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So up until this point in the class
you've learned basics about cell

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molecular biology,
genetics and development,

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how things normally work, how cells
normally function,

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how tissues are formed,
how organisms are formed and

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function.
And hopefully you've had an ample

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founding in understanding normal
biology.  We're going to take a turn

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today and for the next three
lectures talk about abnormalities

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that lead to disease.
And, whereas, I have tried to keep

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things light for you in my lectures
and try to be entertaining if

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possible, the subject of the next
three lectures is not a light one.

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It's a very serious one.
And it is cancer.  It is a disease

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that I know a great deal about and
have worked on in my lab for the

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last 17 years.
It's a very important and very

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devastating disease.
And we're going to try to give you

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an introduction to it.
And you'll see that many of the

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things that you've learned over the
course of this class,

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up until this point, really prepare
you to understand the details of

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cancer, cancer development,
and hopefully also cancer treatment.

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And I'll say right up front that
I'm actually quite optimistic that

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the progress that we've made over
the last several years in

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understanding the molecular basis of
cancer has put us into position to

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treat the disease differently than
we've done in the past

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and more effectively.
The number of drugs that have been

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approved by the Food and Drug
Administration for the treatment of

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cancer today that are directed and
in this more effective class is not

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great, but there are some.
And that number will increase.

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So I think there's reason for
optimism utilizing the information,

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the kinds of information, the
strategies that we'll cover in the

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next three lectures.
So cancer, I think in some respects,

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needs no introduction.
It's a disease that probably has

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affected some of you already in your
lives personally.

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Certainly everybody knows a family
member or friend who has developed

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the disease.  It is a remarkably
common disease.  In this

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country alone --

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-- more than a million people are
diagnosed every year with cancer.

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And this does not include another
million who are diagnosed with the

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less serious forms of skin cancer,
basal cell carcinoma and squamous

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cell carcinoma.
So, in that respect,

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more than two million people get the
diagnosis of cancer every year in

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this country.  Moreover,
each year --

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-- more than half a million people

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die in this country from cancer.
That's more than 1,500 people per

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day.  So in two days more people die
of cancer than died in the World

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Trade Center disaster.
It's a devastating disease.

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Half of the men in this room and a

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third of the females --

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-- will be diagnosed with cancer in
their lifetimes.

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And overall more than a quarter of
all deaths are attributable

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to cancer.
A major problem.

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A major burden.  Clearly something
we need to do something about.

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So I'm going to show you some
slides that introduce you to the

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disease.  Cancer,
as you know, is a generic term that

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covers a class of diseases that
affect many, actually,

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almost all of your organs.
You can get cancers in different

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places.
They're all defined by one common

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property which is too many cells.
Too many cells in a tissue causing

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a lump.  Too many cells in the blood.
Too many cells in lymph organs.

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So that's the common theme that
relates to all cancers,

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but there are very important
differences in cancers in different

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sites.  This is a radiographic image
of lung cancer.

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What you're looking at here is a
standard chest x-ray.

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And this individual, you can see,
has an opacity right here, a fairly

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large opacity that's probably about
the size of your fist in this lobe

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of the lung.  And that's fairly
advanced lung cancer.

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This is a more precise diagnostic
test called computed tomography,

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which is essentially a series of
x-ray slices that get reconstructed.

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It gives better resolution.  And
you can see, again,

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a very large mass in the lung of
this individual.

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So that's a solid tumor imaged by
radiography.  This is leukemia.

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Leukemia is also too many cells but
here it's in the blood.

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This is a normal blood smear.
These pale cells without nuclei are

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your red blood cells.
These nucleated cells are white

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blood cells of different types.
And you can see in this abnormal

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blood smear of a leukemia patient
there is a vast increase in the

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number of white blood cells.
So this is a diagnostic feature of

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leukemia, too many cells.
And it's diagnosed by looking at

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blood counts.  And the blood counts
in leukemia patients of white cell

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counts can be elevated by thousands,
if not hundreds of thousands of fold.

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You can also use other imaging
techniques to detect and diagnose

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cancer.  This is endoscopic
examination, colonoscopy.

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It's now recommended that everyone
undergoes this exam every year when

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they reach age 50 to detect tumors
at an early stage so that they can

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be removed surgically which is,
in fact, the most effective

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treatment for colon cancer.
And, actually, for almost all

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cancers.  The most effective
treatment for cancer is the removal

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of the tumor.  If you can get to the
tumor at an early stage through some

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of these imaging techniques and
eradicate it, remove it,

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you can greatly limit the mortality
associated with the disease.

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So this is endoscopy.
This is what a normal colon looks

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like, sort of a smooth structure.
This is an early stage colon tumor.

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It's called a polyp at this stage.
And I'll give you a little bit more

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nomenclature in a minute.
This is actually not cancer.

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A polyp is not cancer.  It's a
benign tumor.  This may or may not

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progress to a cancer,
but if the doctor were to find a

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polyp like that they might follow it
for one or two years.

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But if were to get bigger they
would remove it.

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And they can actually do it
endoscopically.

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They can remove it using a surgical
endoscope.  They don't actually have

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to do surgery to remove polyps
anymore.  At some frequency these

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polyps do progress to colon cancer.
And this is a true cancer, a

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carcinoma which has changed its
shape and importantly changed its

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relationship to the tissue.
Whereas, the polyp is sort of

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sitting up on top of the tissue,
having grown out of the tissue, the

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colon cancer has invaded into the
tissue.  It has become much more

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destructive in that sense.
And also, importantly,

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has the capacity to move outside of
the colon through that process of

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invasion to other parts of the body,
and thereby cause problems elsewhere.

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Usually, when these are diagnosed
by endoscopy or other methods,

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they are removed.  This is done by
surgery where a portion of the colon

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is actually removed and then the two
resected ends joined.

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And you can see the colon cancer
right here.  If the cancer is

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detected at an early enough stage,
surgery is curative for colon cancer.

