molecular biology of human cancers an advanced student's textbook - wolfgang a. schulz

PART I
M
O
LE
C
ULE
S
, ME
C
H
A
NI
S
M
S
,
A
ND
C
ELL
S
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M
O
LE
CU
LAR BI
O
L
OG

Y
O
F H
U
MAN
C
AN
C
ER
S
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Molecular Biolo
gy
of Human
C
ancers
A
n Advanced Student’s Textboo
k
b
y
WO
LF
G
AN
G
ARTH
U
R
SC

H
U
LZ
Department of Urology and Center for Biological and Medical Research,
Heinrich Heine Universit
y
, Dusseldor
f
, German
y
Springer
eBook ISBN: 1-4020-3186-6
Print ISBN: 1-4020-3185-8
©2005 Springer Science + Business Media, Inc.
Print ©2005 Springer
All rights reserved
No part of this eBook may be reproduced or transmitted in any form or by any means, electronic,
mechanical, recording, or otherwise, without written consent from the Publisher
Created in the United States of America
Visit Springer's eBookstore at:
and the Springer Global Website Online at:
Dordrecht
me
i
nen E
l
tern
g
ew
id

met
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T
ABLE
O
F
CO
NTENT
S
Pre
f
ace: How to read th
i
s book……………………………………………… x
iii
A
cknowledgements ……………………………………………………………. xvii
1
An Introduct
i
on to Human
C
ancers 1
1
.1 An overview o
f
the cancer problem 1
1
.2 Causes o
f

cancer
5
Box 1.1 Reactive ox
yg
en species 1
0
1
.3 Characteristic Properties o
f
Cancers and Cancer Cells 1
1
Box 1.2: Ha
ll
mar
k
s of Cancer 1
8
1
.4 Characterization and Classification of Cancers in the Clinic 1
7
1
.5 Treatment o
f
Cancer 21
Furt
h
er rea
di
n
g

23
2 Tumor
G
enet
i
cs 25
2
.1 Cancer as a
g
enetic
d
isease 26
2
.2. Genetic a
l
terations in cancer ce
ll
s 2
7
2
.3 Inherited predisposition to cancer 3
7
2
.4 Cancer genes 4
2
2
.5 Accumulation o
f

g

enetic an
d
epi
g
enetic chan
g
es in human cancers 44
Further readin
g
45
Box 2.1 Tumor v
i
ruses
i
n
h
uman cancers 46
3 DNA Damage and DNA Repa
i
r 47
3
.1 DNA
d
ama
g
e
d
urin
g
replication: base excision an

d
nucleoti
d
e excision
r
epair 4
8
3
.2 Nucleoti
d
e excision re
p
air an
d
crosslink re
p
air 5
5
3
.3 Stran
d
-break re
p
air 6
2
3
.4 De
f
ects in DNA repair and cancer susceptibilit
y

6
6
3
.5 Ce
ll
protection mec
h
anisms in cancer 6
8
Furt
h
er rea
di
ng 70
4 Onco
g
enes 71
4.1 Retroviral onco
g
enes 7
2
4.2 S
l
ow-acting trans
f
orming retroviruses 7
5
4.3 Approaches to the i
d
enti

f
ication o
f
human onco
g
enes 7
8
4.4 Functions o
f

h
uman onco
g
enes 8
4
Furt
h
er rea
di
n
g
8
9
Box 4.1 Carc
i
nogenes
i
s
b
y HTLV-I 90

5 Tumor Su
pp
ressor Genes 91
5
.1 Tumor suppressor genes in hereditary cancers 9
2
5
.2 RB1 an
d
the cell cycle 9
7
5.3 TP53 as a
d
ifferent kin
d
of tumor suppressor 101
v
ii
PART I – MOLE
C
ULE
S
, ME
C
HANI
S
M
S
, AND
C

ELL
S

5
.4 C
l
assi
f
ication o
f
tumor suppressor
g
enes 10
9
Furt
h
er rea
di
n
g
111
Box 5.1 Human pap
ill
oma v
i
ruses 112
6

C
ancer Pathwa

y
s 113
6
.1 Cancer Pathwa
y
s 114
6
.2 MAPK signa
l
ing as a cancer pat
h
way 11
5
6
.3 The PI3K pathwa
y
119
6
.4 Regulation of the cell cycle by the MAPK an
d
PI3K pathways 123
6
.5 Modulators o
f
the MAPK and PI3K pathwa
y
s 12
6
6.6
T

he
TP
53

netwo
r
k
12
9
6.7 Signaling by TGF
E
F
factors 131
E
6
.8 Signaling through STAT factors 13
2
6.9 The NF
N
F
B pathway 135
N
N
6
.10 Developmental regulatory systems as cancer pathways 13
7
Further readin
g
144
7 A

p
o
p
tosis and Re
p
licative Senescence in Cancer 14
5
7.1 Limits to cell proliferation 146
7.2 Mechanisms o
f
apoptosis 150
7.3 Mechanisms of diminished apoptosis in cancer 15
6
7.4 Replicative senescence and its disturbances in human cancers 15
9
Furt
h
er rea
di
ng 164
Box 7.1: Human aging and cancer 165
8
C
ancer Ep
ig
enet
i
cs 167
8.1 Mec
h

