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TYLER JACKS: OK.
So now we're going to change
gears entirely, and talk
about cancer.
And to put you in the
mood to talk about cancer,
I'm going to show you a
video, which we actually
produced last year for the
American Association for Cancer
Research annual meeting, to
open up that meeting, actually.
Hopefully, there's sound.
Guys, upstairs?
[VIDEO PLAYBACK]
[END PLAYBACK]
TYLER JACKS: Hopefully,
you're inspired.
That video is on YouTube if
you want to watch it again.
It's got to 15,000 hits.
It's not exactly viral, but
still pretty good, pretty good
for a cancer research video.
And the video really
was to kind of get
people excited about both
the progress that's been made
and the opportunity that exists.
But also some of
the great challenges
that we're referred to in some
of those facts and figures
that you saw there.
So I want to review
some of that with you,
and give you a
sense of what we're
doing to improve our progress,
accelerate our progress.
And the bottom line
is I'm actually
extremely excited
about the potential
that we'll have over
the next decade or two
in really changing the course
of some of those numbers
that you saw there.
But just to remind you of the
severity of the problem, when
we consider the statistics
regarding cancer in the United
States, in the United
States over the next year,
there'll be about 1.4 million
new cases in the United States.
That does not include common
forms of skin cancer--
squamous cell skin cancer,
basal cell skin cancer
contribute another
million cases.
So it's a very,
very common disease,
very commonly diagnosed
in this country,
and indeed, around the world.
Again, just considering
the next year,
it's estimated
that there will be
about 560,000 deaths in the
United States due to cancer,
and about 8 million
in the world.
And you might have
seen the statistic
that more people die
in the world of cancer
per year than of malaria,
TB, or HIV aids combined.
So very, very common,
very, very deadly disease.
In this country, the lifetime
risk of developing cancer
is 1 in 2 for men,
1 in 3 for women,
based on current statistics.
Again, hopefully by the
time you guys are old
and cancer typically is a
disease of older people,
these statistics will change.
But that's what they are now.
So if they don't change,
then a large number
of you sitting here will
experience this diagnosis.
And by current statistics, 1
in 4 deaths are due to cancer.
Cancer has recently bypassed
cardiovascular disease
as the leading cause of
death in the United States.
Cardiovascular disease rates
have dropped precipitously.
Cancer rates have dropped
less significantly,
although they are coming down.
Also, the population is aging.
And cancer tends to be a
disease of older people.
So the demographics
also increase
the numbers of people who
are dying from this disease.
So a major problem.
But also think of it
as a major opportunity
to do something really
important if you
choose to get into this field.
So cancer, I think, is
familiar to everybody
on one level or another,
but you might not
have seen the disease up close.
I hope that you haven't.
But I want to teach you a little
bit about what it looks like,
and really what are some of
the fundamental definitions.
So lung cancer, a very commonly
diagnosed cancer in this
country-- we'll talk more
about it in a minute--
is diagnosed either by a chest
x-ray following symptoms,
and you can see perhaps,
although the light isn't great
here, that there's a
dark mass right here.
And this dark mass indicates
the presence of a tumor.
A more refined
diagnosis can be done
by basically serial x-rays,
commuted tomography.
And you can see this very
clearly defined mass growing
in the lung of the individual.
Cancer is an accumulation
of cells, an abnormal number
of cells within a tissue.
And you can see that
solid tumor here and here.
You can also see
cancers in the blood.
Again, an abnormal
number of cells
within the blood, a leukemia.
This is a normal blood smear.
Here are red blood cells.
And here is a normal number
of white blood cells.
These might be B-cells.
These might be neutrophils.
And you can see an accumulation
of these nucleated white blood
cells in this leukemic patient.
Thousands, hundreds of
thousands more of these cells
than should be present
within this blood sample.
This is colon cancer.
Colon cancer, as
you probably know,
can be detected by
colonoscopy, a very important
diagnostic test,
preventative test.
And we can actually see
the lining of the colon.
And this is a normal section
of colonic epithelium.
And here is a tumor developing.
It's called a polyp.
This is an early stage,
precancerous tumor.
We'll talk more about the
details of that in a second.