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Unfortunately,
it's often too late when it's

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diagnosed.  It looks like that.
Because it's already moved outside

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of the colon and tumor cells have
found their way to other parts of

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the body.  So surgical removal of
the primary tumor,

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while helpful, may actually not be
curative.  So I want to go through

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in diagrammatic form some of the
points that I've just made.

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Cancer develops in states.
It doesn't happen all at once.

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As I showed you in the normal colon
polyp to colon cancer series,

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things happen in stages.  It's
actually best worked out in the

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colon.  But we believe the same
phenomena hold true for other

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cancers in other places.
It doesn't happen all at once.

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It happens in stages.  And these
slides illustrate the basic

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principles of that.
This illustrates a normal tissue.

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It could be anywhere, but let's say
that it's in the colon.

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And there are certain important
features to pay attention to.

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One is that the cells have regular
shape and a regular relationship to

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their neighbors.
As you know, tissues are formed for

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normal function.
They have particular genes

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expressed.  They have particular
structures inside them.

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They interact with their neighbors
in order to perform their function.

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So the cells of the colonic
epithelium line up like this

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touching each other,
interacting with each other and

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interacting with the cells
underneath them,

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as well as other material underneath
them.

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Here is a material called the
basement membrane,

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otherwise known as the extracellular
matrix.  And this helps support the

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cells and provides the cells with
certain nutrients and growth factors.

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There are also cells below these
cells in the colon and in other

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tissues which replenish these cells
when they get lost.

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These stem or progenitor cells
exist probably in all adult tissues.

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They get recruited when cells
turnover.

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And we now think,
and it's not illustrated on these

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slides, but we now think that these
cells are probably very important in

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tumor initiation.
We think that these are cells,

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these stem cells of the tissue are
likely to be the place where the

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tumors initiate and then produce
cells, like this brown cell here,

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which is already abnormal.  Cells
that have acquired a mutation which

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makes them different from their
neighbors.  Now,

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the first consequence of those early
changes is that you get too many

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cells.  And this is a process known
as hyperplasia.

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Hyperplasia simply means hyper,
too many, plasia, division, cell

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division.  So there are too many
cells.  But the cells that are

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present there look pretty normal.
They don't histologically, by

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looking at the tissue,
appear different from their normal

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neighbors.  There are just too many
of them.  This process continues

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until you can actually see a
discernable lump,

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a mass, and that is a formation of a
benign tumor.

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In the colon that tumor,
that benign tumor is called an

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adenoma.  It's called other things
in other places but let's say,

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just for the sake of simplicity,
it's a benign tumor.  And, again,

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this is an increase in the number of
cells but the cells themselves don't

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look very different from their
normal neighbors.

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And these tumors are not
life-threatening yet.

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They sometimes will never be
life-threatening but in this form

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they rarely cause problems.
They're just a lump.  Like a wart

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is a benign tumor,
a lump that doesn't cause problems.

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At some frequency these tumors can
progress further.

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And now, as you can see from this
different shading,

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the cells take on different
characteristics.

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They look different from their
normal neighbors.

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Their cyto architecture,
the cell shape looks different.

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The nucleus often looks different
from the normal cells.

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And so they've become fundamentally
changed in their appearance.

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Moreover, they have begun to
recruit a blood supply.

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The presence of these blood vessels
which were not present up here is

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another indication that things
have progressed.

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And tumors require a blood supply of
their own to feed the tissue,

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this abnormal growing tissue.  As
soon as they get to a certain size

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they need to recruit a new blood
supply.  This tumor at this stage

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has changed enough that we now call
it cancer.  This is based on these

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histological changes,
the appearance of the cells,

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as well as the cells' relationship
to one another.

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And this is now considered dangerous.
If you're diagnosed with a cancer,

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even if it's present in the tissue,
the initial tissue alone,

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it would be recommended for removal.
However, it rarely stays there.

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Tumors have the capacity to move
from their original site through a

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process of invasion and then
metastasis.  This illustrates

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invasion, local invasion where the
tumor cells are moving from the mass

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through the basement membrane and
ultimately accessing

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the blood supply.
Literally moving into blood vessels,

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traveling through the blood, and
then moving out of blood vessels and

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beginning to proliferate,
expand in other tissues.  And this

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is the process of metastasis.
And the tumor cells can literally

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go anywhere.  Certain tumors have
preferences to go to certain tissues

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than others.  And when they get
there they begin to grow again and

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turn, become actually more advanced,
more dangerous, cause local tissue

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damage, organ failure.
And it's usually this that causes

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the death of the cancer patient.
It's the metastatic spread of the

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disease as opposed to the primary
tumor that tends to kill cancer

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patients.  And sadly it's this phase
of the disease,

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metastatic spread that we know the
littlest about.

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We actually know rather little
about what allows cells to move from

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their primary site through the blood,
establish themselves elsewhere and

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then grow there.
And since it is the most deadly

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phase of the disease,
it represents a clear need,

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clear opportunity to learn more.
So let me just illustrate, or

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rather emphasize some of these bits
of terminology for you.

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Hyperplasia is simply too many cells.

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You have hyperplastic lesions,
we call them, throughout your body.

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Most of them no problem at all.
They're not going to do anything.

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It's just there are too few many
cells in that particular place.

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These can progress to benign tumors
which are non-aggressive.

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That is the cells are relatively
well-behaved.  They're not dividing

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that much.  They're not moving
around.  They have normal

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relationships with their neighbors.
And with respect to the tissue that

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they reside in,
they're nondestructive.

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They haven't breached the
underlying basement membrane.

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They haven't changed their
relationship with their normal

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neighbors.  And they're also defined
through a lack of spread.

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They haven't moved out into the
local lymph nodes or to

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surrounding tissues.

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These can progress to malignant
tumors.  And these are true cancers.

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We actually only use the term
cancer to refer to malignant tumors,

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not to benign tumors.  These are
true cancers.  And these are

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aggressive.  The cells have changed
shape.  They have much greater

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proliferative capacity.
They move around to a greater

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degree.
They are destructive with respect to

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the tissue in which they reside.
And they have the potential to

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spread.  Not all diagnosed cancers
have already spread,

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but the view of the pathologist is
that they have the potential to

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spread and therefore they are
typically removed.