anisms o
f
epigenetic in
h
eritance 16
8
8.2 Imprintin
g
an
d
X-inactivation 17
0
8.3 DNA methylation 174
8.4
Ch
romatin structure 17
9
8.5 Epigenetics of cell differentiation 18
2
8.6 Epigenetics o
f
tissue
h
omeostasis 185
Further reading 191
Box 8.1 Carc
i
no
g
enes

i
s
by
HIV 192
9 Invas
i
on and metastas
i
s 19
3
9.1 Invasion an
d
metastasis as multiste
p

p
rocesses 19
4
9.2 Genes and
p
roteins involved in cell-to-cell and cell-matrix adhesion 19
7
9.3 Genes and proteins involved in extracellular matrix remodelin
g


d
urin
g
tumor invasion 202

9.4
A
ngiogenesis 206
9.5 Interactions o
f
invasive tumors wit
h
t
h
e immune s
y
stem 21
0
9.6 T
h
e importance o
f
tumor-stroma interactions 21
2
Furt
h
er rea
di
ng 21
6
Box 9.1 Tumor hypoxia and its consequences 217
viii
PART II - HUMAN
C
AN

C
ER
S

1
0 Leukemias and Lymphomas 21
9
1
0.1 Common properties o
f

h
emato
l
o
g
ica
l
cancers 22
1
1
0.2 Genetic aberrations in leukemias and lymphomas 22
3
1
0.3 Mo
l
ecu
l
ar
b

io
l
ogy o
f
Bur
k
itt
l
ymp
h
oma 22
6
1
0.4 Mo
l
ecu
l
ar
b
io
l
ogy o
f
CML 23
2
1
0.5 Molecular biology of PML 23
7
Furt
h

er rea
di
n
g
242
1
1 W
i
lms Tumor
(
nephroblastoma
)
24
3
1
1.1 Histology, etiology an
d
clinical behavior of Wilms tumors 244
1
1.2 Genetics of Wilms tumors an
d
the WT1 gene 24
6
1
1.3 Epi
g
enetics o
f
Wilms tumors and the ‘WT2’ locus 25
0

1
1.4 Towards an improved classification of Wilms tumors 252
Further readin
g
253
1
2
C
ancers o
f
the sk
i
n 25
5
1
2.1 Carcinogenesis in the skin 256
1
2.2 S
q
uamous cell carcinoma 26
0
1
2.3 Basal
C
ell
C
arcinoma 262
1
2.4 Me
l

anoma 26
6
1
2.5 Tumor anti
g
ens 269
Furt
h
er rea
di
ng 270
1
3
C
olon
C
ancer 27
1
1
3. 1 Natural histor
y
o
f
colorectal cancer 27
2
1
3.2 Familial Adenomatous Polyposis Coli and the WNT pathway 27
3
1
3.3 Progression of Colon Cancer an

d
the Multi-Step Mo
d
e
l
of
Tumorigenesis 28
0
1
3.4 Here
d
itar
y
nonpol
y
posis colon carcinoma 28
2
1
3.5 Genomic insta
b
i
l
ity in co
l
on carcinoma 28
4
1
3.6 In
f
lammation and colon cancer 285

Furt
h
er rea
di
ng 28
7
Box 13.1 Positional clonin
g
of tumor suppressor
g
enes in hereditar
y
cancers . 288
1
4 Bladder
C
ancer 28
9
1
4.1 Histology an
d
etiology of bla
dd
er cancer 29
0
1
4.2 Molecular alterations in invasive bla
dd
er cancers 29
7

1
4.3 Molecular alterations in papillar
y
bla
dd
er cancers 30
2
1
4.4 A comparison o
f
bladder cancer subt
y
pes 30
4
Furt
h
er rea
di
ng 30
5
Box 14.1: Tumor suppressor can
did
ates at 9q
i
n
bl
a
dd
er cancer 306
1

5 Renal
C
ell
C
arc
i
noma 307
1
5.1 The diversit
y
o
f
renal cancers 30
8
1
5.2 Cytogenetics of renal cell carcinomas 310
ix
15.3 Molecular biolo
gy
o
f
inherited kidne
y
cancers 31
1
15.4 Von-Hippel-Lindau s
y
ndrome and renal carcinoma 31
6
15.5 Molecular biology of clear cell renal carcinoma 32

1
15.6 Chemotherap
y
an
d
immunotherap
y
o
f
renal carcinomas 32
4
Further readin
g
326
1
6 Liver Cancer 327
16.1 Etio
l
ogy o
f

l
iver cancer 328
16.2 Genetic chan
g
es in hepatocellular carcinoma 33
1
16.3
V
iruses in H

CC
33
6
Furt
h
er rea
di
n
g
33
9
Box 16.1 Hepatoce
ll
u
l
ar carc
i
noma
i
n exper
i
menta
l
an
i
ma
l
s 340
1
7

