1
00:00:15,000 --> 00:00:00,000
molecular biology,
genetics and development,
how things normally work, how cells
normally function,
how tissues are formed,
how organisms are formed and
function.
And hopefully you've had an ample

2
00:00:15,000 --> 00:00:00,000
So up until this point in the class
you've learned basics about cell
phase of the disease,
it represents a clear need,
clear opportunity to learn more.
So let me just illustrate, or
rather emphasize some of these bits
of terminology for you.
You have hyperplastic lesions,
we call them, throughout your body.
Most of them no problem at all.
They're not going to do anything.
It's just there are too few many
cells in that particular place.
These can progress to benign tumors
which are non-aggressive.

3
00:00:39,000 --> 00:00:00,100
founding in understanding normal
biology.  We're going to take a turn
environmental mutagens.
And, as I mentioned, sunlight and
other forms of radiation,
certain dietary things that we
expose ourselves to fall
into this category.
And it's very important that you
know that.  In fact,
more of the mutations that happen in
cancer are due to indigenous
processes, things that happen inside
your bodies regardless of what you
get exposed to,
like DNA replication mistakes.
DNA polymerases that duplicate your
DNA are pretty good,
they have proofreading functions,
but they still make mistakes.

4
00:00:45,000 --> 00:00:00,100
today and for the next three
lectures talk about abnormalities
extracellular matrix to allow the
cells to move around,
and other factors.  Factors,
for example, that allow them to move
into the blood vessels or move back
out of the blood vessels in the
process of metastasis.
So we're going to emphasis
proliferation and cell death in the
next lecture, but I want you to know
that many other aspects of cell
biology are important in
this process as well.

5
00:00:51,000 --> 00:00:00,100
that lead to disease.
And, whereas, I have tried to keep

6
00:00:57,000 --> 00:00:01,000
things light for you in my lectures
and try to be entertaining if

7
00:01:03,000 --> 00:00:01,000
possible, the subject of the next
three lectures is not a light one.

8
00:01:09,000 --> 00:00:01,000
It's a very serious one.
And it is cancer.  It is a disease

9
00:00:01,000 --> 00:00:01,000
that I know a great deal about and
have worked on in my lab for the
last 17 years.
It's a very important and very
devastating disease.
And we're going to try to give you
an introduction to it.
And you'll see that many of the

10
00:01:30,000 --> 00:00:01,100
things that you've learned over the
course of this class,

11
00:01:34,000 --> 00:00:01,100
up until this point, really prepare
you to understand the details of

12
00:01:38,000 --> 00:00:01,100
cancer, cancer development,
and hopefully also cancer treatment.

13
00:01:42,000 --> 00:00:01,100
And I'll say right up front that
I'm actually quite optimistic that

14
00:01:46,000 --> 00:00:01,100
the progress that we've made over
the last several years in

15
00:01:50,000 --> 00:00:01,100
understanding the molecular basis of
cancer has put us into position to

16
00:01:54,000 --> 00:00:01,100
treat the disease differently than
we've done in the past

17
00:01:58,000 --> 00:00:02,000
and more effectively.
The number of drugs that have been

18
00:00:02,000 --> 00:00:02,000
approved by the Food and Drug
Administration for the treatment of
cancer today that are directed and
in this more effective class is not
great, but there are some.
And that number will increase.
So I think there's reason for
optimism utilizing the information,
next three lectures.
So cancer, I think in some respects,
needs no introduction.
It's a disease that probably has

19
00:02:18,000 --> 00:00:02,000
the kinds of information, the
strategies that we'll cover in the

20
00:02:31,000 --> 00:00:02,100
affected some of you already in your
lives personally.

21
00:02:35,000 --> 00:00:02,100
Certainly everybody knows a family
member or friend who has developed

22
00:02:39,000 --> 00:00:02,100
the disease.  It is a remarkably
common disease.  In this

23
00:02:43,000 --> 00:00:02,100
country alone --

24
00:02:57,000 --> 00:00:03,000
-- more than a million people are
diagnosed every year with cancer.

25
00:03:02,000 --> 00:00:03,000
And this does not include another
million who are diagnosed with the

26
00:00:03,000 --> 00:00:03,000
less serious forms of skin cancer,
basal cell carcinoma and squamous
die in this country from cancer.
That's more than 1,500 people per
day.  So in two days more people die
of cancer than died in the World
Trade Center disaster.
It's a devastating disease.