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Now cancers in different places
have different names.

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As I said, you can get cancer in
virtually all tissues of your body.

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There are probably 250 or 300
different types of cancer clinically

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defined, and those are defined in
part based on where they are and in

238
00:00:17 --> 00:00:17:49
what types of cells they occur.
So there are tumors of epithelial

239
00:00:17 --> 00:00:17:54
cells, cells of the skin,
lining of the intestine, mammary

240
00:00:17 --> 00:00:18:00
epithelial cells,
epithelial cells of your brain.

241
00:18:00 --> 00:00:18:04
And these tumors are called
carcinomas.  These cancers are

242
00:00:18 --> 00:00:18:09
called carcinomas.
And you might have heard,

243
00:00:18 --> 00:00:18:13
for example, a subset of carcinomas
called adenocarcinomas.

244
00:00:18 --> 00:00:18:18
Adenocarcinoma is what I showed you
with respect to the colon cancers.

245
00:00:18 --> 00:00:18:22
Adenocarcinoma of the breast.
Adenocarcinoma of the lung.

246
00:00:18 --> 00:00:18:27
These are carcinomas that have a
glandular appearance.

247
00:00:18 --> 00:00:18:32
And there are other kinds of
carcinomas as well.

248
00:18:32 --> 00:00:18:38
Those are the cancers.
And the benign tumors of these

249
00:18:38 --> 00:00:18:44
tissues, especially of the class
that gives rise to adenocarcinomas

250
00:18:44 --> 00:00:18:50
are called adenomas.
There are also tumors of your

251
00:18:50 --> 00:00:18:56
connective tissues like you
cartilage or your muscles

252
00:18:56 --> 00:00:19:02
or your tendons.
These are called sarcomas.

253
00:00:19 --> 00:00:19:09
And you've probably heard of
myosarcomas.  Those are tumors of

254
00:00:19 --> 00:00:19:16
the muscle.  And there are different
types of myosarcomas.

255
00:00:19 --> 00:00:19:23
And then there are tumors of the
blood system.

256
00:19:23 --> 00:00:19:32
These are called leukemias if the

257
00:00:19 --> 00:00:19:37
tumors are present,
tumor cells are present within the

258
00:00:19 --> 00:00:19:42
blood itself.  And I showed you an
example of that.

259
00:00:19 --> 00:00:19:47
Or lymphomas.  And here it's
defined as tumors which stay within

260
00:00:19 --> 00:00:19:52
lymph organs like lymph nodes or
spleen or thymus.

261
00:00:19 --> 00:00:19:57
They haven't made their way out
into the blood,

262
00:00:19 --> 00:00:20:02
but they are still tumors of the
blood cells.

263
00:20:02 --> 00:00:20:06
OK.  So we know a lot about what
these tumors look like based on

264
00:00:20 --> 00:00:20:11
visual inspection.
We also know what they look like

265
00:00:20 --> 00:00:20:15
based on histological analysis.
This is a progression series

266
00:00:20 --> 00:00:20:20
actually taken from a mouse model of
cancer generated in my lab.

267
00:20:20 --> 00:00:20:25
It's a tumor of the lung.  You
might be able to see the lacey

268
00:00:20 --> 00:00:20:29
appearance of the lung here.
And this circle you can see

269
00:00:20 --> 00:00:20:34
hyperplasia, too many cells.
Cells, if you were to see them up

270
00:00:20 --> 00:00:20:38
close, look pretty much like their
neighbors, but there are just too

271
00:20:38 --> 00:00:20:42
many of them.  These progress into
lumps, masses called adenomas in

272
00:00:20 --> 00:00:20:46
this case.  These are benign tumors.
They don't have the features of the

273
00:00:20 --> 00:00:20:50
more aggressive malignant cells.
And you can see them here.  They

274
00:00:20 --> 00:00:20:54
all look pretty much the same.
And if you saw them next to a

275
00:00:20 --> 00:00:20:59
normal cell they would look pretty
much like those.

276
00:20:59 --> 00:00:21:02
But these can progress into
adenocarcinomas,

277
00:00:21 --> 00:00:21:05
more advanced tumors.
These are true cancers.

278
00:00:21 --> 00:00:21:09
And you can tell that based on the
fact that the nuclei,

279
00:00:21 --> 00:00:21:12
if you compare one cell to another,
looks very different, and the cell

280
00:00:21 --> 00:00:21:15
shape looks very different from one
to the other.  So there's

281
00:00:21 --> 00:00:21:19
heterogeneity.
And what you cannot see here is

282
00:00:21 --> 00:00:21:22
that the tumors are also much more
proliferative.

283
00:00:21 --> 00:00:21:26
They are dividing.
The cells are dividing much more

284
00:00:21 --> 00:00:21:29
frequently.  So,
again, histologically we can

285
00:00:21 --> 00:00:21:33
characterize what these
tumors look like.

286
00:21:33 --> 00:00:21:37
What I'm going to tell you about
from this point really to the end of

287
00:00:21 --> 00:00:21:41
the class is that we understand,
at least to a degree, what these

288
00:00:21 --> 00:00:21:45
arrows represent,
what happens to a normal cell on the

289
00:00:21 --> 00:00:21:50
way to hyperplasia or to an adenoma
or to an adenocarcinoma.

290
00:21:50 --> 00:00:21:54
And the answer is defects to genes.
Defects to many genes underlie

291
00:00:21 --> 00:00:21:58
these transitions,
allow a normal cell to develop into

292
00:00:21 --> 00:00:22:04
a cancer cell.
And so in that sense we consider

293
00:00:22 --> 00:00:22:10
cancer as a genetic disease.
Now, cancer actually is also a more

294
00:00:22 --> 00:00:22:17
traditional genetic disease in some
instances.  There are people who are

295
00:00:22 --> 00:00:22:23
genetically predisposed to
developing cancer.

296
00:00:22 --> 00:00:22:30
And I'm actually going to tell you
about them next time.

