MoD:
August
22,
2011
–
Biology
of
Neoplasm
–
Dr.


Moroz



 So
this
lecture
is
about
the
cell
cycle,
cell
division,
and
the
controlling
mechanisms
such
as
apoptosis
 that
regulate
the
cell
cycle.

This
lecture
like
the
rest
of
neoplasia
combines
our
memories
of
 biochemistry
with
pathology.

This
note‐set
will
be
organized
by
learning
objective.

 
 Objective 1: Outline the cell cycle and be able to discuss the significance of each phase, and factors that inhibit and activate the cycle. The
cell
cycle
is
essentially
made
up
of
4
stages
with
1
peripheral
stage.

The
four
stages
are
G1,
S,
G2,
 M.

As
we
all
probably
know
even
from
our
MCAT
days,
cell
growth
occurs
in
G1
and
G2
while
DNA
 synthesis
(S
for
synthesis)
occurs
in
the
S
phase.

The
M
phase
is
mitosis.

The
1
peripheral
stage
is
G0
 (aka
cell
purgatory)
where
cells
not
worthy
of
dividing
(e.g.
quiescent
cells
either
due
to
function
in
the
 body
or
damage)
travel
to.

This
is
much
clearer
in
the
diagrams
below.
 



 
 A
couple
pearls
of
wisdom
include:

 
 1)
Rb
is
the
primary
regulator
at
the
G1/S
site.

Rb
allows
for
the
genes
that
control
the
S
phase
(S
phase
 genes)
to
be
transcribed.

This
allows
the
cell
to
now
pass
into
the
S
phase
and
once
a
cell
passes
into
 the
S
phase,
it
is
committed
for
mitosis.

More
about
Rb
will
be
discussed
later.


 
 |
T 2 
 F o r 
 D u m m i e s , 
 “ M a k i n g 
 S e c o n d 
 Y e a r 
 a 
 L i t t l e 
 E a s i e r ” 
 



a
baseline
cell
population
has
the
decision
to
 proliferate.
the
S
 phase
allows
for
DNA
synthesis.
Dr.
radiation
damage)
the
DNA
is
stressed
and
 damaged.


 
 3)
Cyclin
Dependent
Kinases
(CDKs)
bind
to
cyclins
which
in
turn
phosphorolates
target
proteins
to
keep
 the
cell
cycle
running
are
the
ones
that
press
on
the
gas
pedal
to
ensure
a
G1
to
S
to
G2
to
M
 progression. 
 Dr.
differentiate.MoD:
August
22.INK4 .

Essentially.

It
is
where
this
balance
is
disturbed
that
neoplasms
can
 arise.p1 •! C .p2 .

As
with
anybody
pressing
on
the
gas.
2011
–
Biology
of
Neoplasm
–
Dr.
Moroz
 
 2)
p53
acts
as
the
gatekeeper
of
the
cell
cycle
during
the
late
G1
phase.
and
the
neoplasm
has
ceased
the
host’s
 option
at
life.

To
give
a
sense
on
how
crucial
this
balance
is.

Only
10
doublings
later.
Moroz
did
not
specifically
cover
mechanisms
that
control
cell
populations
outside
of
the
cell
cycle
 but
did
offer
some
general
comments.sarcom .Cip/K (Inhibitor of .

You
would
like
to
make
sure
the
DNA
is
not
damaged
before
getting
to
the
S
phase
 of
the
cell
cycle.
this
system
occurs
very
well.

As
mentioned
above.

More
about
p53
will
be
discussed
later.

 Though
there
are
many
different
CDKs
and
CDKIs. 
 “ M a k i n g 
 S e c o n d 
 Y e a r 
 a 
 L i t t l e 
 E a s i e r ” 
 
 ! Cyclin .
p53
will
examine
the
DNA
and
determine
whether
the
cell
should
continue
on
through
the
 rest
of
the
cell
cycle.
 |
T 2 
 F o r 
 D u m m i e s .g.
it
takes
30
doublings
after
this
disturbance
to
 produce
a
clinically
detectable
mass.
Moroz
told
us
to
specifically
focus
on
p21
 because
p21
is
directly
transcribed
under
p53
to
arrest
the
cell
cycle
and
hit
the
breaks
on
the
cell
cycle
 if
there
is
DNA
damage
that
is
detected.
or
go
through
apoptosis.