If this is diagnosed
during endoscopy,
they're actually removed
right during the procedure.
And this is very important
to prevent those tumors
from progressing further
into true cancer.
And actually, colon cancer
rates have dropped significantly
because of this test.
When these lesions are
discovered, they are removed.
And therefore,
they can't progress
into true colon cancer.
However, sometimes you see this.
And this is a tumor that
has progressed further.
It's divided more.
It's taken on additional
abnormal properties
and actually moved through
the wall of the colon
and is beginning to spread
throughout the body.
This is true cancer and
much, much harder to treat.
Not impossible, but
much harder to treat.
When this is discovered,
you can't just
remove the specific lesion.
You have to have surgery.
And a section of
the colon is removed
to take out the
tumor in the hope
that that will get rid
of the disease entirely.
But the concern is,
in this situation,
that the diseased cells
might have moved out
into the body in the
process of metastasis,
which will make the disease
much more difficult to treat.
OK.
So I've given you some
terminology there.
Let me just explain some
of it in greater detail.
Actually, before I do
that, let me show you
one more, a couple of slides.
So as indicated on
that slide, cancer
develops in stages
from normal cells
through the development of a
benign, precancerous lesion,
finally to the development
of true cancer.
And we can depict that
graphically, as shown here.
This is a normal tissue.
Here are normal cells.
These might be epithelial
cells lining the intestine.
Those cells sit on top of
a basement membrane made
of extracellular matrix
proteins, which provide them
structure and some function.
There might be other cells
present in this region,
stem cells or
progenitor cells, which
will replenish those
differentiated cells as they
are sloughed off and die.
These cells can
acquire alterations--
and we'll discuss this in great
detail today and next time--
alterations in
their genes, which
allow those cells to do
things they shouldn't do,
namely to proliferate
abnormally.
So rather than having
a single line of cells,
we now have a little
clump of cells.
These cells might look
identical to their neighbors,
but there are too many of them.
This is a process we call
hyperplasia, too many cells,
too much growth.
Within this collection of
cells, additional alterations
may take place that allow those
cells to divide more rapidly
and to do even more
abnormal things,
to pile up on one or another,
which they shouldn't normally
do.
This is the development of one
of those early stage tumors.
I showed you a
polyp in the colon.
That's a stage of cancer,
in the case of colon cancer,
called an adenoma.
That's a benign tumor.
It's not yet cancer.
It's actually not
yet life threatening.
But it's detectable because
it's a mass of cells
that shouldn't be there.
Within that collection of
cells, still further alterations
can take place.
And now the cells
do additional things
that are wrong and
potentially dangerous.
One, they're recruiting
a blood supply.
They're recruiting blood
vessels into the tumor
to nourish the tumor and
bring factors that the tumor
cells need for their survival.
In addition, the
cells are starting
to degrade that
extracellular matrix.
They're starting to acquire
the ability to move away
from their normal site.
Most cells in your body know
where they're supposed to be,
and they stay there.
Cancer cells acquire the ability
to leave their primary site
and to disseminate
throughout the body,
creating secondary tumors.
This happens when the cells
access the blood vessels.
They can then travel
within the blood system
and then take up residence
in some secondary site.
And this we call metastasis.
Metastatic tumors
are tumors that
are derived from
the primary cancer--
and this is true cancer here--
derived from the
primary cancer, that
have now created a secondary
tumor somewhere else.
And this is actually the
most lethal phase of cancer.
Of the 560 cancer--
560,000 cancer deaths
that will occur
in this country this
year, 500,000 of them
are due to this
phase of the disease.
It's actually not
a phase that we
understand terribly
well today, but clearly
a very important one.
So cancer arises
from normal cells
through the
sequential acquisition
of alterations that allow
those cells to do things
they should not
normally do, including
invade and metastasize.
This is what it looks
like in real life.
This is a tumor.
It's actually a tumor from
a mouse created in my lab.
It's lung cancer.
This lacy appearance is
the normal lung epithelium.
There's a lot of air
spaces in the lung
to allow you to get gas
exchange in the lung.
And you can see in
this region right here,
there's a bit of a thickening
of those epithelial structures.