297
00:22:30 --> 00:00:22:33
But even for people who are not
genetically predisposed to cancer,

298
00:00:22 --> 00:00:22:37
the development of cancer in them is
a genetic disease.

299
00:00:22 --> 00:00:22:40
How do we know that?
Why do we think that?

300
00:00:22 --> 00:00:22:44
Well, we think that for a number of
reasons.  And one of them,

301
00:00:22 --> 00:00:22:47
which we've appreciated for more
than a hundred years is that the

302
00:00:22 --> 00:00:22:51
chromosomes of cancer cells are
screwed up.  They look different

303
00:00:22 --> 00:00:22:55
than normal cells.
I've actually shown you this slide

304
00:00:22 --> 00:00:22:59
before.
This is a karyotype of a normal cell,

305
00:00:22 --> 00:00:23:03
46 chromosomes,
23 pairs.  These are highlighted by

306
00:00:23 --> 00:00:23:08
stains that allow us to distinguish
one chromosome from another.

307
00:00:23 --> 00:00:23:12
So chromosome one stains yellow,
chromosome two stains red, and so on

308
00:00:23 --> 00:00:23:17
and so forth.  And this is the
karyotype of a cancer cell.

309
00:00:23 --> 00:00:23:22
It's different in many ways.
Name me two.

310
00:23:22 --> 00:00:23:29
I didn't hear anybody.

311
00:00:23 --> 00:00:23:34
I heard there was mumbling but I
didn't hear anybody.  Say again.

312
00:23:34 --> 00:00:23:37
The number and shape of chromosomes.
Good.  So clearly there are too

313
00:00:23 --> 00:00:23:40
many chromosomes.
I didn't count them up,

314
00:00:23 --> 00:00:23:43
but there is more than double the
proper number of chromosomes in this

315
00:00:23 --> 00:00:23:46
cancer cell.  So chromosome number
defects are quite common in cancer

316
00:00:23 --> 00:00:23:49
cells.  But also structure,
and I've boxed two of them here,

317
00:00:23 --> 00:00:23:52
the structure of chromosomes in
cancer cells are different.

318
00:00:23 --> 00:00:23:55
This chromosome has undergone what
we call a translocation in which a

319
00:00:23 --> 00:00:23:58
piece of one chromosome has been
joined to a piece of a

320
00:00:23 --> 00:00:24:02
different chromosome.
And we now know that when that

321
00:00:24 --> 00:00:24:06
happens it's reflective of a
mutation that either is inactivating

322
00:00:24 --> 00:00:24:11
or activating a gene that's present
at the point of translocation.

323
00:00:24 --> 00:00:24:15
And this chromosome has undergone a
truncation, a deletion.

324
00:00:24 --> 00:00:24:20
Genetic material has been loss.
And this, again, indicates that

325
00:00:24 --> 00:00:24:24
there was a gene present there that
the tumor cell wanted to get rid of

326
00:00:24 --> 00:00:24:29
in the development of the cancer.
So chromosomal abnormalities are

327
00:00:24 --> 00:00:24:34
quite common, which was a first clue
that cancer is a genetic disease.

328
00:24:34 --> 00:00:24:51
The second indication,

329
00:00:24 --> 00:00:24:58
which came along as early as the
1920s, is that many carcinogens,

330
00:24:58 --> 00:00:25:05
and what I mean by that is agents
that cause cancer.

331
00:25:05 --> 00:00:25:17
Many carcinogens are mutagens,

332
00:25:17 --> 00:00:25:31
agents that cause what?  Yeah?

333
00:25:31 --> 00:00:25:35
Not all.  But there is a very high
correlation between things that will

334
00:25:35 --> 00:00:25:39
cause cancer and things that will
cause mutation in simple

335
00:25:39 --> 00:00:25:50
mutation assays.

336
00:25:50 --> 00:00:25:55
And you can do assays to determine
the carcinogenicity or mutagenicity

337
00:00:25 --> 00:00:26:08
of an agent of interest.

338
00:26:08 --> 00:00:26:13
Carcinogenicity assays are done
typically in experimental animals,

339
00:00:26 --> 00:00:26:18
mice or rats.  And one takes the
animal and exposes it to agent X.

340
00:00:26 --> 00:00:26:23
It might be injected into the
animal or it might be painted on the

341
00:00:26 --> 00:00:26:28
skin of the animal.
And then one waits a period of time

342
00:00:26 --> 00:00:26:34
and asks the question did the animal
develop a tumor?

343
00:26:34 --> 00:00:26:38
And if so the agent is a carcinogen.
And you can actually determine how

344
00:26:38 --> 00:00:26:43
strong a carcinogen is,
how strong a carcinogen it is by

345
00:26:43 --> 00:00:26:47
determine the dose,
the amount of the agent needed to

346
00:26:47 --> 00:00:26:52
produce a tumor.
There are also mutagenicity tests.

347
00:26:52 --> 00:00:27:01
And this is typically done in

348
00:00:27 --> 00:00:27:07
bacteria.  So one takes a bacterial
strain and asks whether the agent

349
00:00:27 --> 00:00:27:13
can cause mutations in that strain.
And usually to do this one takes a

350
00:00:27 --> 00:00:27:18
bacterial strain that already has a
mutation, a bacteria that is

351
00:00:27 --> 00:00:27:24
histidine deficient,
which means that it's not able to

352
00:00:27 --> 00:00:27:30
synthesize its own histidine
and amino acid.

353
00:27:30 --> 00:00:27:36
That means that if you take that
bacteria strain and plate it onto a

354
00:00:27 --> 00:00:27:42
Petri dish that lacks histidine,
you haven't added histidine to the

355
00:00:27 --> 00:00:27:49
media, will it grow?
No.  It's histidine minus,

356
00:00:27 --> 00:00:27:55
it cannot make its own, if you don't
provide it, cells cannot grow,

357
00:00:27 --> 00:00:28:01
so you get no colonies.
However, if I now add agent X,

358
00:28:01 --> 00:00:28:06
which I think might be a mutagen,
to these bacteria, if it is a

359
00:28:06 --> 00:00:28:11
mutagen it might mutate the
defective histidine gene and turn it

360
00:28:11 --> 00:00:28:16
into a normally functioning
histidine gene such that if I now

361
00:28:16 --> 00:00:28:21
plate these bacteria that have been
treated with the mutagen I may get

362
00:28:21 --> 00:00:28:26
some colonies.
And you're still using a his-minus

363
00:28:26 --> 00:00:28:31
plate here.
And the number of colonies that I

364
00:00:28 --> 00:00:28:35
get is an indication of the strength
of the mutagen.