 
 Inhib .

If
for
whatever
reason
(e.
a
regulator
needs
to
hit
the
breaks.

In
a
homeostatic
environment
outside
of
the
 neoplastic
world.p1 
 •! M •!i More
detail
than
needed
but
added
for
completeness
(notice
p21
exerts
its
action
right
after
where
p53
exerts
 its
action
in
late
G1)
 
 2) Organize and be able to discuss different mechanisms that control cell populations.breast ! CDK4 .

This
role
belongs
 to
the
Cyclin
Dependent
Kinase
Inhibitors
(CDKIs)
which
exert
negative
control
over
the
cell
cycle.

This
objective
is
best
addressed
with
the
figure
to
the
left
in
Objective
1. and permanent) giving examples of each.

This
explains
why
MIs
and
strokes
can
be
so
fatal!
 
 
 determining cell proliferation rates.MoD:
August
22.

Therefore.
it
can
enter
the
cell
cycle.

First
of
all. describe methods and be able to discuss different methods for Three
methods
were
discussed
in
lecture. 
 “ M a k i n g 
 S e c o n d 
 Y e a r 
 a 
 L i t t l e 
 E a s i e r ” 
 
 . their proliferative potential and mechanisms that control their population.

Through
the
 proper
tools.
there
is
the
mitotic
figure
count.
cells
can
be
 described
as
quiescent.

These
of
 course
include
your
cardiac
cells
and
your
neurons.




 Finally.

Also
if
the
 mitotic
figure
count
is
very
high
in
a
typically
quiescent
cell
(hepatocytes).
Moroz
 
 
 3) Organize and be able to discuss characteristics of different cell types (labile.

Liver
damage
should
not
be
constant
unless
constant/excessive
alcohol
and/or
hepatitis
is
 a
primary
problem.
permanent
cells
can
never
enter
the
cell
cycle
and
once
damaged
cannot
be
replaced.
if
 there
was
an
excessive
amount
of
mitosis
going
on
(the
CDKIs
may
not
be
working
or
the
CDKs
are
 simply
overworking).
the
amount
of
mitosis
in
a
given
cell
population
can
actually
be
quantified.

These
are
the
only
normal
cells
that
hang
out
in
G0
on
a
consistent
basis
and
 are
not
there
because
p53
told
them
to
go
there. quiescent.
2011
–
Biology
of
Neoplasm
–
Dr.

Essentially.
under
normal
conditions.
there
is
no
reason
for
these
cells
to
be
 constantly
dividing
on
a
regular
basis
but
if
need
be. 
 4) List.
cells
can
be
 described
as
labile.

You
can
only
imagine
with
constant
 sloughing.

An
example
would
be
 hepatocytes.

This
essentially
means
that
these
cells
are
constantly
dividing
and
hence
going
 through
the
cell
cycle.
these
cells
need
to
continuously
divide
to
replace
the
older
cells.
there
might
be
a
concern
in
why
the
cell
proliferation
rate
is
so
high.

First
of
all.

An
example
would
be
skin
(epidermis)
cells.
hepatocytes
are
quiescent.

Therefore.

Secondly.
that
might
also
raise
some
 |
T 2 
 F o r 
 D u m m i e s .


Moroz
 
 concern.
 1.

Information
 garnered
can
be
used
to
determine
the
best
course
of
treatment
(e.

Finally.
the
number
of
cells
in
the
S
 munohistochemical Proliferation Markers phase
by
examining
DNA
content.g. Not 0.
cells
will
exhibit
mild
convolution
with
chromatin
compaction
and
cytoplasm
 condensation
in
the
initial
stage.

Flow
cytometry
allows
for
microscopic
particles
to
be
suspended
in
a
fluid
 ow Cytometry and S-phase and
passed
through
an
electric
counter.

This
can
determine.

The
mitotic
index
can
be
depicted
via
the
 totic Index DI
formula
shown
below.5.

Secondly. |
T 2 
 F o r 
 D u m m i e s .
radiation.
 –! Proliferating Cell Nuclear Antigen (PCNA) 
 –! Ki-67 (MIB-1) 
 DI = DNA content of G0/1 of sample cells DNA content of G0/1 of diploid reference cells Ultimately.00 Diploid (2N): 46 chr 0.MoD:
August
22.
chemo.0 Aneuploid discuss morphological features of apoptosis. 1.5 Haploid: 23 chr 2.