Too many cells, that's this
area we call hyperplasia.
Over time, these will
give way to solid growths.
The cells within those solid
growths look pretty normal.
And you might be able
to see that here.
The cells are pretty
well organized.
They are all lined up.
There's just too many of them.
That's a benign
tumor, an adenoma.
Over time, these will give rise
to true cancers, carcinomas.
And these have the
ability to spread locally
and throughout the body.
In addition, the cells
look even more abnormal.
They don't look like the
cells that gave rise to them.
OK.
Now let me give you some more
details of the terminology
that I've just been using.
Hyperplasia is
increased cell number.
But the architecture of the
cells is otherwise normal.
They look like normal cells.
If progression occurs, a
benign tumor might arise.
This is not yet cancer.
These tumors are
so-called not aggressive.
They basically stay
where they started.
They don't destroy
the local tissue.
And they don't leave the site.
And if they are detected,
for example in a colonoscopy,
they can be removed.
If they're detected in the lung
when they're at this stage,
they can be removed surgically
and the patient will be fine.
However, they can progress
into a malignant tumor.
And this is where we
use the term cancer.
Cancer actually refers
not to just any tumor,
but a malignant tumor.
And these, by contrast,
are aggressive.
The cells are
dividing more rapidly.
They're also causing changes
within the local tissue
such that they're
locally destructive
to the local tissue.
And they have the
potential to spread,
to get outside of their local
area, access the blood vessels,
and move to a distant site.
And that leads to
this final phase
of metastasis, which
is the tumor growing
at a distant site.
And that can be one site
or it can be many sites.
And again, it's the
combined effects
of the metastatic tumors that
tends to kill cancer patients.
Now cancers can arise
in virtually all organs,
all tissues.
Cancer is an umbrella
term that actually
refers to many different
diseases of abnormal growth.
The most common tumors in humans
affect epithelial tissues,
epithelial tissues.
And these epithelial
tissues will give rise
to a cancer type
called carcinomas.
Carcinomas are cancers
of epithelial tissues.
Breast cancer, lung
cancer pancreas cancer--
these are all cancers
of epithelial tissues.
The precursor lesions are
called adenomas, in many cases.
And these are benign.
We can also have cancers
of connective tissues,
and these are
called, collectively,
sarcomas, sarcomas.
Muscle tumors, myosarcomas.
Fibroblast derived
tumors, fibrosarcomas.
Cartilage derived tumors, these
tumors are rarer in humans,
but they occur.
And when they occur, they can
be quite problematic, as well.
And they go through similar
stages of progression,
as I've been describing
for the other tumor types.
And we can have tumors of
blood cells, leukemias, too
many cells in the blood.
And I showed you a blood
smear of a leukemic patient.
The blood smear indicates
that there are too many cells
circulating.
That contrasts to
lymphomas, which
is also a blood cell tumor.
But here the tumor cells are
confined to lymph organs,
like the thymus or the
spleen or lymph nodes.
So there actually aren't
too many cells circulating,
but there are too many of these
cells in these structures,
which likewise
can cause problems
within those local structures,
and surrounding tissues
as well.
OK.
So some terminology.
Cancers affect all tissues,
or virtually all tissues.
There are probably 200, 250
different types of cancer
when we think about
all the different cell
types in your body that
can undergo these changes
and result in one or
another type of cancer.
All right.
So cancers arise
from normal cells.
They develop in stages.
What causes them to
change over time?
What gives them the ability
to divide inappropriately,
to grow abnormally?
The answer to this question
is that alterations take place
in the DNA of the
developing cancer cells.
And in this respect, cancer
is a genetic disease.
And I'm going to use
this term in quotes
because when we talk
about a genetic disease,
we tend to talk about
inherited diseases.
You inherit a disease allele
from one of your parents.
You develop a disease.
In this case, cancer can
arise as a consequence
of an inherited mutation.
We'll talk about that
in a subsequent lecture.
But what I'm referring to
here is genetic alterations
that take place within
you, within your cells.
And this accumulates over time,
over decades in some cases,
and allows the cells to progress
through these various stages.
