710070P-Y5°5°3'3*5*5*GyrAGyrBParCParEP-Y5*5*5*BE.HumansAFig.(1).Primary

domain

structure

of

the

topoisomerase

la

and

topoisomerase

Iβ

isozymes.The

homologous

N-terminal

ATPase

regionand

central

catalytic

core

regions

ofthe

two

enzymes

are

depicted

bysimilarly

filled

boxes,whereas

the

non-homologus

C-terminal

regula-

tory

domains

are

depicted

by

boxes

with

different

stripes.NLS

indicates

nuclear

localization

signal;pSer

and

pThr

indicate

phosphorylated

serine

and

phosphorylated

threonine

amino

acid

residue,respectively.The

amino

acid

numbers

are

based

on

the

topoisomerase

Ia

sequence-SwissProt

accession

P11388and

topoisomerase

IIβsequence-SwissProt

accession

Q02880.pSerpSer

pSer

pSer

pSer14001

424

146615241550NLS

Regulatory

C1626pSerpThr

pSer

pSer

pSer14131431152215261553C-Terminal.Tyr-826DNA

Binding/DNA

CleavageATPase

DNA

Binding/DNA

Cleavage

NLSpSerpSerpThr

pSer

pSer

pSer

pSer

pSer

1213

1332134313741392146914711476pSer

pSer

pSer

pSer

pSer

pThr

pSer

pSer12471337135413771393147014741525N-Terminal

CatalyticCoreTopoismerase

I

βgulatory1531ll

apSe

29TopoismerasepSer-1106Tyr-805ATPaseCNN物

质

代

谢

及

酶的

变

化核

酸

代

谢端粒酶distiihv

e

mDa

tecinhr

rous

tmue,

nhdichh

re

entsvapasrecosoprolianncEaIt

is

thought

that

length

or

integrity

of

chromosomethe

degradation

and

fusion

of

chromosome

endsby

helping

distinguish

chromosome

ends

from

aendisusedasamitoticcountingmechanismdoublestrandbreak

inthe

genomic

DNA.in

vitro物

质

代

谢

及

酶

的

变

化核

酸

代

谢端粒酶Mammalian

haveastretchofasimple

repeatsequenceFifty

i

0(

lo

e

li

n

A

i

h

s

roundof

mitosis.When

average

DNA

reaches

aIrreversibly.tbakn0orte15-2ssNthcer,mintnf

thGGoGpA0T2ttouncritically

short

length,about

4-7

kb,is

arrested物质代谢及酶的变化核

酸

代

谢蛋

白

质

代

谢√

糖

代

谢酶

系

统物质代谢及酶的变化酶系统增殖相关和分化相关的酶》转化相关和演进相关的酶转化相关

细胞恶变的指标。主要正常细胞发生转化，

总可出现这类酶活性的改变。演进相关的酶酶活性于恶性程度呈平行关系的酶肿瘤细胞的分化√分化的概念特定的生理功能特定的生化特征特定的形态结构各种不同

类型细胞

(分化细胞)同一来源的幼稚细胞细胞分化特点：稳定性全能性·选择性·条件可逆性未分化恶性肿瘤是由于起源组织中的干细胞

丧失了分化的能力。肿瘤细胞分化异常的机制遗传学改变信号转化异常微环境的影响诱导分化治疗肿瘤肿瘤细胞的生长细胞增殖活性的原位检测方法及意义细胞增殖活性：

细胞增生快慢的能力DNA

含量测定

确定增生细胞的比例Flow

cytometry

法DNA

ploidyand

proliferativeactivityasA

linkexists

between

highSPFvaluesandincreasedriskofrecurrence

and

deathforpatientswith

primary

BC,represented

by

the

S-phase

fraction(SPF).肿瘤细胞的生长免疫组织化学方法Only

papers

published

in

English

in

peerreviewedjournals

beforeJune>Ki-67Several

monoclonal

antibodies

reactingwithdifferent

proliferating

cell

nuclear

antigens

havebeendescribed,suchas

PCNA,Ki-67and

MIB

1,KiS1andothersThe

Ki-67/MIB

1

protein

hasa

prognosticvalue2004that

include

at

least

100

evaluable

patientswereselected.Inaddition,the

prognostic

and

predictive

role

ofthe

proliferative

markershadto

be

assessedthrough

multivariate

analyses.One

hundred

andtyl

papersfulfilled

these

criteria

and

159516

patientsyzed-twoanhirfor

many

types

of

malignant

tumors.肿

瘤

细

胞的

生

长免疫组织化学方法细胞周期蛋白Thedifferentcyclins:theconcentration

rise

andfallatspecificstagesthroughoutthecell

cycle,haveatemporallydistinctand

highly

regulatedpattern

ofexpression,i.e.they

are

synthesized

anddegraded

at

specific

stages

of

the

cell

cycle.Cyclin

E

isthe