Below
is
an
awesome
table
from
 lecture
that
compares
and
contrasts
apoptosis
and
necrosis.0.

The
second
technique
of
mitotic
index
is
related
to
mitotic
figure
count
and
simply
gives
the
 totic Figure Count ratio
of
cells
undergoing
mitosis
to
total
cells
in
the
population. 
 “ M a k i n g 
 S e c o n d 
 Y e a r 
 a 
 L i t t l e 
 E a s i e r ” 
 
 . Define. and compare and contrast apoptosis and necrosis.
the
nuclear
fragmentation
will
lead
to
cell
blebbing
 (essentially
the
cell
breaks
up
into
little
chunks
and
ultimately
fragments).00 Tetraploid (4N): 92 chrBe able to 5).
phagocytosis
will
take
 care
of
the
free
floating
apoptotic
bodies
like
the
vultures
they
are.
2011
–
Biology
of
Neoplasm
–
Dr.
for
example.
surgery). or 2.
this
is
clinically
relevant
as
that
a
high
proliferation
rate
(many
cells
in
mitosis)
could
 suggest
high
cell
turnover
via
apoptosis
or
simply
a
highly
progressive
neoplasm.

 This
can
be
done
via
antibodies
for
the
 nuclear
antigen
Ki‐67
(stained
brown
in
the
picture
below). Under
the
apoptosis
signal.



Remember. diffuse ATP depletion Membrane injury Inflammation Fibrosis DNA breakdown Tissue reaction 6).
cyclin
D
 which
binds
to
CDK
4.

Therefore.
this
leads
to
progression
into
the
S
 phase
and
the
cell
cycle
is
now
committed
through
mitosis.
the
S
phase
cannot
occur
if
E2F
is
bound
to
Rb.
then
it
cannot
transcribe
the
genes
needed
for
 DNA
synthesis.

Remember
p21
from
earlier.

This
leads
to
cell
cycle
arrest
and
the
cell
will
go
off
to
see
 |
T 2 
 F o r 
 D u m m i e s .
p21
serves
as
a
CDK
inhibitor
which
stops
the
 cell
cycle
if
p53
suspects
something
is
wrong.
I
am
going
to
have
to
call
upon
some
biochem
so
I
apologize
up
front. In
terms
of
time
spent
in
lecture.
RB
serves
as
the
major
regulator
at
the
G1/S
checkpoint.
it
serves
its
role
during
late
G1.
cells
stay
in
G0
and
do
not
 progress
through
the
cell
cycle.

If
a
damaged
(or
threatening
cell
b/c
it
could
cause
 cancer)
finds
its
way
into
late
G1
trying
to
get
into
S.
via
radiation)
being
synthesized
and
ultimately
going
through
mitosis.
 p53
has
the
ability
to
induce
cell
cycle
arrest
and
trigger
repair
mechanisms/apoptosis
if
a
damaged
 cell
comes
rolling
through.
p53
is
suppose
to
block
this
cell
b/c
you
don’t
want
 damaged
DNA
(e.
Moroz
 
 APOPTO S I S Stimuli Histology Physiologic and pat h o l o g i c Single cells Cellular shrinkage Karyorhexis Apoptotic necrosis Apoptotic bodies Internucleosomal Gene activation Endonuclease No inflammation Phagocytosis of apoptotic bodies NECRO S I S Pathologic (injury) Groups of cells Cellular swelling Karyolysis Coagulation necrosis Disruption of organelles Random. 
 “ M a k i n g 
 S e c o n d 
 Y e a r 
 a 
 L i t t l e 
 E a s i e r ” 
 
 .MoD:
August
22.6
and
cyclin
E
which
binds
to
CDK
2
are
integral
in
driving
the
cell
cycle. Be able to discuss the definitions of terms describing various DNA contents of neoplastic cells and their clinical significance.

From
the
logic
presented
above.

In
terms
of
a
concrete
example
let’s
take
a
look
into
the
world
of
TSA
 agents.

We’ll
revisit
this
analogy
after
 looking
at
p53

 
 Now
looking
at
p53.

