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The Biology Of Cancer (2007) - Robert A. Weinberg - Ch. 15

The Biology Of Cancer (2007) - Robert A. Weinberg - Ch. 15

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Published by Sri Harsha
The Biology Of Cancer (2007) - Robert A. Weinberg - Ch. 15
The Biology Of Cancer (2007) - Robert A. Weinberg - Ch. 15

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Published by: Sri Harsha on Jan 31, 2013
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03/20/2015

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Chapter 15
Crowd Control:Tumor Immunology andImmunotherapy
It
is
by no means inconceivable thatsmallaccumulations
oftumour
cellsmay develop and,because of their possession of new antigenic potentialities, provokeaneffective immunological reaction withregression of the tumour and noclinicalhint of its existence.Macfarlane Burnet,immunologist,
1957
T
hroughout this text, we have studied various defenses that the body erectsagainst theappearanceof cancerous growths.Many of these defenses are inherent in cells, more specifically in their hard-wired regulatory circuitry. Themost obvious
of
these are thecontrolsimposed on cells by the apoptoticmachinery, whichispoised to trigger the death of cells that are misbehaving orsuffering certain types of damage or physiologic stress. The pRb circuit
and
the
DNA
repair apparatus are similarly configured to frustrate the designs of incipi
ent
cancer cells.The organization of tissues also places constraints on how incipient cancercellscan proliferate. For example, normal epithelial cells that lose their tethering to thebasement membrane activate the form of apoptosis that
is
calledanoikis.This mechanism limits the ability of epithelialcellsto stray from their normal locationswithin tissues and grow in ectopic
(i.e.,
abnormal) sites.
At
the same time, thespecial status afforded to stem cells
and
their genomes(Section
12.3)
also reduces theprobability of mutant cancercells'gainingafootholdwithina tissue.
 
Chapter 15:Crowd Control: Tumor Immunology and Immunotherapy
Beyond these cell-
and
tissue-specific mechanisms,
mammals
may haveanother line of
defense-the
immune
system. The
immune
system
is
highlyeffective in detecting and eliminating foreign infectious agents, includingviruses, bacteria,
and
fungi, from our tissues. One of the major questions in cancer research over
the
last half century has been whether the
immune
system canalso recognize cancer cells as foreigners
and
proceed to
kill
them.Actually, evidence
is
rapidly accumulating that
the immune
system does indeedcontribute to the body's multilayered defenses against tumors. The difficultiesassociated with establishing this type of anti-cancer defense are apparent fromthe outset: the immune system
is
organized to recognize
and
eliminate foreignagents from the body while leaving the body's own tissues unmolested. Cancercells, however, are native to the body
and
are, in
many
respects, indistinguishable from the body's normal cells. How can cancer cells be recognized
by
the
immune
system
as
being different
and
,therefore,appropriate targets of
immune-mediated
killing?
We
will wrestle with this problem
and
its ramifications repeatedly throughout this chapter.The field of
tumor
immunology, more than any other area of cancer research,remains in great flux,with basic concepts still a matter
of
great debate.Consequently, in this chapter, you will find
many
observations
and
conclusionsto be
much
more tentatively stated
than
elsewhere in this book
and
subject, nodoubt, to future revision.Still, this
is
an area of cancer biology
that
is well worthour time
and
study, since
it
holds great promise for new insights into cancerpathogenesis
and
new ways of treating
hwnan
tumors.Research conducted
on
mammals
over the past three decades has.revealed an
immune
system of great complexity and subtlety. Before
we
enter into discussions of its anti-tumor functions,
we
need to take an excursion into
the
workingsof the general
immune
system.
An
understanding of its mechanisms of action,at least in outline, is a prerequisite for engaging the three major questions
that
will occupy us in this chapter. First, what specific molecular
and
cellular mechanisms enable the
immune
system to recognize
and
attack incipient cancercells? Second, do these
immune
mechanisms represent effective defenses thatprevent the appearance oftwnors? Third, how can the
immune
system be mobilized by oncologists to attack tumors once they have formed?
(An
introductionto immunology will occupy
our
attention in Sections
15
.1 through
15
.
6;
anoverview
will
be provided in Figure 15.14.)
15.1 
The
immune system functions in complex ways todestroy foreign invaders and abnormal cells in thebody's tissues
The mammalian
immune
system launches several types of attack against foreign infectious agents
and
the body's own cells that
happen
to
be infected ""
ith
such agents. It identifies its targets by recognizing specific molecular
entities
antigens-that
are made
by
these agents. Having done
so,
the
immune
systemundertakes to
neutralize
or destroy the infectious particles (bacterial and fungal cells, virus particles),as well as infected cells displaying these antigens.
To
the extent that the
immune
system also functions to ward off cancer,oneassumes
that
it exploits
many
of the same mechanisms
that
it uses to eliminateforeign infectious agents.The most familiar of
the
immunological defense strategies involves
the
humoral
immune
response-the
arm of the
immune
system that generates soluble
antibody
molecules capable of specifically recognizing
and
binding antigens (Figure
15
.
1).
Thus,a virus particle or bacterium displaying antigens on itssurface may rapidly become coated with antibody molecules, which may resultin the neutralization of these pathogens (Figure
15
.
2).
Similarly, an infected cell
 