365
00:00:28 --> 00:00:28:39
Lots of colonies,
strong mutagen.  Fewer,

366
00:00:28 --> 00:00:28:43
not so strong.  And what I'm saying
is that there's a strong correlation

367
00:00:28 --> 00:00:28:47
between things that pass this assay
and things that pass that assay,

368
00:00:28 --> 00:00:28:51
another indication that cancer might
be caused by mutations to DNA.

369
00:00:28 --> 00:00:28:55
Now some things that we know for
sure are carcinogens.

370
00:00:28 --> 00:00:29:00
They pass this carcinogenicity test
very, very strongly.

371
00:29:00 --> 00:00:29:06
Fail in this simple mutagenicity
test.  Why?  How can that be?

372
00:00:29 --> 00:00:29:12
They clearly are cancer-causing.
But if you mix them with bacteria

373
00:00:29 --> 00:00:29:18
in isolation here you don't get any
increased mutation frequency.

374
00:00:29 --> 00:00:29:24
What's different?  What's different
about this situation versus

375
00:00:29 --> 00:00:29:42
this situation?  Yes?

376
00:29:42 --> 00:00:29:49
Excellent.  Precisely correct.
There are certain agents which in

377
00:00:29 --> 00:00:29:57
their native form are not mutagenic.
We call them promutagens.  However,

378
00:00:29 --> 00:00:30:05
when acted on by the body in the
process of metabolism they

379
00:00:30 --> 00:00:30:11
become mutagens.
The body senses that these are

380
00:00:30 --> 00:00:30:15
actually dangerous compounds and
will try to detoxify them,

381
00:00:30 --> 00:00:30:19
typically by adding hydroxyl groups
to them to make them more

382
00:00:30 --> 00:00:30:23
water-soluble so that they can be
secreted or excreted by the body.

383
00:00:30 --> 00:00:30:27
But in the process of making them
more water-soluble they go through

384
00:00:30 --> 00:00:30:32
an intermediate form which turns out
to be highly mutagenic.

385
00:30:32 --> 00:00:30:36
And that's illustrated here for a
very powerful carcinogen known as

386
00:00:30 --> 00:00:30:40
benzo(a)pyrene.
This is an agent found in cigarette

387
00:30:40 --> 00:00:30:45
smoke, for example.
This agent is not highly mutagenic

388
00:30:45 --> 00:00:30:49
on its own, but in this type of test
it is highly carcinogenic.

389
00:00:30 --> 00:00:30:54
And what happens is that the body,
in an attempt to add hydroxyl groups

390
00:30:54 --> 00:00:30:58
to make it more water-soluble,
will actually introduce epoxides in

391
00:00:30 --> 00:00:31:02
different ring positions of this
molecule, as an intermediate towards

392
00:00:31 --> 00:00:31:07
making it more hydroxylated.
And these epoxides are very

393
00:31:07 --> 00:00:31:12
interactive with DNA and therefore
mutagenic.  So the body turns

394
00:31:12 --> 00:00:31:17
something that actually wasn't
mutagenic into something that is

395
00:31:17 --> 00:00:31:22
mutagenic.  And therefore this test,
this mutagenicity test has been

396
00:31:22 --> 00:00:31:27
modified, principally based on the
work of a bacteriologist at Berkeley

397
00:31:27 --> 00:00:31:32
named Bruce Ames.
And so we now call it the Ames Test.

398
00:00:31 --> 00:00:31:38
And the Ames Test takes the
compound, the agent that you're

399
00:00:31 --> 00:00:31:44
trying to test the mutagenicity of,
and rather than adding it directly

400
00:00:31 --> 00:00:31:50
back to bacteria it's mixed first
with an extract of the liver.

401
00:00:31 --> 00:00:31:56
Many of the enzymes that do this
detoxification are present in your

402
00:00:31 --> 00:00:32:02
liver.  Cytochrome P450
enzymes, for example.

403
00:32:02 --> 00:00:32:07
In which case the compound becomes
modified, or might become modified.

404
00:00:32 --> 00:00:32:12
And through that modification
becomes mutagenic.

405
00:00:32 --> 00:00:32:17
And then the agent gets tested in
the standard bacterial

406
00:00:32 --> 00:00:32:26
mutagenicity test.

407
00:32:26 --> 00:00:32:30
OK.  So we can now expand our list
of things that are mutagenic through

408
00:32:30 --> 00:00:32:34
exposing them to some of the body's
own enzymes.

409
00:32:34 --> 00:00:32:37
In this sense,
the body is actually doing you a

410
00:00:32 --> 00:00:32:41
disservice in thinking it's actually
trying to help you.

411
00:00:32 --> 00:00:32:45
There are still other agents which
are not mutagens,

412
00:00:32 --> 00:00:32:49
even in the Ames Test,
but are clearly carcinogens.

413
00:00:32 --> 00:00:32:53
Asbestos, for example.  That stuff
in packing material that's now been

414
00:00:32 --> 00:00:32:57
banned exposure to which gives
people, or can give people

415
00:00:32 --> 00:00:33:01
mesotheliomia,
a tumor of the lining of the lungs.

416
00:00:33 --> 00:00:33:05
It's not a mutagen.

417
00:00:33 --> 00:00:33:09
However, you test it,
it's not a mutagen.  Alcohol,

418
00:00:33 --> 00:00:33:13
which is clearly associated with
liver cancer, is not a mutagen.