S
tomach
C
ancer 341
17.1 Etio
l
o
gy
o
f
stomac
h
cancer 342
17.2 Mo
l
ecu
l
ar mec
h
anisms in gastric cancer 34
5
17.3 Helicobacter pylori an
d
stomach cancer 34
8
Further reading 35
4
Box 17.1: Barrett esopha
g
us and esopha

g
eal cancer 355
1
8 Breast
C
ancer 35
7
18.1 Breast biology 35
8
18.2 Etiolo
gy
o
f
breast cancer 36
4
18.3 Hereditary breast cancer 365
18.4 Estro
g
en receptors and ERBB proteins in breast cancer 373
18.5 C
l
assi
f
ication o
f

b
reast cancers 37
8
Further reading: 382

1
9 Prostate
C
ancer 38
3
19.1 Epi
d
emiology of prostate cancer 38
4
19.2 Androgens in prostate cancer 38
9
19.3 Genetics an
d
epi
g
enetics o
f
prostate cancer 39
4
19
.4 Tumor-stroma interactions in prostate cancer
398
Further reading 402
PART III - PREVENTION, DIA
G
NO
S
I
S
, AND THERAPY

2
0 Cancer Prevention 403
20.1 The importance o
f
cancer prevention 40
3
20.2 Primar
y
prevention 40
4
20.3 Cancer prevention and diet 408
20.4 Prevention of cancers in groups at high risk 41
5
20.5 Prevention o
f
prostate cancer
b
y screening t
h
e aging ma
l
e popu
l
ation 420
20.6 Other t
y
pes o
f
prevention 423
Furt

h
er rea
di
n
g
426
x
21 Cancer Diagnosis 427
2
1.1 The evolvin
g
scope o
f
molecular
d
ia
g
nostics 42
7
2
1.2 Molecular diagnosis of hematological cancers 42
9
2
1.3 Molecular detection of carcinomas 43
3
2
1.4 Molecular classification of carcinomas 43
9
2
1.5 Prospects o

f
molecular dia
g
nostics in the a
g
e o
f
individualized therap
y
44
2
Furt
h
er rea
di
n
g
447
22 Cancer Therapy 44
9
2
2.1 Limitations of current cancer
t
hera
p
ies 449
2
2.2 Mo
l
ecu

l
ar mec
h
anisms o
f
cancer c
h
emot
h
erap
y
45
0
2
2.3 Principles of targeted
d
rug therapy 459
2
2.4 Examples of new target-
d
irecte
d

d
rug therapies 46
4
2
2.5 New concepts in cancer therapy: Immunotherapy 47
5
2

2.6 New concepts in cancer therap
y
: Gene therap
y
47
9
2
2.7 T
h
e
f
uture o
f
cancer t
h
erapy 48
6

KEY
WO
RD I
N
DEX 489
xi
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P
REFA
C
E: H
OW

T
O
READ THI
S
B
OOK

Th
e present
b
oo
k

g
rew out from a
l
ecture course I
h
ave tau
gh
t for more t
h
an 5
y
ears,
o
ften to
g
ether with collea
g

ues who covered topics and cancers the
y
are more
f
am
ili
ar w
i
t
h
t
h
an myse
l
f. T
h
ese
l
ectures were ma
i
n
l
y atten
d
e
d

b
y
bi

o
l
ogy an
d

m
edical students well advanced in their curricula, but also by clinical trainees doing
c
ancer research in the lab, and b
y

g
raduate students and postdocs havin
g
entere
d

c
ancer research from different fields, including chemistry, pharmacology,
developmental
g
enetics, ph
y
sics, and even mathematics. This experience reflects
how cancer research, cancer prevention, and even cancer treatment increasin
g
l
y

become interdisciplinar

y
efforts.
Whil
e wr
i
t
i
ng t
h
e
b
oo
k
I
h
a
d
t
hi
s mot
l
ey group of peop
l
e
i
n m
i
n
d
, f

i
gur
i
ng t
h
a
t

t
hey all, with their different backgrounds, could make use of an introduction to the
m
o
l
ecu
l
ar
bi
o
l
ogy of
h
uman cancers. Spec
i
f
i
ca
ll
y, I fe
l
t t

h
at a text
b
oo
k
for more
a
dvanced students was required to fill a
g
ap between standard textbooks on one
h
an
d
an
d
spec
i
a
li
ze
d
rev
i
ews or even or
i
g
i
na
l
researc

h
papers on t
h
e ot
h
er
h
an
d
.
Moreover, the textbooks on molecular biology and genetics are usually read by
bi
o
l
og
i
sts an
d
t
h
ose on pat
h
o
l
ogy an
d
c
li
n
i

ca
l
onco
l
ogy on
l
y
b
y me
di
ca
l
stu
d
ents.
A
ccordin
g
l
y
, for biolo
g
ists and chemists medical terms had to be introduced, and fo
r

th
e rea
d
ers from t
h

e me
di
ca
l
profess
i
on some
g
enera
l
mo
l
ecu
l
ar
bi
o
l
o
gy

h
a
d
to
b
e
e
xp
l

a
i
ne
d
. So, p
l
ease
d
o not scoff
i
f some statements
i
n t
hi
s
b
oo
k
are foun
d
on t
h
e
fi
rst f
i
ve pages of t
h
e stan
d

ar
d
text
b
oo
k

i
n your spec
i
a
l
ty. However, t
hi
s
i
s ne
i
t
h
er a
book on biochemical mechanisms nor on clinical oncolo
gy
. So, if
y
ou do no
t

u
nderstand medical terms or molecular issues in the book,

p
lease borrow a textboo
k

f
rom a stu
d
ent of t
h
e ot
h
er
di
sc
i
p
li
ne or
(b
etter…
)
as
k
t
h
em to exp
l
a
i
n