(C)
'.1--
light
Function
of
the humoral immune response
lig
ht
(L)
chain
(B)
constantregiondi
su
lfidebonds
(A)
Figure 15.1
Structure
of
antibody
molecules and
theirbinding
to
antigens
The
most abundant antibody molecule
in
the plasma
is
theimmunoglobulin
y
(lgG)molecule.
(A)
X-raycrystallography of
an
IgG
molecule
reveals
the symmetry that allows the
two
antigen-bindingdomains
(top left, topright)
to bind
two
antigenmoleculesSmultaneousl
y.
(B)
IgG
molecules
are
dividedinto t
wo
functionalregi
ons.
Oneregion
is
designedto recognizeandbindantigenmolecules.
Because
the
IgG
molecul
es
in
plasma
can
recognize
an
essentiallyunlimitednumber
of
antigens,
IgG
molecules
have
a comparable diversity
of
structures
in
their antigen-binding portions,which
are
ca
ll
ed
their
variable
domains
(red),
to recognizethisdiversity
The
remainder
of
the
IgG
molecule
is
termed its
constant
region
(blue)
and
is
invariant
am
ong
all IgG
molecules
of
agiven
subclass,
e.
g,
all IgG
1
molecules. An
IgG
molecule
as
awhole
is
a heterotetramercomposed of
two
light(L)chains and
two
heavy(H) chains.
Two
separateantigen-recognizing andbinding pockets
are
displayed
(topleft,topright),
each
composed
of
an
H-
and
an
L-chain N-terminaldomain
(concave
shapes).
(C)
The
detailedstructu
re
of
an
antigen-antibody complex
is
seen
here
in
thisspace-fillingmolecular model
in
w
hi
ch the antigen-binding domains
of
the
hea
vy
chain
(purple)
andlightchain
(yel/ow)
are
seen
to contact the antigenicmolecule,
in
this
case
thechicken egg-whitel
yso
zymemolecule
(lightblue).
Onlyparts
of
thevariab
le
regions
of
the heavyandlightchains
are
shownhere.(Aglutamineresidue,
red,
is
indicated thatisimportant for thehydrogen bonding
of
the antigen
to
the antibody molecule
.)
(From
CA
Janeway
Jr.
et
ai,
Immunobiology,6th
ed
.New
York
Garland
Science,
2005)
may displayon itssurfacetheantigensmadebytheagentsth
at
have infectedit
and
itssurface may becomecoatedwith antibodiesthatrecognize
and
bindtheseantigens.Onceamammaliancellor an infectious agent
is
coatedbyanti- body molecules,it may be recognized, engulfed,
and
destroyed by phagocytic
t-
A
~
l'--
J;
).
~
;..
- <
~
lJ).. 
antigen(chicken egg-Whitelysozyme)heavy(
H)
chain(
L)
chainFigure 15.2
Neutralization
by
antibody
molecules
(A)
Vir
us
partic
le
s
(red)
can
becomecoatedbyantibody molecules
(blue)
developed bythe immunesystem
of
an
infected host.
This
coating
neutralizes
(inactivates)the infectiv
it
y
of
the particles by blockingtheir adsorption to host
cells
.(B)Similarly,a bacteriumdisplaying certain surfaceantigens
(red)
can alsobe
prevented fromadheringto host
cells
(A)
antibody
preventsviraladsorption
(B)
antibodyprevents bacterial adherence
by
boundantibodymolecule
s.
6

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