The case that cancer develops
through the acquisition
of mutations in genes has been
building for about a century.
We've been suspecting that
cancer was a genetic disease
for a very long time.
And now we know it's
true because we've
seen the alterations in
the genes of cancer cells.
And we'll come to those
specific alterations
in subsequent lectures.
But I want to give you the
background that led us there.
The first and the oldest was
the observation going back
almost 100 years that cancer
cells have abnormal number
and structure of chromosomes.
As you know, your cells have
46 chromosomes, 23 pairs.
And most of your cells look
like the cells on the left,
where there's a pair
of chromosome 1, 2, 3,
and so forth.
These chromosomes are painted
with a specific chromosome
specific paint so we can
distinguish which one is which,
and this is a so-called
normal karyotype.
Cancer cells can look like this.
And you can see that they're
different in many respects
from normal cells.
A, there's way too
many chromosomes.
This is a condition
we call aneuploidy.
Aneuploidy, as opposed
to being diploid,
the cells are aneuploid, an
abnormal number of chromosomes.
Moreover, you can see in
some of the highlighted areas
that the chromosome
structure is abnormal.
We have this chromosome
here, which has a little bit
of the pale blue chromosome--
which may be chromosome 4,
I can't read it--
and a little bit of this
pink chromosome, which
is one of these guys here.
A translocation has taken
place so that the structure
of the chromosome is abnormal.
So we have aneuploidy,
defects in chromosome number,
but also defects in chromosome
structure, like translocations.
We also have deletions-- not
easy to see in this slide--
where chromosomes have incurred
big losses of genetic material.
OK?
Chromosome
abnormalities in cancer
have been known about
for a very long time.
A second and very
important observation,
which occurred
sometime in the '40s--
maybe '30s, '40s, and '50s--
and built up over
time since then,
is that carcinogens,
carcinogens, which
are cancer causing agents, are
almost always mutagens, which
are mutation causing agents.
So something that
can cause cancer in,
for example, a
laboratory animal,
can be shown to alter the
DNA and cause mutations.
That would suggest
that the carcinogen
is acting through the
alterations in the DNA.
And this observation was
made much more convincing
through the work
of an investigator
by the name of Bruce Ames, who
developed the so-called Ames
test.
And I want to tell
you about that.
But actually, before I do, let
me just show you graphically
how the agent can be tested for
its carcinogenic capabilities
and its mutagenic capabilities.
The carcinogen is tested
by treating an animal--
a mouse or a rat--
injecting the animal
with the carcinogen
or painting the carcinogen
or the potential carcinogen
on the skin of the
animal, and then
waiting a certain amount of
time and asking the question
whether the animal
developed a tumor.
And you can do this with
different doses of the agent,
with large numbers of
animals, and actually
get quantitative
data that tells you
the potency of this
potential carcinogen.
So that's the
carcinogenesis assay.
To test whether something is a
mutagen, you can take the agent
and treat cells and ask
whether you can cause mutations
in those cells.
You could do this in lots
of different types of cells.
But the easiest types
of cells to do it in
are bacterial cells, for
example, salmonella bacteria
or E. coli.
And the way this
assay is done is
to use cells that are
defective in the production
of an amino acid,
let's say histidine.
So the cells have mutations
in a biosynthetic enzyme--
and I'll tell you more
about this in a second--
that is required for the
cells to make histidine.
Now these cells can live if
you provide histidine to them
exogenously, for example,
on the Petri dish.
But if you take those
cells and you plate them
on a Petri dish that is lacking
histidine, none of the cells
will be able to grow
because they require
exogenous histidine to live.
However, if you
take that mutagen
and you add it to these
histidine minus cells,
the mutagen might
correct the mutation
in the histidine
biosynthesis gene,
thereby converting
it to a wild type
form at some low frequency.
Such that if you plate these
now mutagen-treated cells
on a histidine minus
plate, you might
get a few colonies growing.
And these would
be histidine plus,
capable of producing histidine
themselves, revertants.
They've reverted the mutation
to now a wild type form.
OK?
And it was this that was
the basis of the Ames test,
to test the mutagenicity
of potential compounds.