.
Th
e
b
oo
k

i
s
i
nten
d
e
d
to prov
id
e a re
l
at
i
ve
l
y s
h
ort overv
i
ew of
i
mportant
c

oncepts and notions on the molecular biolo
gy
of human cancers (accordin
g
to the
a
ut
h
or’s op
i
n
i
on
)
,
i
nc
l
u
di
ng many facts essent
i
a
l
to f
i
n
d
one’s way
i

n t
hi
s f
i
e
ld
. It
i
s,
however, not meant to be comprehensive and probabl
y
cannot be, as our knowled
g
e
i
s rap
idl
y grow
i
ng. A
li
st of ot
h
er text
b
oo
k
s an
d

h
an
db
oo
k
s can
b
e foun
d

i
n t
h
e
‘
furt
h
er rea
di
ng’ sect
i
on of C
h
apter 1.
T
his book is named ‘Molecular Biology of Human Cancers’ because molecular
bi
o
l
o

gy

i
s at
i
ts center, a
l
t
h
ou
gh

i
n some p
l
aces I
h
ave attempte
d
to put t
hi
s spec
i
f
i
c
a
n
g
le of approach to the cancer problem into a broader, ‘real world’ perspective,

part
i
cu
l
ar
ly

i
n Part III. ‘Human’
i
s suppose
d
to stress t
h
at cancers
i
n
h
umans an
d
no
t

i
n ot
h
er organ
i
sms or
i

n v
i
tro mo
d
e
l
s of cancer are t
h
e ma
i
n
i
ssue
(
most ev
id
ent
l
y
i
n
t
he central Part II). The plural ‘Cancers’ is to indicate that the diversit
y
of human
c
ancers is stressed, although common mechanisms are treated in depth.
T
he subtitle is also pro
g

rammatic. It reads ‘An Advanced Student’s Textbook’
m
ost of a
ll

b
ecause t
h
e
b
oo
k

i
s suppose
d
to
b
r
id
ge t
h
e gap from un
d
ergra
d
uate
t
ext
b

oo
k
s to t
h
e spec
i
a
li
ze
d

li
terature. T
hi
s
i
s on
ly
one of severa
l
reasons for putt
i
n
g
‘
Advanced’ in the subtitle. Advanced students also understand that knowledge is
e
volvin
g
and must be constantl

y
questioned. So I have not avoided to point out the
limits of current knowled
g
e and open questions, as the
y
appear to me. Advance
d

x
ii
i
stu
d
ents
h
ave
l
earne
d
t
h
at sc
i
ent
i
f
i
c quest
i

ons are pursue
d

i
n a rea
l
wor
ld
, w
hi
c
h
i
mposes
li
m
i
ts on w
h
at we un
d
erstan
d
a
b
out
h
uman cancers an
d
w

h
at we can
d
o
a
bout them. I have therefore not avoided to mention limits of that sort either
,
where
a
ppropr
i
ate. A
d
vance
d
stu
d
ents a
l
so
k
now
h
ow to f
i
n
d

li
terature on a su

bj
ect,
i
f t
h
ey
w
ant t
o

c
h
ec
k
s
tat
e
m
e
nt
s
in th
e

boo
k
.
F
o
r that r

e
a
so
n an
d
t
o
limit th
e

s
iz
e

o
f th
e
v
olume, I have restricted the references to su
gg
estions for further readin
g
, which
f
o
ll
ow eac
h
c
h

apter. Most references are rev
i
ew art
i
c
l
es, an
d
a
l
most a
ll
are
i
n
E
ng
li
s
h.
I
h
ave tr
i
e
d
to
k
eep t
h

e
b
oo
k
to a s
i
ze t
h
at can
b
e rea
d

i
n a coup
l
e of wee
k
s
(
one
o
r two chapters per da
y
) and to write in a st
y
le that is not so dr
y
as to make readin
g

a
t
rial in endurance. Hopefully, you will not find it too journalistic. Ideally, you woul
d

rea
d
t
h
e vo
l
ume from start to f
i
n
i
s
h
. If you
d
o so, you w
ill
not
i
ce t
h
at many
i
mportant facts an
d

id
eas appear
i
n severa
l
p
l
aces, often
d
escr
ib
e
d
from
di
fferen
t

a
ng
l
es. T
hi
s re
d
un
d
ancy
i
s

i
nten
d
e
d
to
h
e
l
p memor
i
ze
i
mportant
i
ssues an
d

li
n
k

f
acts and concepts to each other. If you find essential points missing, please follow
my
request
i
n t
h
e

l
ast para
g
rap
h
of t
hi
s preface.
A secon
d
rea
di
ng strategy
i
s to fo
ll
ow t
h
e many cross-references
i
n t
h
e
b
oo
k
an
d

