613

Cancer

Singie i n i t i a l

Basal lamina proliiertive cett

A single
lpmento
t
of
lon
population, whic
carcinomas
initially altered cell gives rise to
progresses first to benign adenomas of
a

and
then nalignant carcinoma. The cancer cells invade the
to mal
size
size
aive tissue and penetrate blood and lymphatic vessels,
ughout the body. thereby Conne trye

tissue

Lyrnphatic
Blood vessel
mine, and nick
nickel compounds) are the vossel

major identified
moking is the undisputed cause of 80 to 90% of
human cancer. Smo
Proliferative
cell population
nas well as being implicated in cancers of the oral cavity, phar-
arNers,as e

karynx, esophagus, and other sites. In total,

it is estimated that smok-
onsible for nearly one-third of all cancer deaths-an impressive
l r asingle
carcinogenic agent.
e r carcinogens c o n ontribute to cancer development by stimulating cell
eion, rather than by inducing mutations. Such compounds are
liferation, rathe

t oa s t u m o r moters, since the increased cell division

erred

or
for the outgrowth
they
of a proliferative cell population dur-
required
atue
is nor development. The
Small adenoma
early stages
of tumo: phorbol esters that stimulate
g roliferation by tivating protein kinase C (see Figure 13.26) are clas-
mples. Their activity was defined by studies of chemical induction
Sdintumors in mice (Figure 15.7). Tumorigenesis in this system can be
iated by a single treatment with a mutagenic carcinogen. Tumors do
t develop, however, unless the mice are subsequently treated with a
nr Dromoter (usually a phorbol ester) to stimulate proliferation of the
mutated cells.
Hormones, particularly estrogens, are important as tumor promoters in
e development of some human cancers. The proliferation of cells of the Intermediate
erine endometrium, for example, is stimulated by estrogen, and exposure adenoma
pexcess estrogen significantly increases the likelihood that a woman will
ivelop endometrial cancer. The risk of endometrial cancer is therefore
shstantially increased by long-term postmenopausal estrogen replacement
serapy with high doses of estrogen alone. Fortunately, this risk is mini-
ized by administration of progesterone to counteract the stimulatory
iect of estrogen on endometrial cell
proliferation. However, long-term
Large adenoma
plus carcinoma

igure 15.6
nucture of
representative chemical carcinogens

O
Aflatoxin Benzo(a)pyrene
Invasion of biood
and lymphatic
vessels

Nickel carbonyl
-o-cts
Dimethylnitrosamine
O=C H,C
N-N=o
O=C
c-O H,C
612 Chapter 15

Initiation igure 15.4

Stages of tumor development The development of cancer initiates when a singie
mutated cell begins to proliferate abnormally, Additional mutations followed nv
00c@c@c00000000
Mutatin
selection for more rapidly growing cells within the population then result in pro-
gression of the tumor to increasingly rapid growth and malignancy