limitingfactorforG1

phaseprogression

andSphaseentryRecently,several

splice

variants

of

cyclin

E1,whichare

not

present

in

normalcells,havealso

beendiscovered;whichstimulatecellstoprogressthroughthecellcycle

much

more

efficiently

than

the

full

length

cyclin

E1肿瘤细胞的生长免疫组织化学方法细胞周期蛋白Cyclin

E

was

prognostic

in

seven

out

of

10

studies.The

overexpression

of

cyclin

E

was

accompanied

bystatus.theappearanceoflowmolecularweight

(LMW)isoforms,and

both

were

a

reliable

prognostic

markerin

stage

l-lll

BC

patients.High

levels

of

cyclin

E1were

predictive

ofresistance

to

tamoxifen

adjuvant

therapy

in

108node-positive

BC

patients,independently

of

ER肿瘤细胞的生长细胞

周

期蛋白Cyclin

D1D-typecyclinsareotherkey

regulator

proteinsThe

protein

issynthesizedin

responsetoto

p

dinkt

h

citahlet

e

dllrivise

c

itotedth

o

ei

tirdi

ionectmsomcellcoerecruoCgrowth

factors;itslevelsreachamaximuminthe1

r

ft

c

gli1on

Din

tceybfnoeiodssociatycle

anachatthethe

cellsoppeahaseapItGopid-drmoftheG1phase

progression.肿瘤细胞的生长细胞周期

蛋

白Cyclin

D1Astrongcorrelationbetweenoverexpressionofcyclin

D1and

HR-positivity

hasbeenreported

in

the

majority

oftrials,but

cyclin

D1does

notappeartobea

strong

prognosticmarker.Infact,itsoverexpressionhas

beenassociatedwithbetterRFS

in

only

one

study肿

瘤

的

生

长

与

扩

散肿瘤的扩散方式直接蔓延转移

metastasi

S瘤细胞从原发部位侵入淋巴管、血管和体腔，>扩散到其它部位，

形成与原发瘤相同的肿瘤。肿瘤的生长与扩散肿瘤的扩散方式转

移

metastasis淋巴道转移Lymphatic

metastasis

is

aoutcomeinmanysolidpredictor

of

poormalignanciesThe

presence

of

lymph

node

metastasesdecreases

the

5-year

survival

of

melanomafactors

of

the

primary

tumor.patientsindependentofotherprognostic

-R-CD3::ss:

ecrt

drlyl

rpp'hngFioio

ea

i

cEteC

inn

DpSrPEEEVWVFigure1.Development

oflymphatic

vessels

inembryogenesis

and

cancerSome

ofthe

proteins

that

areimportant

in

theseevents

are

shown

underneatheach

section.Arrows

denote

the

direction

oflymph

flow

in

thelymphatic

vessels.肿

瘤的

生

长

与

扩

散肿瘤的扩散方式转

移

metastasis血

道

转

移肿瘤的生长与扩散肿瘤的扩散方式转

移

metastasis种

植性

转

移体腔内脏器的肿瘤蔓延至器官表面时，

瘤细胞可脱落种植于体腔和各器官表面形成多数转移瘤。肿瘤细胞扩散的过程机制肿瘤侵袭是转移的前提；侵袭和转移的步骤：脱离原发瘤群体产向周围组织浸润与局部血管或淋巴管密切接触，穿过其管壁>穿透管壁，

在基质中增生>

转移灶的形成和生长肿瘤细胞扩散的过程机制侵袭和转移的步骤：脱离原发瘤群体细胞黏附与细胞黏附分子以配体核受体结合的形式，

使细胞间发生粘连integrin跨膜糖蛋白○十六种a

亚单位和8种b亚单位肿瘤细胞扩散的过程机制细胞黏附与细胞黏附分子cadherin与细胞骨架连接☆人类至少有10多种钙粘蛋白E;

N;

D)肿瘤细胞扩散的过程机制细胞黏附与细胞黏附分子IgSF跨膜蛋白十具有与1g

类似的结构肿瘤细胞扩散的过程机制细胞黏附与细胞黏附分子Selectinfamilycancercellsadheretobya

process

similar

tothat

of

LC

homing.In

this

model,cells

in

flowarecapturedontheendothelialsurface.肿瘤细胞扩散的过程机制细胞黏附与细胞黏附分子Selectinfamilytransient

adhesive

interactions

by

cells

with

endothelialselectins(rolling),and

firmly

anchored

on(firm

adhesion)to

enable

entry

into

the

underlying

tissue.The

selectins,particularly

E-selectin,are

recognized

to

mediateadhesion

and

thus

potentiate

of

certain

cancers肿

瘤

细

胞

扩

散

的

过

程

机

制细胞黏附与细胞黏附分子CD44A

transmembrane

proteinEssential

for

the

homing

and

properties

of

leukemic

Cells,+CD44

has

also

been

found

to

support

anchorage-tgarlo

sv

l

r

rowth

andsgcancetumorddinoasofrmodelwth

inenntimdeexperdepeninin肿瘤细胞扩散的过程机制肿瘤细胞从原发灶分离的机制肿瘤细胞表面黏附分子减少。癌细胞钙含量降低>恶性肿瘤细胞间连接结构数量减少>肿瘤细胞表面电荷增加肿瘤细胞向周围组织的浸润细胞外基质的降解瘤细胞的运动趋化因子的作用肿瘤血管