‘

surf’
i
t. T
hi
s approac
h

i
s strong
l
y recommen
d
e
d
to casua
l
rea
d
ers an
d
a
l
so to t
h
ose
who are already familiar with cancer molecular biology. To help you scan the book
a
nd find out what interests
y
ou, all chapters (except the first introductor

y
one and
t
he three more essa
y
-st
y
le chapters in Part III) contain a short introductor
y
section
li
st
i
ng t
h
e
i
r essent
i
a
l
po
i
nts. Eac
h
c
h
apter t
h
en procee

d
s to a more
d
eta
il
e
d

e
xpos
i
t
i
on,
b
ut a
l
so conta
i
ns a
ddi
t
i
ona
l
po
i
nts t
h
at are too spec

i
a
li
ze
d

(
or too
specu
l
at
i
ve
)
to
b
e of
i
nterest to every rea
d
er. So, you cou
ld

b
rowse t
hi
s
b
oo
k

b
y
readin
g
the one or two introductor
y
pa
g
es of each chapter and if
y
ou think ’I know
all
t
hi
s’ move on to t
h
e next one. Some
i
ssues w
hi
c
h

did
not f
i
t we
ll

i
nto t
h
e
g
enera
l

stream of thought are placed in separate boxes. Be aware that these are treated in a
part
i
cu
l
ar
l
y cursory fas
hi
on.
Part I starts with a brief overview chapter, which serves mainl
y
to define terms
a
nd introduce concepts and issues that are treated in more depth and detail in later
c
hapters. The followin
g
chapters deal with molecules and mechanisms important in
h
uman cancers. A
l

t
h
oug
h
t
h
ese c
h
apters conta
i
n a
l
ot of
i
nformat
i
on, t
h
ey presen
t

o
n
l
y a fract
i
on of w
h
at
i

s
k
nown
i
n t
hi
s regar
d
, s
i
nce
k
now
l
e
d
ge on
i
n
di
v
id
ua
l

m
o
l
ecu
l

es an
d
t
h
e
i
r
i
nteract
i
ons
i
s present
l
y expan
di
ng at a part
i
cu
l
ar
l
y rap
id
pace.
For instance
,

|
2

50 genes are now considered oncogenes or tumor suppressor genes
in humans, by a strict definition, and at least ten times as many are implicated as
important in cancer biolo
gy
. Some molecules and man
y
mechanisms are common to
several human cancers, but the actual mechanisms for each t
y
pe or even subt
y
pe o
f

c
ancer
di
ffer. One cou
ld
p
i
cture t
hi
s re
l
at
i
ons
hi
p as a

l
ar
g
e set of onco
g
en
i
c
m
echanisms
,
from which various subsets are relevant in different cancers.
In some cancers, t
h
e mec
h
an
i
sms
i
nvo
l
ve
d

i
n carc
i
nogenes
i

s, cancer progress
i
on,
o
r response to therap
y
are rather well understood, and the role of specific
g
enes and
prote
i
ns
h
as
b
een we
ll
e
l
uc
id
ate
d
. In m
y
op
i
n
i
on, t

h
e most exc
i
t
i
n
g
an
d
prom
i
s
i
n
g

development in cancer research is an increasin
g
abilit
y
to not onl
y
identif
y
and lis
t

m
o
l

ecu
l
ar c
h
anges,
b
ut a
l
so to re
l
ate t
h
em to t
h
e c
h
aracter
i
st
i
c
bi
o
l
og
i
ca
l
propert
i

es
x
i
v
an
d
c
li
n
i
ca
l

b
e
h
av
i
or of spec
i
f
i
c
h
uman cancers. T
h
e cancers
di
scusse
d

i
n Part II are
s
e
l
ecte
d
accor
di
ng to t
hi
s cr
i
ter
i
on. T
h
ey are t
h
erefore not necessar
il
y t
h
e mos
t

prevalent or lethal cancers, although many of these are treated. Accordingly, the
t
reatment of eac

h
cancer type
i
s not compre
h
ens
i
ve e
i
t
h
er,
b
ut focuses on t
h
ose
se
l
ec
t
ed
i
ssues
an
d
m
ec
hani
s
m

s
that
we

u
n
de
r
s
tan
d

bes
t
.
Application of the knowled
g
e presented in Part I and Part II has be
g
un to
i
mprove t
h
e prevent
i
on,
di
agnos
i
s, an

d
t
h
erapy of
h
uman cancers. Part III t
h
erefore
gi
ves a s
h
ort s
k
etc
h
of t
h
e progress, pro
bl
ems, an
d
poss
ibl
e future of t
h
e
developments in these areas. Clearly, there is a still a long way to go until the
i
nsi
g

hts from molecular biolo
g
ical research are full
y
translated into a benefit for
f
ellow humans. Hopefully, this part will have to be much longer in future books.
Fi
na
ll
y, I
h
ave a request to t
h
e rea
d
ers. I
h
ave tr
i
e
d
, w
i
t
h
t
h
e
h

e
l
p of my
co
ll
eagues ac
k
now
l
e
d
ge
d

i
n t
h
e fo
ll
ow
i
ng ac
k
now
l
e
d
gement sect
i
on to

k
eep t
hi
s
b
oo
k
as free of m
i
sta
k
es as poss
ibl
e, to
d
ea
l
w
i
t
h
t
h
e most
i
mportant
i
ssues
i
n cancer

m
olecular biology and to label opinions and speculations as such, but certainly many
e
rrors rema
i
n. P
l
ease, sen
d
a s
h
ort note on an
y
t
h
at
y
ou f
i
n
d
,
b
est
by
e-ma
il