000000000000006
Cell
increasing capacity for proliferation, survival, invasion, and metastasis
prolieratio
(Figure 15.4). The first step in the process, tumor initiation, is thought to be
Progression the result of a genetic alteration leading to abnormal proliferation of a sin-
gle cell. Cell proliferation then leads to the outgrowth of a population of
8000000O000000
Initial tumor ce
clonally derived tumor cells. Tumor progression continues as additional
mutations occur within cells of the tumor population. Some of these muta-
Pyulation
Mutaton tions confer a selective advantage to the cell, such as more rapid growth,
and the descendants of a cell bearing such a mutation will consequently
become dominant within the tumor population. The process is called clonal
selection, since a new clone of tumor cells has evolved on the basis of its
Variant cell
with increased increased growth rate or other properties (such as survival, invasion, or
8rowth potential metastasis) that confer a selective advantage. Clonal selection continues
throughout tumor development, so tu ors ontinuously become more
Selecton kr
rapid growth rapid-growing and increasingly malignant.
Studies of colon carcinomas have provideda clear example of tumor
progression during the development of a common human malignancy (Fig-
O0c0.0o0000000 ure 15.5). The earliest stage in tumor development is increased proliferation
oooOOVarianttumor of colon epithelial cells. One of the cells within this proliferative cell popu-
ooo0 cell population lation is then thought to give rise to a small benign neoplasm (an adenoma
or polyp). Further rounds of clonal selection lead to the growth of adeno-
Mutation
mas of increasing size and proliferative potential. Malignant carcinomas
then arise from the benign adenomas, indicated by invasion of the tumor
80000000000000
OOoOStill more
cells through the basal lamina into underlying connective tissue. The can-
cer cells then continue to proliferate and spread through the connective tis-
Yooo rapidly sues of the colon wal. Eventually the cancer cells penetrate the wall of the
8rowing colon and invade other abdominal organs, such as the bladder or small
variant cell
intestine. In addition, the cancer cells invade blood and lymphatic vessels,
allowing them to metastasize throughout the body.
Selection
Causes of Cancer
Substances that cause cancer, called carcinogens, have been identified both
000000000G byststudies in experimental animals and by epidemiological analysis of
cancer frequencies in human populations (eg, the high incidence of lung
cancer among cigarette smokers). Since the development of malignancy is
OIOIC More a complex multistep process, many factors may atfect the likelihood that
rapidly cancer will develop, and it is overly simplistic to speak of single causes of
8rowing
variant most cancers. Nonetheless, many agents, including radiation, chemicals,
tumor cell and viruses, have beern found to induce cancer in both experimental ani-
population mals and humans.
Radiation and many chemical carcinogens (Figure 15.6) act by damaging
DNA and inducing mutations. These carcinogens are generally referred to
as initiating agents, since the induction of mutations in key target genes is
thought to be the initial event leading to cancer development. Some of the
initiating agents that contribute to human cancers include solar ultraviolet
radiation (the major cause of skin cancer), carcinogenic chemicals in
tobacco smoke, and aflatoxin (a potent liver carcinogen produced by some
molds that contaminate improperly stored supplies of peanuts and other
grains). The carcinogens in tobacco smoke (including benzo(a)pyrene,
 its

nents, such
B e c a u s e

changes
in
l
o t h e r cell.
a
NAS or prote
mequer
io oteins.
h o w e v e r ,

of incorrect
in s during DNA,
occ
alterations incorporatiaon
the
rsulttrom chemical
changes
NA either SpoA
can

In
addition,
various

or as
a
result of
e x p o s u r e
to
replications
hemicals or radiatio
por
ion or ranscriptio
(Figure
damage
5. 19) to DNA Can bloCk
P0 Such
tion uences that are
of mu
tnquency
a high of cel
result in
had to evoh:

chanidisvmsided toino
standpoint

trom
the theretore
able
cells have e
genomes, of DNA repair
their
aged
DNA. These mechanisms
of the chemical ro te
dirnct reversal
eral classes: (1) removal of the damaged base
damage,
and (2)
DNA. Where NA
ollowed t tle
newly synthesized
with
ment olved to enable cells to cope
with thes , a

A) Deamination

NH
HN
CH H

CH O=C CH
O=C

Cytosine Uracil

HN
HC
HC

Adenine
(B) Depurination
Hypoxanthine

us damage to HN-C CH
wo major formsDNA
of
sponta-
damage: (A) deamination
cytosine, and
ation (loss of guanine, and
DNA chainn
m cleavage ofpurine bases)
purine bases and
the bond CH DNA chain
an deoxyri-
apurinic (AP) site
' deoxyguanosine in A -CH
ate.
A
dGMP
AP site
 192 Chapter 5

DNA Repair
other
molcule, undergo a variety of
any
DNA,ike
copy ofchemi
serves as a perm
manent

oc the
Because DNA uniquely
tur ae of much
however
changes
in its
structui

component. as
Teater cons
RNAs or
other cell
in
alterations

result from
the
incorporation
tbases duringprote
of incornect
JensDN
can

In addition,
addition,
various
chemical

result ofexposure
as es
changes
to chem
occur
DNA
icals orCitheradia
rs
(Figure
5.19) o r
as aa

to DNA
resuan block replication
cani
or
Such damage transinriptian
5.20).
high frequency cell
sultfrom the
result in a
inhe standpoint of
nsequences
mutationso
of
that an
ell reproduction. To
able
their genomes,

aged
stanuthereroNA repairreatcanmechani
DNA. These
cells have
therefore hhad to evolve
m e c h a n i s m s of l sms toin
be divided
chemical
direct reversal ot the tion responsk
eral classes:(1) removal of the damaged
bases follov
damage, and (2) DNA. Where DNAedby
ment with newly
synthesized
to enable cells to cope with
the
have evolved
mechanisms
damage
A) Deamination