419
00:00:33 --> 00:00:33:17
These agents we think act as
irritants.  They case damage to

420
00:00:33 --> 00:00:33:21
tissue which causes the cells to
have to increase their proliferation

421
00:00:33 --> 00:00:33:25
to repair the tissue,
and that is inherently a mutagenic

422
00:00:33 --> 00:00:33:29
process.  And so these things can
act as carcinogens in that

423
00:00:33 --> 00:00:33:34
very indirect way.
OK.  Now there are many things in

424
00:33:34 --> 00:00:33:38
our environment that
are carcinogens --

425
00:33:38 --> 00:00:33:48
-- that we get exposed to either

426
00:33:48 --> 00:00:33:52
passively or deliberately.
Sunlight, for example, is a

427
00:33:52 --> 00:00:33:56
carcinogen and a mutagen.
It causes damage to DNA, causes

428
00:33:56 --> 00:00:34:00
mutation, increases your
risk of skin cancer.

429
00:34:00 --> 00:00:34:04
Other things that we do to ourselves.
Certain dietary carcinogens we

430
00:00:34 --> 00:00:34:09
impose on ourselves.
But what's the biggest carcinogen

431
00:00:34 --> 00:00:34:14
that we impose on ourselves?
Smoke.  Tobacco smoke.

432
00:34:14 --> 00:00:34:21
And obviously tobacco smoke is

433
00:34:21 --> 00:00:34:26
associated with one particular type
of cancer, although it's not limited

434
00:34:26 --> 00:00:34:32
to lung cancer.
Any idea how many people die of lung

435
00:00:34 --> 00:00:34:40
cancer in this country per year?
Anybody want to hazard a guess?  10,

436
00:00:34 --> 00:00:34:48
00?  100,000?  175,
00.  175,000 people per year die of

437
00:00:34 --> 00:00:34:56
lung cancer each year.
And more than 150,000 of them it's

438
00:00:34 --> 00:00:35:05
because of smoking.

439
00:35:05 --> 00:00:35:09
Lung cancer is the number one cancer
killer.  It kills more people in

440
00:00:35 --> 00:00:35:14
this country than breast cancer,
colon cancer and prostate cancer

441
00:00:35 --> 00:00:35:18
combined.  And it's completely
preventable, or almost completely

442
00:00:35 --> 00:00:35:23
preventable through a change of
habit, failure to smoke.

443
00:00:35 --> 00:00:35:28
So let me just emphasize the
importance of this.

444
00:35:28 --> 00:00:35:32
These are curves that show the
smoking frequency in this country

445
00:00:35 --> 00:00:35:36
among men and women and the
incidence of cancer,

446
00:00:35 --> 00:00:35:40
lung cancer in this country among
men and women.

447
00:00:35 --> 00:00:35:45
You can see that early on,
in the early part of the century

448
00:00:35 --> 00:00:35:49
smoking was  uncommon and lung
cancer was uncommon.

449
00:00:35 --> 00:00:35:53
But as people began to smoke this
frequency increased and then years

450
00:00:35 --> 00:00:35:57
later the incidence of lung cancer
increased dramatically.  It

451
00:00:35 --> 00:00:36:02
takes a little while.
You've got to expose yourself to

452
00:00:36 --> 00:00:36:06
these carcinogens for a period of
time for this process to have its

453
00:00:36 --> 00:00:36:10
effect, but eventually that smoking
exposure leads to the development of

454
00:00:36 --> 00:00:36:14
lung cancer.  You can see that women
started smoking a little bit later,

455
00:00:36 --> 00:00:36:19
but they quickly caught up.  And now
the lung cancer incidence in women

456
00:00:36 --> 00:00:36:23
is also extremely high.
Lung cancer among women is the

457
00:00:36 --> 00:00:36:27
leading cause of cancer deaths.
It's now surpassed breast cancer as

458
00:00:36 --> 00:00:36:37
the leading cancer killer of women.
The statistics about smoking in this

459
00:00:36 --> 00:00:36:51
country, despite these facts,
are remarkable.  47 million adults

460
00:00:36 --> 00:00:37:06
smoke.  Roughly one in four men,
and almost as many women smoke.

461
00:37:06 --> 00:00:37:13
Even more amazing to me than that,
in 2002, I don't have more recent

462
00:00:37 --> 00:00:37:20
statistics than that,
but in 2002 the percent of high

463
00:00:37 --> 00:00:37:27
school students who responded to a
survey about whether they

464
00:00:37 --> 00:00:37:33
smoked was what?
What do you think?

465
00:00:37 --> 00:00:37:37
High school students.
28%.  So this is not just people

466
00:00:37 --> 00:00:37:42
who have been smoking a long time,
who started when they didn't know

467
00:00:37 --> 00:00:37:47
any better.  Kids who get exposed to
the message about smoking and lung

468
00:00:37 --> 00:00:37:51
cancer from an early age are not
paying attention.

469
00:00:37 --> 00:00:37:56
So the problem is not going away.
These folks obviously have a

470
00:00:37 --> 00:00:38:01
dramatically increased risk of dying
from lung cancer.

471
00:38:01 --> 00:00:38:06
And it's not just lung cancer.
Smoking increases your risk of

472
00:00:38 --> 00:00:38:11
heart disease,
of stroke, of emphysema.

473
00:00:38 --> 00:00:38:16
I read a startling statistic when I
was preparing this.

474
00:00:38 --> 00:00:38:21
Of all the people who are alive
today on this planet,

475
00:00:38 --> 00:00:38:27
500 million of them will die early
due to tobacco usage.

476
00:38:27 --> 00:00:38:32
500 million people who are alive
today would live longer if not for

477
00:00:38 --> 00:00:38:38
exposure to tobacco products.
So if you learn nothing else from

478
00:00:38 --> 00:00:38:44
this class this year,
if you now smoke, stop.

479
00:00:38 --> 00:00:38:50
If you don't smoke, don't start.
OK.  So carcinogens in our

480
00:00:38 --> 00:00:38:56
environment and carcinogens that we
exposure ourselves to are important.

481
00:00:38 --> 00:00:39:02
No doubt about it, they can be a
cause of cancer.