(
)

, I
h
ave as
k
e
d
for an extra-
l
ar
g
e s
i
ze ma
ilb
ox
on our universit
y
server.
x
v
This page intentionally left blank
A
C
KN
OW
LED
G
EMENT
S
M

an
y
co
ll
ea
g
ues from our un
i
vers
i
t
y

h
ave contr
ib
ute
d
f
ig
ures an
d
references for
t
he book. The
y
are usuall
y
acknowled
g

ed in the fi
g
ure le
g
ends. I am particularl
y

g
ratefu
l
to Prof. C
l
aus-D
i
eter Ger
h
arz for most of t
h
e
hi
sto
l
ogy f
i
gures, to Dr. Georg
Kronenwett for expert advice on hematological cancers, and to Dr. Andrea
L
innemann-Florl for drawin
g
man

y
fi
g
ures and improvin
g
man
y
of m
y
own. I am
f
urther obliged to them and several other colleagues for reading and commenting on
i
ndividual chapters or lar
g
e parts of the book, specificall
y
Dr. Aristoteles
A
nastasiadis, Dr. S
y
lvia Geisel, Michèle Hoffmann, Prof. Joseph Locker, Prof.
S
tephan Ludwi
g
, Dr. Dieter Niederacher, Dr. Julia Reifenber
g
er, Dr. In
g
o Schmitz,

D
r. Va
l
er
i
e Sc
h
umac
h
er, an
d
Dr. Hans-He
l
ge Se
i
fert. Ms. Bett
i
na Mö
ll
er
h
as
ki
n
dl
y
helped with the formatting and editing of the final version and Ms. Olga Schulz with
the

i

n
de
x
.

I have to apolo
g
ize to m
y
co-workers in the lab, Andrea Linnemann–Florl,
M
i
c
h
è
l
e Hoffmann
,
C
h
r
i
st
i
ane Ha
d
er
,
An
d

rea Pr
i
or
,
an
d
Marc Cronauer
,
for not
gi
v
i
ng t
h
em my fu
ll
attent
i
on for more t
h
an a year an
d
even more to our
l
a
b
stu
d
ents
a

n
d
tra
i
nees
d
ur
i
ng t
h
at per
i
o
d
. I am very gratefu
l
to a
ll
of t
h
em for compensat
i
ng
t
hrou
g
h their own initiative. I am also
g
rateful to our head of department, Prof.
A

ckermann, for supportin
g
the endeavor.
At Kluwer press (now Sprin
g
er), Ebru Umar talked me into writin
g
the book,
a
n
d

l
ater C
h
r
i
st
i
na
d
os Santos an
d
Me
l
an
i
a Ru
i
z too

k
care of t
h
e pro
j
ect.
If I ever
did
won
d
er w
h
y
b
oo
k
aut
h
ors fee
l
o
bli
ge
d
to t
h
an
k
t
h

e
i
r fam
ili
es for
support, I now
k
now. So, t
h
an
k
you, Ge
li
, O
l
ga, an
d
E
d
w
i
n!
D
üsseldorf, September 2004
W
AS
xv
ii
This page intentionally left blank
1

C
H
A
PTER 1
A
N INTR
O
DU
C
TI
O
N T
O
HUM
A
N
CA
N
C
ER
S
1
.1
A
N
O
VERVIEW
O
F THE
CA

N
C
ER PR
O
BLEM
What is commonly called ‘human cancer’ comprises in fact more than 200 differen
t

diseases. Together, they account for about one fifth of all deaths in the industrialized
countr
i
es of t
h
e Western Wor
ld
. L
ik
ew
i
se, one person out of t
h
ree w
ill

b
e treate
d
fo
r

a severe cancer
i
n t
h
e
i
r
li
fe-t
i
me. In a typ
i
ca
l
Western
i
n
d
ustr
i
a
li
ze
d
country
lik
e
Germany w
i
t

h

i
ts 82 m
illi
on
i
n
h
a
bi
tants, >400,000 persons are new
l
y
di
agnose
d

with cancer each
y
ear, an
d

|
200,000 succumb to the disease. Since the incidence of
m
ost cancers
i
ncreases w
i

t
h
age, t
h
ese f
i
gures are go
i
ng to r
i
se,
i
f
li
fe expectancy
c
ont
i
nues to
i
ncrease
.
If one considers the incidence and mortality by organ site, while ignoring furthe
r

biolo
g
ical and clinical differences, cancers fall into three lar
g
e

g
roups (Fi
g
ure 1.1).
C
ancers arising from epithelia are called ‘carcinomas’. These are the most prevalent
c
ancers overa
ll
. Four carc
i
nomas are part
i
cu
l
ar
i
mportant w
i
t
h
re
g
ar
d
to
i
nc
id
ence as

we
ll
as morta
li
ty. Cancers of t
h
e
l
ung an
d
t
h
e
l
arge
i
ntest
i
ne
(
co
l
on an
d
rectum,
o
13) are the most si
g
nificant problem in both
g