Now we actually use different
versions of his minus bacteria,
because different mutagens cause
different types of mutations.
And if you use just
one mutant bacteria,
you might miss certain
potential mutagens.
So for example, if we have
a specific mutant, which
is in a gene required for
the conversion of histidinol,
in an enzyme that is called
histidinol dihydrogenase,
this enzyme is required
to produce histidine
in the final step
of the synthesis.
The wild type enzyme would
have a particular sequence,
which would encode a
particular pair of amino acids,
glutamine and serine.
And it is this collection
of histidine minus bacteria,
this collection of
histidine minus bacteria
that we use in this
assay, we might
have one mutant, which
has an alteration, which
converts that C to a T.
This creates a
termination codon.
So this is why that bacterium
can't make histidine,
because it can't
make that enzyme.
It has a stop codon
on that position.
A second mutant might have
a different stop codon.
This is determination codon.
Here, this C has been
converted to a G,
creating the stop codon.
And a third mutant might
have an abnormal number
of bases in this region, an
insertion of an A residue,
which would cause a frame shift.
These are three
different mutants,
which would require three
different types of alterations
in the DNA to convert
back to the wild type.
Here, this pyrimidine
would have to be converted
to a different pyrimidine.
Here, this purine would have to
be converted to a pyrimidine.
And here this abnormal
number of bases
would have to be corrected
to the correct number.
This would allow
one to find agents
which function as
point mutagens, which
is a class of mutagens.
They create point mutations.
And this type of
bacteria would allow
you to find what are called
frame shift mutagens.
So these bacteria
are mixed together.
The mutagen is added.
And then you count the
number of cells that
survive on the his minus plate.
That's the original Ames test.
As Ames and others continue
to do this kind of testing,
they discovered,
to their surprise,
that some clearly
established carcinogens
failed the Ames test.
They cause lots of
tumors in animals,
but they didn't
revert any bacteria
in that bacterial assay.
So can anybody
think why that is?
Why might an agent, which
can clearly cause cancer,
fail that test?
Well, one answer-- and
the most common answer--
is that the agent itself
is not itself a mutation.
But it can be
converted in the body
through the process
of metabolism.
As your body tries to convert
that agent into something,
for example, that
it can excrete,
it alters it chemically
and converts it
from a promutagenic form
into a mutagenic form.
And in this form, it can
cause mutations in your DNA,
and in theory, in the
bacterial cases as well.
And here's an example
of a promutagen called
benzo(a)pyrene, a very important
mutation in cigarette smoke.
This is converted,
through various steps
inside your liver, to a form
that is much more mutagenic.
These epoxides are
much more mutagenic
compared to the
original compound,
much more reactive, much
more reactive to DNA.
And in these forms, the compound
will actually covalently
attach to the bases of
DNA and cause mutations.
OK?
So in this sense, your body is
actually part of the problem.
It's trying to get
rid of this bad stuff,
but in the process of doing
that, it's making it worse.
Recognizing that this
was an issue for actually
quite a few potential
mutagens, Ames and others
modified the Ames test.
It's now called the
Modified Ames test.
In which case, you take
the compound of interest,
the potential mutagen, you mix
it with some extract from liver
to allow this
metabolism to occur.
And then you take those,
the metabolized compound,
and you do the bacterial,
the bacterial mutagenesis
test that I just
reviewed for you.
OK?
And now you find that many
of these things that failed
initially, score positively.
OK.
So stuff that we get exposed
to, like benzo(a)pyrene,
and other agents
in the environment,
can cause mutations, and
these can also cause cancer.
I just want to
take a few seconds
to rail against tobacco
smoke and cigarette smoking.
Lung cancer is the most common
form of cancer in this country.
175,000 deaths due to
lung cancer each year.
About 150,000 of those
deaths are due to smoking.
It's the most common
form of cancer,
and among the most
preventable forms of cancer,
through to the failure to
expose the body to carcinogens
in cigarette smoke.
Not only is there benzo(a)pyrene
in cigarette smoke,
but there's about 1,000 other
carcinogens in cigarette smoke.
Cigarette smoking is still
very common in this country,
remarkably common
in this country.