HN

O=C CH
CH
O=C

Uracil
Cytosine

NH

HN

HC
HC
Adenine Hypoxanthine

B: Depurination

HN
CH
Figure 5.19
HN-C
Spontaneous damage to DNA
There are two major forms of sponta-
neous DNA damage: (A) deamination DNA chain DNA chain
of adenine, cytosine, and guanine, and -CH:
(B) depurination (loss of purine bases) CH
resulting from cleavage of the bond
between the purine bases and deoxyri-
bose, leaving an apurinic (AP) site in O
DNA. dGMP = deoxyguanosine
AP sile
monophosphate. dGMP
 Replication, Maintenance, and DNA 193
gements of Genomi.

CH
H
CH
Cycobutare ring

C=0

thmies in DNA
CH
ANN Thymine dimer

CH
HN-C
Guanine
0-methylguanine

CRechoewith carcinogen

HN

H HN-

OH

Guanine
OH
OH

Bulky group addition

Figure 5.20o
Examples of DNA damage induced
by radiation and chemicals (A) UV
ect Reversal
of DNA Damage light induces the formation of pyrimi-
Most damage toDNA is repaired by removal of the damaged bases fol dine dimers, in which two adjacent
wedby resynthesis of the excised region. Some lesions in DNA, however, pyrimidines (eg., thymines) are joined
be rep by a cycobutane ring structure
by direct reversal of the damage, which may be a more etti- (B) AlIkylation is the addition of methy
way of dealing with specific types of DNA damage that occur fre- or ethyl gups to various positions on
in this way, Fartic the DNA bases. In this example, alkyl-
e w types of DNA damage are repaired ultraviolet (UV) light ation of the O position of guanine
n e dimers nesulting from exposure to the addition of results in formation of O-methylgua-
u a n i n e residues that have been modified by nine. (C) Many carcinogens (eg. benzo
t y l groups at the O position of the purine ing (a)pyrene) nact with DNA bases,
ght is one of the major is also the
of damage to DNA and
sources
resulting in the addition of lange bulky
mecha- chemical groups to the DNA molecule
roughly studied form of DNA
Its aportance is illustrated damage
by the
in terms of repair
fact that exposure to solar UV
 194 Chapter 5 all skin ca
almost
of
irradiation
is the
cause

by UV light is the humans. Th

formatition of pyri
Thymine dimer
of damage
which adjacent
induced
pyrimidines
on .the same strar d
of
ring resulting fre m SaturatiOn of
imidine
DNA ate
of a cyclobutane see Figure 5
(s
6
N.The fomai
formation and 5
DN
carbons
between
bonds s t r u c t u r e of
the in and
amage, so theirepair
is blcloocks
distorts the
repa
sely tcro ary
dimers
the site of dam
replication past
to survive
UVi
irradiation.One mechanism«
the ability cells
of reversal.echani
Light dimers is direct
UV-induced pyrimidine photoreac
al of the
Photoreactivating
enzyme
tion. The process
is called

ioht is utilized to break cyclobutane rine

the
dimetu
The original
pyrimidine
bases remain (
from the fact thatestored,
DNA, nov structure
in
be expected
mal state. As might Ui
source of
DNA damage tor diverse cell tvn
major is common to a ait
dine dimers by
photoreactivation
E. coli, yeasts, and.
including
avariety ofp
and eukaryotic cells, me speciess
Figure 5.21
Direct repair of thymine dimers and animals. Curiously,
however, oreactivation
is r ot univer
lack this mechanism of
humans) NA
damage resultingrepaifom
UV-induced thymine dimers can be
species (including direct
repaired by photoreactivation, in Another form of repair deals with
which energy from visible light is used
alkylating agents and DNA. Alkylatino
to split the bonds forming the cyclobu- tion between
compounds that can transfer methyl or thyl groups t agents ate
tane ring
the (see Figure 520R
base
thereby chemically modifying Apat
important type of damage
is methylation of the 0 posit