enders, to
g
ether with breast cance
r

(
o
18) in women and
p
rostate cancer (
o
1
9) in men. A second group of cancers are
not qu
i
te as preva
l
ent as t
h
ese ‘ma
j
or four’ cancers. T
h
ey compr
i
se carc
i
nomas o
f

t
he bladder (
o
14), stomach
(
o
1
7), liver (
o
16), kidne
y
(
o
1
5),
p
ancreas,
e
sop
h
agus, an
d
of t
h
e cerv
i
x an
d
ovary
i

n women. Eac
h
accounts for a few percent
o
f the total cancer incidence and mortality. Each of them is roughly as frequent as all
l
eu
k
em
i
as or
ly
mp
h
omas
(
o
1
0
)
ta
k
en to
g
et
h
er. T
h
e most preva
l

ent cancers are
t
hose of the skin
(
o
12), not shown in fi
g
ure 1.1. The
y
are rarel
y
lethal, with the
im
p
ortant exce
p
tion of melanoma. Cancers of soft tissues, brain, testes, bone, an
d

o
ther or
g
ans are relativel
y
rare; but can constitute a si
g
nificant health problem in
specific a
g
e

g
roups and
g
eo
g
raphic re
g
ions. For instance, testicular cancer is
genera
ll
y t
h
e most frequent neop
l
as
i
a affect
i
ng young a
d
u
l
t ma
l
es, w
i
t
h
an
i

nc
id
ence
o
f >1% in this group in some Scandinavian countries and in Switzerland.
Th
e
h
ea
l
t
h
s
i
tuat
i
on
i
n
l
ess-
i
n
d
ustr
i
a
li
ze
d

countr
i
es
di
ffers pr
i
nc
i
pa
ll
y from t
h
a
t

in the hi
g
hl
y
industrialized part of the world because of the continuin
g
, recurrin
g
o
r

new
l
y emerge
d

t
h
reat of
i
nfect
i
ous
di
seases, w
hi
c
h

i
nc
l
u
d
e ma
l
ar
i
a, tu
b
ercu
l
os
i
s,
a

nd AIDS. Nevertheless, cancer is im
p
ortant in these countries as well, with
di
fferent patterns of
i
nc
id
ence an
d
often
hi
g
h
er morta
li
t
i
es. Cancers of t
h
e stomac
h

(
o
17), liver
(
o
1
6), bladder

(
o
1
4), esopha
g
us, and the cervix are each endemic in
c
ertain parts of the world (Fi
g
ure 1.2). Often, the
y
manifest at
y
oun
g
er a
g
es than in
industrialized countries. Conversely, of the major four cancers in industrialize
d

c
ountr
i
es, on
ly

l
un
g

cancer
h
as t
h
e same
i
mpact
i
n
d
eve
l
op
i
n
g
countr
i
es.
2

C
H
A
PTER 1
T
his snapshot view of present-da
y
cancer incidence of course conceals chan
g

es
o
ver t
i
me
(
F
i
gure 1.3
)
. For
i
nstance,
l
arge-sca
l
e
i
n
d
ustr
i
a
li
zat
i
on an
d
t
h

e sprea
d
o
f

c
i
g
arette smokin
g
are
g
enerall
y
associated with an increased incidence of lun
g
,
kid
ney, an
d

bl
a
dd
er cancer. On t
h
e pos
i
t
i

ve s
id
e,
i
mprovements
i
n genera
l

h
yg
i
ene
a
nd food qualit
y
ma
y
have contributed to the spectacular decrease in stomach cance
r

F
i
gure 1.1 Inci
d
ence (top) an
d
mortality (bottom) of cancers (cases per year) by organ
site for females (grey bars) an
d

males (black bars) in Germany in 2000.
Data are from t
h
e Ro
b
ert Koc
h
Inst
i
tute
(
www.r
ki
.
d
e
)
.
A
N
AA
I
NTR
O
D
UC
TI
O
N T
O

H
U
M
A
N
C
A
N
C
ER
S

3

i
nc
id
ence t
h
at
i
s cont
i
nu
i
n
g

i
n

i
n
d
ustr
i
a
li
ze
d
countr
i
es
(
o
1
7.1
)
. On t
h
e ne
g
at
i
ve
side, prostate and testicular cancer appear to have increased over the last decades. In
p
rostate cancer, a s
li
g
h

t
i
ncrease
i
n t
h
e age-a
dj
uste
d

i
nc
id
ence
i
s exacer
b
ate
d

b
y t
h
e
o
verall aging of the population (
o
1
9.1).In some regions, the incidence of melanoma

h
as esca
l
ate
d

i
n an a
l
arm
i
ng fas
hi
on. T
hi
s
i
ncrease
i
s not re
l
ate
d
to t
h
e ag
i
ng of t
h
e

p
opulation, but perhaps to life-st
y
le factors (
o
1
2.1
).
O
ne
i
mportant a
i
m of mo
l
ecu
l
ar
bi
o
l
ogy researc
h
on
h
uman cancers
i
s to
understand the causes underl
y

in
g
the
g
eo
g
raphical and temporal differences in
cancer incidence. This understandin
g
is one important prerequisite for cance
r