482
00:39:02 --> 00:00:39:17
I call these exogenous or

483
00:00:39 --> 00:00:39:23
environmental mutagens.
And, as I mentioned, sunlight and

484
00:00:39 --> 00:00:39:29
other forms of radiation,
certain dietary things that we

485
00:00:39 --> 00:00:39:35
expose ourselves to fall
into this category.

486
00:39:35 --> 00:00:39:38
But they're not the only thing that
causes cancer.

487
00:00:39 --> 00:00:39:42
And it's very important that you
know that.  In fact,

488
00:00:39 --> 00:00:39:45
more of the mutations that happen in
cancer are due to indigenous

489
00:00:39 --> 00:00:39:49
processes, things that happen inside
your bodies regardless of what you

490
00:00:39 --> 00:00:39:52
get exposed to,
like DNA replication mistakes.

491
00:00:39 --> 00:00:39:56
DNA polymerases that duplicate your
DNA are pretty good,

492
00:00:39 --> 00:00:40:00
they have proofreading functions,
but they still make mistakes.

493
00:40:00 --> 00:00:40:05
And these mistakes can be then in
critical genes which can ultimately

494
00:00:40 --> 00:00:40:12
lead to tumor development.

495
00:40:12 --> 00:00:40:15
Your DNA can sometimes get broken.
It gets moved around inside the

496
00:00:40 --> 00:00:40:18
cell during various processes.
Sometimes it gets broken, and

497
00:00:40 --> 00:00:40:21
sometimes those breaks are not
properly repaired.

498
00:00:40 --> 00:00:40:24
And this can lead to some of the
defects that I've shown you on this

499
00:00:40 --> 00:00:40:27
slide like the translocations where
different pieces get rearranged with

500
00:00:40 --> 00:00:40:36
the wrong other piece.

501
00:40:36 --> 00:00:40:39
Defects in chromosome segregation.
We talked about mitosis early in

502
00:00:40 --> 00:00:40:43
the class and how the cells have an
intricate ability to properly

503
00:00:40 --> 00:00:40:47
segregate their chromosomes,
that each daughter cell gets the

504
00:00:40 --> 00:00:40:51
right number.  Sometimes that
process doesn't work properly so

505
00:00:40 --> 00:00:40:55
that one cell gets too many
chromosomes or one cell gets too few.

506
00:00:40 --> 00:00:40:59
These chromosomal imbalances can
also contribute to tumor

507
00:00:40 --> 00:00:41:04
development.
Defects in DNA repair.

508
00:41:04 --> 00:00:41:12
Your cells have all sorts of enzymes

509
00:00:41 --> 00:00:41:17
that will try to find damaged DNA
and fix it, but these enzymes

510
00:00:41 --> 00:00:41:22
themselves can be mutationally
inactivated in the development of

511
00:00:41 --> 00:00:41:28
cancer.  So now you've debilitated
the cell's ability to fix the damage

512
00:00:41 --> 00:00:41:33
leading to an increased frequency of
damage, increased frequency of

513
00:00:41 --> 00:00:41:38
mutation, increased cancer risk.
And importantly --

514
00:41:38 --> 00:00:41:53
-- production of indigenous mutagens

515
00:41:53 --> 00:00:41:57
in contrast to exogenous mutagens.
Your body actually produces things

516
00:41:57 --> 00:00:42:03
that are mutagenic.
And the biggest class of these are

517
00:00:42 --> 00:00:42:11
oxygen radicals such
as superoxide --

518
00:42:11 --> 00:00:42:29
-- or hydrogen peroxide.

519
00:42:29 --> 00:00:42:31
And these radicals are highly

520
00:00:42 --> 00:00:42:35
reactive to DNA,
can cause DNA breaks and base

521
00:00:42 --> 00:00:42:39
changes, and cause mutation.
And your body produces these

522
00:00:42 --> 00:00:42:43
naturally in the process of
metabolism.  You have enzymes that

523
00:00:42 --> 00:00:42:46
will kind of keep the concentrations
of these down but,

524
00:00:42 --> 00:00:42:50
nevertheless, they're present and
cause damage at a certain frequency

525
00:00:42 --> 00:00:42:54
in all cells.  If that damage occurs
in the wrong cell at the wrong time

526
00:00:42 --> 00:00:42:58
it can be cancer-causing.
So there are lots of ways that the

527
00:00:42 --> 00:00:43:02
DNA of your cells can get mutated,
which then overall contributes to

528
00:00:43 --> 00:00:43:06
the development of cancer.
Now, this doesn't happen all at once,

529
00:43:06 --> 00:00:43:10
as I've tried to indicate to you.
It doesn't happen from normal cell

530
00:43:10 --> 00:00:43:14
to cancer cell in a single step.
We think that this process happens

531
00:43:14 --> 00:00:43:18
over time.  And in humans over
decades of time.

532
00:43:18 --> 00:00:43:22
Cancers often initiate maybe in
mid-life, but they don't present

533
00:43:22 --> 00:00:43:26
themselves as a clinically advanced
tumor until late in life.

534
00:43:26 --> 00:00:43:30
and that's because the process
requires lots of steps that require

535
00:43:30 --> 00:00:43:34
lots of time to accumulate.
And so we now consider tumor

536
00:00:43 --> 00:00:43:38
development from a normal cell to a
more advanced cancer cell as a

537
00:00:43 --> 00:00:43:42
clonal evolution process.
A clonal evolution process whereby

538
00:00:43 --> 00:00:43:46
abnormal cells arise in a population.
These now have a selected advantage

539
00:00:43 --> 00:00:43:50
compared to their normal cells and
will grow, for example,

540
00:00:43 --> 00:00:43:54
better than their normal cells,
divide faster than their normal

541
00:00:43 --> 00:00:43:59
cells, make more of themselves.
The mutation that took place is now

542
00:00:43 --> 00:00:44:03
present in all the daughter cells of
that abnormal cell.