CH

N
CH
H,N-C Cysteine

0-CHh O. HS-CH

A A
HO H

0-methylguanine 0-methylguanine
methytransierase

HN
CH
H,N-C Methylcysteine

Gs-CH
Figure 5.22
Repair of 0-methylguanine O-methyl
guanine methyltransferasetransfers the
A
methyl group from O-methylguanine to a HO
cysteine residue in the enzyme's active site.
Guanine
 Replioation, Maintenane,
e , a nand
d Rearamgements of Cenomic DNA 195
Rearrangeme
methylguanine, torms
conmplementary
p n n f i n t .

dof cytosine. This lesion can be base pais

lguanine methyltrans repaind
that
by an
enzyme
#Omethy
transfers the methyl
methy lguanine to a ysteine residue in its
entially mutagenic chemical modification active
is thus
site
(Figure
r g a lgua anine is restore removed,
Enzymes that catalyze this
in both direct
t a n Wasptd prokaryotes and eukaryotes, inchud

pair
an etticien
tnyuin is way of
dealing with particular types of
,ecision npair iis a more
general means of
emical alterations DNA. Consequently, the repairing
a wide
various types of
t h e most impNortant DNA epair mechanisms in both pro-
t i c cells. In excision nepnir, the
danmaged DNA is rcog-
nnoved,
either free bases or as nuceotides
The nsulting is
i n by synthesis ot a new DNA strand, using the undamaged gap
d and com- DNA containing U formed by
deamination of C
strand as a template.
Three types of excision
nucleotide-excision
repair--base-exci-
repair, and mismatch repair-enable cells to
ha variety of different kinds of DNA damage.
of il-containing DNAis a good example of base-excision
he Ryuir
which damaged
single dar bases are recognized and removed from
it inmolecule (Figure
w i ti n
5.23). Uracil can arise in DNA by two mecha-
iracil (as dUTP [deoxyuridine triphosphate]) is occasionally
(
DNAglycosylase
td in place of thymine
during DNAsynthesis, and (2) uracil can AP site
in DNA by the mination of cytosine (see Figure 5.19A). The
med
because it
mechanism is of much greater biological significance
base pairing and thus repre
i the normal pattern ofThecomplementary
excision of uracil in DNA is catalyzed by
event.
gnt a mutagenic
an enzyme that cleaves the bond linking
the base
PNA glvcosylase,
DNA backbone. This reaction yields free
iadl) to the deoxyribose of the AP endonuclease
site-a sugar with no base attached. DNA gly-
ail and an apyrimidinic
and remove other abnormal bases, including
aslases also recognize deamination of adenine,
hpouanthine formed by the
pyrimidine dimers,
and bases danmaged by oxi
ayilated purines other than O-alkylguanine,
haon or ionizing radiation.
formation of an apyridiminic
The result of DNA glycosylase action is the
in DNA. Similar AP sites are
zurinic site (generally called an AP site)
as the result of the spontaneous
loss of purine bases (see Figure Deoxyribosephosphodiesterase
rmed under normal cellular
conditions.
5), which occurs at a significant rate is estimated to lose several thou-
hreample, each cell in the human body AP endonuclease,
are repaired by
X purine bases daily. These sites The remaining
an cleaves adjacent to the AP siteand (see Figure 5.23). is
the resulting single-base gap
Tbose moiety is then removed,
ed by DNA
polymerase and ligase.
DNA polymerase

Ligase
igm 5.23 deamination
s-encisi has been formed by
(pair In this example, uracil (U) complementary
0tine (C) (G) in the
tand of DNand is therefor opposite a guanine
uracil and the deoxyribose sDNA (an AP site).
DNA NA. The bond betweenwith base attached in the
chain. The
cosylase, leaving a suga no
which cleaves
the DNA
The result-
vemaiprinisg, drecognized by AP donuclease, leoxyribosephosphodiesterase.

yribose is removed by and sealed by ligase, leading to

incor-

then f oy DNA polymerase

aton of the correct
u base (C) Pposite the G.
whes NA wlas iexe

it,
INNe as

HHHHHIHEH
HHHHHTH
AULUNVAULU