About 46 million adults
still smoke in this country.
A remarkable number of
high school students
still smoke in this country.
And it's because of this that
lung cancer rates are still
very, very high.
Moreover, smoking
causes all sorts
of other diseases--
emphysema, kidney diseases,
cardiovascular diseases.
It's now estimated that among
the however many billions
of people are on
the planet today--
what's that number, 6 billion
people on the planet today?
Something like 650
million of them
will die due to the
exposure to cigarette smoke.
So my little lesson here is that
if you're currently smoking,
stop.
If you're not
smoking, don't start.
It's the easiest way
to protect yourself
against many, many
dangerous future problems.
All right.
So cigarette smoke is
something we do to ourselves.
We expose ourselves to
mutagens that cause cancer
cells to develop in your
lungs and in other parts
of your body.
There are other so-called
exogenous mutagens,
things that we get exposed to.
Sunlight, for example, sunlight,
the UV rays in sunlight,
can cause damage to your
DNA, causing skin cancer
and melanoma.
Dietary carcinogens,
barbecued beef,
has certain dietary carcinogens
in the category, actually,
of benzo(a)pyrene, that can
cause damage to your DNA
and induce colon cancer.
Not at high numbers, not saying
you shouldn't eat barbecue.
But still, this is
an example of stuff
we get exposed to that
increases our cancer risk.
Replication errors.
Your cells are good
at copying the DNA.
They're very good at it.
They have proofreading functions
that make them better at it.
But they're not perfect.
So every time your cells
divide, you actually
run the risk of
making a mistake.
And replication errors
are a common source
of mutations in cancer.
As your cells are
moving DNA around,
they also sometimes break it.
And these DNA breaks are
sometimes sealed properly,
but sometimes not.
And deletions can occur.
And translocations can occur.
And another endogenous process
that leads to mutations,
including in cancer cells.
Defects in DNA repair.
You have lots of enzymes
that are looking at your DNA
at all times for adducts
that have formed,
and other alterations.
And those enzymes remove those
damaged bases and fix them.
But sometimes they fail.
Sometimes they actually get
mutated in cancer cells,
raising the risk still further.
So defects in DNA damage and
DNA damage repair enzymes.
Your cells also produce
endogenous mutagens.
Various reactive oxygen species
are produced, for example,
in the process of metabolism.
And these reactive
oxygen species,
like superoxide,
hydrogen peroxide,
can interact with the
DNA and cause mutations.
This is why antioxidants are
useful in preventing cancer
in some settings.
OK?
So various things
that we get exposed to
or we expose ourselves to
cause mutations in DNA.
And this results, ultimately,
in the development of cancers.
The last thing
I'll mention to you
is that this doesn't
happen overnight.
It's not that a single
alteration in a single gene
is sufficient to derive
tumor development.
Instead, it's a process
that occurs over time
and requires alterations
to many genes.
So if you imagine a
cell, a normal cell,
which divides to produce two
daughters with the same DNA
content, at some frequency, this
cell might acquire a mutation.
Maybe it got exposed
to cigarette smoke.
Maybe it got exposed
to superoxide.
Maybe it made a mistake.
And this mutation then
confers upon that cell
the ability to divide
especially well.
And now all of its daughter
cells carry that same mutation.
And as that cell divides
further and produces
daughter cells of its own,
perhaps one of those cells--
and this might not be in
the very next cell division,
it might be five years later--
one of those cells
acquires a second mutation.
And that mutation
gives that cell
the ability to divide
even more rapidly,
or survive even better.
And again, all of
its descendant cells
will have that same
abnormal genotype.
And maybe within
that clone of cells,
a third mutation takes place.
And on and on we go.
We now think that we
need somewhere between 5
and 10 mutations
in cellular genes
to allow the cells
to progress all
the way to that
full blown cancer
that I showed you
in pictures before.
So this process continues
until we have true malignancy.
And this process of developing
clones with increasing ability
to develop into cancer, we call
the clonal evolution theory,
the clonal evolution of
increasingly abnormal clones,
which eventually will
develop into a cancer.
And next time we'll
talk about what
are the genes that are mutated
in these developing cancers.