543
00:00:44 --> 00:00:44:07
And within that now-expanded clone
of abnormal cells a second mutation

544
00:00:44 --> 00:00:44:11
takes place which increases the
capacity of that cell to grow and

545
00:00:44 --> 00:00:44:16
divide, survive,
move around compared to its

546
00:00:44 --> 00:00:44:20
neighbors.  So now this cell and of
its descendents have two mutations.

547
00:00:44 --> 00:00:44:24
And within that expanded clone a
third mutation can take place and so

548
00:00:44 --> 00:00:44:29
and so forth.
We now think that cancers,

549
00:00:44 --> 00:00:44:34
advanced cancers in human probably
have five, ten,

550
00:00:44 --> 00:00:44:38
maybe twenty distinct mutations in
genes controlling important

551
00:00:44 --> 00:00:44:43
processes.  What are those processes?
There are many.

552
00:00:44 --> 00:00:44:48
We're going to emphasis,
in this class, just proliferation

553
00:00:44 --> 00:00:44:53
and cell death.
I'll say a bit more about that in a

554
00:00:44 --> 00:00:44:58
second.  But it's also important for
you to know that the cancer cells

555
00:00:44 --> 00:00:45:03
also regulate factors that increase
the blood supply.

556
00:45:03 --> 00:00:45:06
Cancer cells turn on growth factors
that recruit blood vessels.

557
00:45:06 --> 00:00:45:10
If they didn't do so they would
never be able to progress.

558
00:45:10 --> 00:00:45:14
You cannot actually make a solid
tumor bigger than two millimeters in

559
00:45:14 --> 00:00:45:18
diameter without recruiting a new
blood supply.  And so the tumor

560
00:45:18 --> 00:00:45:21
cells turn on these factors to deal
with angiogenesis.

561
00:45:21 --> 00:00:45:25
They also turn on factors that
allow them to move around to a

562
00:45:25 --> 00:00:45:29
greater degree or separate
themselves from their neighbors to

563
00:45:29 --> 00:00:45:33
invade into the basement tissues,
the basement membranes.

564
00:45:33 --> 00:00:45:36
To turn on proteases,
for example, that chew up the

565
00:00:45 --> 00:00:45:39
extracellular matrix to allow the
cells to move around,

566
00:00:45 --> 00:00:45:42
and other factors.  Factors,
for example, that allow them to move

567
00:00:45 --> 00:00:45:45
into the blood vessels or move back
out of the blood vessels in the

568
00:00:45 --> 00:00:45:48
process of metastasis.
So we're going to emphasis

569
00:00:45 --> 00:00:45:52
proliferation and cell death in the
next lecture, but I want you to know

570
00:00:45 --> 00:00:45:55
that many other aspects of cell
biology are important in

571
00:00:45 --> 00:00:46:07
this process as well.

572
00:46:07 --> 00:00:46:12
So proliferation,
it's kind of obvious that in cancers

573
00:00:46 --> 00:00:46:18
there might be changes that lead to
more cell division.

574
00:00:46 --> 00:00:46:23
And, indeed, the original
cancer-associated genes did this.

575
00:00:46 --> 00:00:46:29
And many of the important
cancer-associated genes that we know

576
00:00:46 --> 00:00:46:35
about are involved in promoting
increased cell division.

577
00:46:35 --> 00:00:46:40
But we also know that cell death or
apoptosis, which I briefly

578
00:46:40 --> 00:00:46:45
introduced you to in an earlier
lecture, is important in tumor

579
00:46:45 --> 00:00:46:50
development.  And do you find more
apoptosis or less apoptosis during

580
00:46:50 --> 00:00:46:55
tumor development?
Less.  There's decreased amounts of

581
00:46:55 --> 00:00:47:00
cell death in tumor cells compared
to normal cells.

582
00:47:00 --> 00:00:47:05
And this is due to mutations in
genes that regulate apoptosis,

583
00:00:47 --> 00:00:47:10
positive mutations that block
apoptosis, loss of function

584
00:00:47 --> 00:00:47:15
mutations in genes that are normally
required for apoptosis.

585
00:00:47 --> 00:00:47:21
And we think, therefore,
that the balance, if you think of

586
00:00:47 --> 00:00:47:26
this as a scale where proliferation
is on one end and cell death

587
00:00:47 --> 00:00:47:32
is on the other.
Whereas, this process is well

588
00:00:47 --> 00:00:47:38
balanced in normal tissues,
what we call normal homeostasis,

589
00:00:47 --> 00:00:47:44
you produce as many cells as you
need, you kill off as many cells as

590
00:00:47 --> 00:00:47:50
you need in order to give rise to a
normal, average cell number.

591
00:00:47 --> 00:00:47:56
In cancer this process is deranged.
And this can happen in one of two

592
00:00:47 --> 00:00:48:02
ways, and typically in both.
There can be an increase in

593
00:00:48 --> 00:00:48:07
proliferation and a reduction in
cell death.  And we'll talk about

594
00:00:48 --> 00:00:48:11
some of the factors that control
those specifically next time.

595
00:00:48 --> 00:00:48:16
But the final way that we know that
cancer is a genetic disease is by

596
00:00:48 --> 00:00:48:21
looking in the DNA of a tumor,
by looking at the genes themselves.

597
00:00:48 --> 00:00:48:26
You know about genes.  You know
about gene sequences.

598
00:00:48 --> 00:00:48:31
You know how to figure out what the
sequence of a gene is.

599
00:48:31 --> 00:00:48:35
When this is done in a cancer cell
compared to a normal cell one finds

600
00:00:48 --> 00:00:48:39
mutations.  And this is actually the
very first cancer gene found in the

601
00:00:48 --> 00:00:48:43
context of human cancer.
It was found here at MIT by Bob

602
00:00:48 --> 00:00:48:47
Weinberg's lab.
And when its DNA was sequenced

603
00:00:48 --> 00:00:48:51
compared to the normal sequence
shown above it incurred a mutation,

604
00:00:48 --> 00:00:48:55
a mutation which blocked the ability
of this protein to be properly

605
00:00:48 --> 00:00:49:00
regulated leading to increased
proliferation.

606
00:49:00 --> 00:00:49:03
And I'll tell you that
story next time.