p
revent
i
on
(
o
20
)
. O
b
v
i
ous
l
y, t
h
e prospects for prevent
i

on are
b
r
i
g
h
test for t
h
ose
cancers that exhibit lar
g
e
g
eo
g
raphical differences or the
g
reat chan
g
es over time in
t
h
e
i
r
i
nc
id
ences. To g
i

ve
j
ust one examp
l
e: T
h
e
i
nc
id
ence of prostate cancer of Eas
t

Asia residents may be 10-20-fold lower than that of their relatives who grow up in
the USA
(
o
1
9.1). It is easy imagining the potential for prevention, if the causes fo
r

t
his

di
ff
e
r
e
n

ce

we
r
e

u
n
de
r
s
t
ood.
Unfortunately, overall, neither incidence nor mortality of human cancer have
b
een muc
h

di
m
i
n
i
s
h
e
d

b
y consc

i
ous
h
uman
i
ntervent
i
on over t
h
e
l
ast
d
eca
d
es. T
h
e
mainsta
y
of treatment of the ‘bi
g
four’ cancers and of the carcinomas in the secon
d

g
roup out
li
ne
d

a
b
ove rema
i
n sur
g
er
y
, ra
di
ot
h
erap
y
, an
d
c
h
emot
h
erap
y
, as t
h
e
y
were
3
0
y

ears a
g
o. Sur
g
er
y
an
d
ra
di
ot
h
erap
y
are often successfu
l

i
n or
g
an-conf
i
ne
d
cases,
an
d
c
h
emot

h
erap
y

i
s mo
d
erate
ly
eff
i
cac
i
ous for some a
d
vance
d
cancers. In
g
enera
l
,
only modest improvements have been made in cure and survival rates for these.
Importantl
y
, the qualit
y
of life for the patients is now widel
y
accepted as a criterion

Fi
g
ure 1.
2
Mortalit
y
o
f
selected cancers b
y
or
g
an site in di
ff
erent re
g
ions o
f
the World
I
n each
g
roup of bars from left to ri
g
ht: World avera
g
e, Africa, North-America, South-
A
merica, North-West Europe, China. Data source: Shiba
y

a et al, BMC Cancer 2, 37ff
4
C
H
A
PTER 1
f
or successful therap
y
. Modern cancer therap
y
reco
g
nizes that not ever
y
mali
g
nan
t

t
umor can
b
e cure
d

b
y t
h
e means present

l
y ava
il
a
bl
e. So, treatment nee
d
s to
b
e
c
arefully chosen to maximize the chance for a cure while retaining a maximum of
li
fe qua
li
ty. Prov
idi
ng a
b
etter
b
as
i
s for t
hi
s c
h
o
i
ce w

ill
per
h
aps const
i
tute t
h
e mos
t

i
mmediate application of new insi
g
hts on the molecular biolo
gy
of cancers
(
o
21
)
.
In addition,
p
alliative treatments have become more so
p
histicated and
p
ain
m
edications are less restrictivel

y
administered. Nevertheless, the treatment of
m
etastat
i
c carc
i
nomas rema
i
ns t
h
e wea
k
est po
i
nt of current cancer t
h
erap
y
an
d
a
c
ruc
i
a
l
goa
l
of cancer researc

h

(
o
22
).
F
i
gure 1.3 Tren
d
s in the mortality of selecte
d
cancers in the USA
Th
e or
i
g
i
na
l

d
ata f
i
gure
i
s from t
h
e Amer
i

can Cancer Soc
i
ety.
Great ste
p
s towards successful treatment have been made with s
p
ecific cancers,
u
nfortunate
ly
most
ly
from t
h
e t
hi
r
d

g
roup a
b
ove. T
h
ese
i
mprovement
h
ave

h
a
d

li
tt
l
e
e
ffect on t
h
e
i
mpact of cancer on t
h
e overa
ll
popu
l
at
i
on,
b
ut
h
ave
h
e
l
pe

d
many
i
n
di
v
id
ua
l
s, often young peop
l
e an
d
c
hild
ren. Former
l
y
i
ncura
bl
e
l
eu
k
em
i
as an
d

lymphomas can now be successfully treated by chemotherapy and/or stem cell
t
ransp
l
antat
i
on, part
i
cu
l
ar
ly

i
n c
hild
ren an
d

y
oun
g
a
d
u
l
ts. L
ik
ew
i

se, t
h
e r
i
se
i
n
t
esticular cancer incidence is stemmed b
y
hi
g
hl
y
efficacious chemo- an
d

ra
di
ot
h
erapy, w
i
t
h
cure rates excee
di
ng 90%. O
b
v

i
ous
l
y, t
h
ere
i
s a nee
d
to
u
nderstand why these cancers, but not others respond so well to the
c
hemotherapeutic dru
g
s currentl
y
available. It is hoped that a better understandin
g
o
f

t
he molecular and cellular basis underl
y
in
g
this difference will eventuall
y
open the

d
oor to successfu
l
treatment of t
h
e ma
j
or carc
i
nomas, as w
ill
t
h
e
d
eve
l
opment of
novel dru
g
s and novel therapies based on the results of molecular biolo
g
ical cance
r

research
(
o
2
2).