27
00:03:13,000 --> 00:00:03,000
cell carcinoma.
So, in that respect,

28
00:03:18,000 --> 00:00:03,000
more than two million people get the
diagnosis of cancer every year in

29
00:03:24,000 --> 00:00:03,100
this country.  Moreover,
each year --

30
00:03:30,000 --> 00:00:03,100
-- more than half a million people

31
00:03:53,000 --> 00:00:04,000
Half of the men in this room and a

32
00:04:03,000 --> 00:00:04,000
third of the females --

33
00:04:17,000 --> 00:00:04,000
-- will be diagnosed with cancer in
their lifetimes.

34
00:04:23,000 --> 00:00:04,000
And overall more than a quarter of
all deaths are attributable

35
00:04:29,000 --> 00:00:04,100
to cancer.
A major problem.

36
00:00:04,000 --> 00:00:04,100
A major burden.  Clearly something
we need to do something about.
So I'm going to show you some
slides that introduce you to the
disease.  Cancer,
as you know, is a generic term that
covers a class of diseases that
affect many, actually,
almost all of your organs.
You can get cancers in different
places.
They're all defined by one common

37
00:00:05,000 --> 00:00:05,000
property which is too many cells.
Too many cells in a tissue causing
a lump.  Too many cells in the blood.
Too many cells in lymph organs.
So that's the common theme that
relates to all cancers,
but there are very important
differences in cancers in different
sites.  This is a radiographic image
of lung cancer.
And this individual, you can see,
has an opacity right here, a fairly
large opacity that's probably about
the size of your fist in this lobe
of the lung.  And that's fairly
advanced lung cancer.
This is a more precise diagnostic
test called computed tomography,
which is essentially a series of
x-ray slices that get reconstructed.
It gives better resolution.  And
you can see, again,
a very large mass in the lung of
this individual.

38
00:05:29,000 --> 00:00:05,100
What you're looking at here is a
standard chest x-ray.

39
00:06:00,000 --> 00:00:06,000
So that's a solid tumor imaged by
radiography.  This is leukemia.

40
00:00:06,000 --> 00:00:06,000
Leukemia is also too many cells but
here it's in the blood.
This is a normal blood smear.
These pale cells without nuclei are
your red blood cells.
These nucleated cells are white
blood cells of different types.
And you can see in this abnormal
blood smear of a leukemia patient
there is a vast increase in the
number of white blood cells.
So this is a diagnostic feature of
leukemia, too many cells.
And it's diagnosed by looking at
blood counts.  And the blood counts
in leukemia patients of white cell
counts can be elevated by thousands,
if not hundreds of thousands of fold.
You can also use other imaging
techniques to detect and diagnose
cancer.  This is endoscopic
examination, colonoscopy.
they reach age 50 to detect tumors
at an early stage so that they can

41
00:06:53,000 --> 00:00:06,100
It's now recommended that everyone
undergoes this exam every year when

42
00:00:07,000 --> 00:00:07,000
be removed surgically which is,
in fact, the most effective
treatment for colon cancer.
And, actually, for almost all
cancers.  The most effective
treatment for cancer is the removal
of the tumor.  If you can get to the
tumor at an early stage through some
of these imaging techniques and
eradicate it, remove it,
you can greatly limit the mortality
associated with the disease.
So this is endoscopy.
This is what a normal colon looks
like, sort of a smooth structure.
This is an early stage colon tumor.
It's called a polyp at this stage.
And I'll give you a little bit more
nomenclature in a minute.
This is actually not cancer.
A polyp is not cancer.  It's a
benign tumor.  This may or may not
progress to a cancer,
but if the doctor were to find a
polyp like that they might follow it
for one or two years.
But if were to get bigger they
would remove it.
And they can actually do it
endoscopically.

43
00:07:58,000 --> 00:00:08,000
They can remove it using a surgical
endoscope.  They don't actually have

44
00:00:08,000 --> 00:00:08,000
to do surgery to remove polyps
anymore.  At some frequency these
polyps do progress to colon cancer.
And this is a true cancer, a
carcinoma which has changed its
shape and importantly changed its
relationship to the tissue.
Whereas, the polyp is sort of
sitting up on top of the tissue,
having grown out of the tissue, the
colon cancer has invaded into the
tissue.  It has become much more
destructive in that sense.
And also, importantly,
has the capacity to move outside of
the colon through that process of
invasion to other parts of the body,
and thereby cause problems elsewhere.
Usually, when these are diagnosed
by endoscopy or other methods,
they are removed.  This is done by
surgery where a portion of the colon
is actually removed and then the two
resected ends joined.

45
00:09:00,000 --> 00:00:09,000
And you can see the colon cancer
right here.  If the cancer is

46
00:09:03,000 --> 00:00:09,000
detected at an early enough stage,
surgery is curative for colon cancer.