生

成肿瘤细胞向周围组织的浸润肿

瘤

血

管

生

成肿瘤血管生成肿瘤组织中微血管的来源瘤细胞生成的多种生长因子诱导瘤体生成微血管>残存于流体的宿主血管逐渐变为肿瘤血管·VEGF是迄今鉴定出来的

最重要的血管生成因子FGFR-1FGFR-2

FGFR-3

FGFR-4Endothelial

cellsPericytesVSMCsTumor

cells

to

hl

e

l

ll

typesesr

ccelonoseur23FGF

LigandsFGF-1

FGF-2StromalcellsTKActive

angiogenesisHypoxiaFig.1

Switching

on

the

angiogenic

phenotype

in

tumors

by

geneticGeneticalteration

ofoncogenes&tumorsuppressorsFGF-2PDGF-BB

HGFAng-1VEGF-Ac-mycp53VHLUpregulationofangiogenicfactorsCytokinesProteasesand

epigenetic

factors.Both

malignant

and

nonmalignant

cellsproduce

multiple

angiogenic

factors

and

cytokines

to

induce

tumorneovascularization.Endogenous

angiogenesis

inhibitors

are

downNon-malignantcellsInflammatorycellsStromal

cellsEndothelial

cellsMultipleCelltypesregulated

to

support

the

angiogenic

phenotypeDownregulationofangiogenesisinhibitorsTSP-1EndostatinMalignantcells肿瘤细胞侵入血管和淋巴管侵入血管和淋巴管———在循环中运行到达远处部位Fig.1.Schematic

diagram

showing

how

production

of

VEGF-C

and

VEGF-C

in

tumorscan

induce

lymphangiogenesis,leading

to

increased

lymphatic

vessel

density

in

thevicinity

of

the

tumor,and

subsequently

to

metastasis

of

invasive

tumor

cells

via

thelymph

vessels.转移灶的形成和生长肿瘤侵袭和转移相关基因Nm23基因NM23-H1

andNM23-H2inhumanNucleoside

diphosphatekinases(NDPKs)catalyze

theexchange

of

y-phosphatebetweennucleoside(and2'-deoxynucleoside)triphosphates

and

diphosphates

withformation

of

a

high-energy

phosphohistidine(Parks

and

Agarwal

1973).They

are

encoded·参与调节

.态NM23)细胞内微管系统的genes

(also

known·高度表达nm23表现为低转移属性intermediateby

the

NME肿瘤侵袭和转移相关基因肿

瘤

转

移

相

关

基

因

mtal肿瘤侵袭和转移相关基因Tiam1

基因

鼠T

淋巴细胞瘤中克隆出来的基因。。TIAM1

T-cell

lymphoma

invasion

and

metastasis

1

[Homo

sapiens]产物具有1591个氨基酸残基，把蛋白质锚定在质膜上Currently,many

GEFs,including

Vav1,LARG,Bcr

and

T-lymphoma

invasion

and[Overexpressio

h

n

.

and

metastaticZhang

XM,Ding

Y,Chen

JZ,Jin

H,Yu

LN,Li

YF,Ding

YQ.asive68-72v2a]i)n:fnoeg1itygBinofonZmetastasis1(Tiam1),have

been

identified

as

oncogenes.肿瘤侵袭和转移相关基因Tiam1基因

鼠T淋巴细胞瘤中克隆出来的基因。。verexpressionsignificantlyincreasedtheabilities

ofoS:TiamRESULadhesion,migratoryandinvasionofC666-1and

CNE1cells,ngwiththatofthecontrol

untransfected

cells iLioncorrelateswiththeinvasionandmetastasisexpressUSION:am1ONCTC)iof

nasopharyngeal

carcinoma

cells.肿瘤侵袭和转移相关基因Tiam1

基因鼠T

淋巴细胞瘤中克隆出来的基因。。Int.J.Cancer:124,653-658

200

)

Wiley-Liss,Inc.Overexpression

of

Tiam1

in

hepatocellular

carcinomasYi

Ding1,Bin

Chen2,Shuang

Wang3,Liang

Zhao3,Juanzhi

Chen3,Yanqing

Ding3,Longhua

Chen1*andRongcheng

Luo2*predicts

poor

prognosis

of

HCC

patients肿瘤侵袭和转移相关基因Ras

基因包括H-ras,

K-ras

和N-ras

三类，生长因子通过Ras

信号通路，导致细胞增殖。。。转染给NIH3T3细胞，引起大量侵袭和转移。BritishJournalofCancer104,1038-1048(15March2011)S

Rachagani,S

S

n

p

h

b