Once
you
as
the
passenger
get
through. List and be able to discuss functions of p53 and retinoblastoma (Rb) gene.
there
is
no
stopping
you
 from
getting
onto
the
airplane
regardless
of
any
threat
you
might
pose
so
these
TSA
agents
better
make
 sure
to
1)
moderate
the
line
and
2)
look
out
for
anything
suspicious.

If
Rb
binds
E2F.

If
E2F
is
bound
to
RB.
think
of
Rb
as
the
TSA
agents
that
monitor
the
X‐ray
machine
and
the
fact
that
you
have
a
 boarding
pass.

Their
true
 role
lies
in
its
ability
to
phosphorylate
Rb
placing
Rb
into
an
inactive
hyperphosphorylated
state
at
 which
point
Rb
cannot
bind
E2F.

Rb’s
primary
role
is
to
 bind
a
growth
factor
named
E2F.

They
ensure
there
is
a
steady
flow
but
also
have
the
power
to
slow
down/shut
down
the
 line
to
keep
the
pace
manageable.

In
other
words.

To
make
this
easier
to
 explain.
this
objective
is
probably
the
meat
and
potatoes
part
of
this
lecture!

 As
mentioned
above.
2011
–
Biology
of
Neoplasm
–
Dr.g.


the
cell
can
go
back
 into
the
cell
cycle
and
continue
on
its
way.
you
truly
are
a
threat.
Moroz
 
 if
it
can
be
repaired.
p53
cannot
spot
anything
suspicious
meaning
that
if
either
mechanism
 goes
down. E7 binds to Rb to make it non-functional while E6 degrades p53 and Bax .

These
other
agents
represent
p53
and
if
you
as
the
passenger
 pose
a
threat.
proteins
that
govern
apoptosis
such
as
BAX
will
promote
apoptosis
leading
 to
cell
death
and
it
not
being
re‐introduced
into
the
cell
cycle. If the other Rb allele is damaged by some other environmental force. Rb is completely non-functional leading to Retinoblastoma! HPV upon integration into the genome produces proteins E6 and E7.

If
after
inspection/questioning
they
 see
you
are
no
longer
a
threat.
the
agents
you
see
out
on
the
floor
are
 moderating
the
line
so
that
other
agents
(typically
those
in
black
suits
and
sunglasses
hiding
in
the
back)
 can
look
out
for
something
suspicious.

IF
Rb
 does
not
moderate
the
flow. 
 “ M a k i n g 
 S e c o n d 
 Y e a r 
 a 
 L i t t l e 
 E a s i e r ” 
 
 .

If
however.
the
risk
for
neoplastic
growth
increases!




 
 Now
let’s
bring
in
the
pathology:
 
 Disease Retinoblastoma Relation to Rb/p53 The Rb gene is mutated and cannot bind EF2. Typically.
they
 probably
don’t
kill
you
on
the
spot
but
through
whatever
our
government
has
planned. This is the classic example of the two hit hypothesis.
out
they
come
to
tackle
you
(or
at
least
detain
you).

So
back
to
the
TSA.
2011
–
Biology
of
Neoplasm
–
Dr.

If
repair
is
successful.

If
not. Hmm imagine the airport with absolutely no metal detectors or TSA agents… Human Papilloma Virus (HPV) 
 
 |
T 2 
 F o r 
 D u m m i e s . those with familial (germ line) retinoblastoma inherit a mutated copy of Rb (the 1st hit).
you
are
allowed
to
go
through.MoD:
August
22.
you
have
been
 taken
out
of
the
passenger
flow
just
like
a
cell
that
remains
a
threat
is
taken
out
of
the
cell
cycle.


Moroz
 
 
 
 The
second
part
of
this
objective
along
with
objective
#7
were
not
addressed
in
lecture.
2011
–
Biology
of
Neoplasm
–
Dr.
 
 Questions
and/or
comments?
 
 BLeong@tulane.edu
 
 
 

 |
T 2 
 F o r 
 D u m m i e s .

It
was
 mentioned
that
through
the
methods
of
determining
cell
proliferation
rates.MoD:
August
22.
one
could
determine
the
 severity
of
the
tumor
hence
defining
what
treatment
mechanism
to
use. 
 “ M a k i n g 
 S e c o n d 
 Y e a r 
 a 
 L i t t l e 
 E a s i e r ” 
 
 .

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