47
00:09:07,000 --> 00:00:09,000
Unfortunately,
it's often too late when it's

48
00:09:11,000 --> 00:00:09,000
diagnosed.  It looks like that.
Because it's already moved outside

49
00:09:15,000 --> 00:00:09,000
of the colon and tumor cells have
found their way to other parts of

50
00:09:18,000 --> 00:00:09,000
the body.  So surgical removal of
the primary tumor,

51
00:09:22,000 --> 00:00:09,000
while helpful, may actually not be
curative.  So I want to go through

52
00:09:26,000 --> 00:00:09,100
in diagrammatic form some of the
points that I've just made.

53
00:09:30,000 --> 00:00:09,100
Cancer develops in states.
It doesn't happen all at once.

54
00:09:33,000 --> 00:00:09,100
As I showed you in the normal colon
polyp to colon cancer series,

55
00:09:37,000 --> 00:00:09,100
things happen in stages.  It's
actually best worked out in the

56
00:09:41,000 --> 00:00:09,100
colon.  But we believe the same
phenomena hold true for other

57
00:09:45,000 --> 00:00:09,100
cancers in other places.
It doesn't happen all at once.

58
00:09:48,000 --> 00:00:09,100
It happens in stages.  And these
slides illustrate the basic

59
00:09:52,000 --> 00:00:09,100
principles of that.
This illustrates a normal tissue.

60
00:09:56,000 --> 00:00:10,000
It could be anywhere, but let's say
that it's in the colon.

61
00:10:00,000 --> 00:00:10,000
And there are certain important
features to pay attention to.

62
00:00:10,000 --> 00:00:10,000
One is that the cells have regular
shape and a regular relationship to
their neighbors.
As you know, tissues are formed for
normal function.
They have particular genes
expressed.  They have particular
structures inside them.
They interact with their neighbors
in order to perform their function.
So the cells of the colonic
epithelium line up like this
touching each other,
interacting with each other and
interacting with the cells
underneath them,
as well as other material underneath
them.
otherwise known as the extracellular
matrix.  And this helps support the
cells and provides the cells with
certain nutrients and growth factors.
There are also cells below these
cells in the colon and in other
tissues which replenish these cells
when they get lost.
These stem or progenitor cells
exist probably in all adult tissues.
They get recruited when cells
turnover.

63
00:10:33,000 --> 00:00:10,100
Here is a material called the
basement membrane,

64
00:10:58,000 --> 00:00:11,000
And we now think,
and it's not illustrated on these

65
00:00:11,000 --> 00:00:11,000
slides, but we now think that these
cells are probably very important in
tumor initiation.
We think that these are cells,
these stem cells of the tissue are
likely to be the place where the
tumors initiate and then produce
cells, like this brown cell here,
which is already abnormal.  Cells
that have acquired a mutation which
makes them different from their
neighbors.  Now,
the first consequence of those early
changes is that you get too many
cells.  And this is a process known
as hyperplasia.

66
00:11:30,000 --> 00:00:11,100
Hyperplasia simply means hyper,
too many, plasia, division, cell

67
00:11:34,000 --> 00:00:11,100
division.  So there are too many
cells.  But the cells that are

68
00:11:38,000 --> 00:00:11,100
present there look pretty normal.
They don't histologically, by

69
00:11:42,000 --> 00:00:11,100
looking at the tissue,
appear different from their normal

70
00:11:46,000 --> 00:00:11,100
neighbors.  There are just too many
of them.  This process continues

71
00:11:50,000 --> 00:00:11,100
until you can actually see a
discernable lump,

72
00:11:54,000 --> 00:00:11,100
a mass, and that is a formation of a
benign tumor.

73
00:11:58,000 --> 00:00:12,000
In the colon that tumor,
that benign tumor is called an

74
00:00:12,000 --> 00:00:12,000
adenoma.  It's called other things
in other places but let's say,
just for the sake of simplicity,
it's a benign tumor.  And, again,
this is an increase in the number of
cells but the cells themselves don't
look very different from their
normal neighbors.
And these tumors are not
life-threatening yet.
They sometimes will never be
life-threatening but in this form
they rarely cause problems.
They're just a lump.  Like a wart
is a benign tumor,
a lump that doesn't cause problems.
And now, as you can see from this
different shading,
the cells take on different
characteristics.
And so they've become fundamentally
changed in their appearance.
Moreover, they have begun to
recruit a blood supply.

75
00:12:29,000 --> 00:00:12,100
At some frequency these tumors can
progress further.

76
00:12:39,000 --> 00:00:12,100
They look different from their
normal neighbors.

77
00:12:42,000 --> 00:00:12,100
Their cyto architecture,
the cell shape looks different.

78
00:12:46,000 --> 00:00:12,100
The nucleus often looks different
from the normal cells.

79
00:12:56,000 --> 00:00:12,100
The presence of these blood vessels
which were not present up here is

80
00:12:59,000 --> 00:00:13,000
another indication that things
have progressed.

81
00:13:03,000 --> 00:00:13,000
And tumors require a blood supply of
their own to feed the tissue,

82
00:13:07,000 --> 00:00:13,000
this abnormal growing tissue.  As
soon as they get to a certain size

83
00:13:12,000 --> 00:00:13,000
they need to recruit a new blood
supply.  This tumor at this stage

84
00:13:16,000 --> 00:00:13,000
has changed enough that we now call
it cancer.  This is based on these

85
00:13:21,000 --> 00:00:13,000
histological changes,
the appearance of the cells,

86
00:13:25,000 --> 00:00:13,100
as well as the cells' relationship
to one another.

87
00:13:30,000 --> 00:00:13,100
And this is now considered dangerous.
If you're diagnosed with a cancer,

88
00:00:13,000 --> 00:00:13,100
even if it's present in the tissue,
the initial tissue alone,
it would be recommended for removal.
However, it rarely stays there.
Tumors have the capacity to move
from their original site through a
process of invasion and then
metastasis.  This illustrates
invasion, local invasion where the
tumor cells are moving from the mass
through the basement membrane and
ultimately accessing

89
00:00:14,000 --> 00:00:14,000
the blood supply.
Literally moving into blood vessels,
the death of the cancer patient.
It's the metastatic spread of the
disease as opposed to the primary
tumor that tends to kill cancer
patients.  And sadly it's this phase
of the disease,
metastatic spread that we know the
littlest about.
We actually know rather little
about what allows cells to move from
their primary site through the blood,
establish themselves elsewhere and
then grow there.
And since it is the most deadly

90
00:14:07,000 --> 00:00:14,000
traveling through the blood, and
then moving out of blood vessels and

91
00:14:11,000 --> 00:00:14,000
beginning to proliferate,
expand in other tissues.  And this

92
00:14:15,000 --> 00:00:14,000
is the process of metastasis.
And the tumor cells can literally

93
00:14:19,000 --> 00:00:14,000
go anywhere.  Certain tumors have
preferences to go to certain tissues

94
00:14:23,000 --> 00:00:14,000
than others.  And when they get
there they begin to grow again and

95
00:14:27,000 --> 00:00:14,100
turn, become actually more advanced,
more dangerous, cause local tissue

96
00:14:31,000 --> 00:00:14,100
damage, organ failure.
And it's usually this that causes

97
00:15:13,000 --> 00:00:15,100
Hyperplasia is simply too many cells.

98
00:16:00,000 --> 00:00:16,000
That is the cells are relatively
well-behaved.  They're not dividing

99
00:00:16,000 --> 00:00:16,000
that much.  They're not moving
around.  They have normal
relationships with their neighbors.
And with respect to the tissue that
they reside in,
they're nondestructive.
They haven't breached the
underlying basement membrane.
They haven't changed their
relationship with their normal
neighbors.  And they're also defined
through a lack of spread.
They haven't moved out into the
local lymph nodes or to
surrounding tissues.
We actually only use the term
cancer to refer to malignant tumors,
not to benign tumors.  These are
true cancers.  And these are
proliferative capacity.
They move around to a greater
degree.
They are destructive with respect to

100
00:16:36,000 --> 00:00:16,100
These can progress to malignant
tumors.  And these are true cancers.

101
00:16:49,000 --> 00:00:16,100
aggressive.  The cells have changed
shape.  They have much greater

102
00:00:17,000 --> 00:00:17,000
the tissue in which they reside.
And they have the potential to
spread.  Not all diagnosed cancers
have already spread,
but the view of the pathologist is
that they have the potential to
spread and therefore they are
typically removed.
Now cancers in different places
have different names.
As I said, you can get cancer in
virtually all tissues of your body.
defined, and those are defined in
part based on where they are and in
what types of cells they occur.
So there are tumors of epithelial
cells, cells of the skin,
lining of the intestine, mammary
epithelial cells,
epithelial cells of your brain.

103
00:17:34,000 --> 00:00:17,100
There are probably 250 or 300
different types of cancer clinically

104
00:18:00,000 --> 00:00:18,000
And these tumors are called
carcinomas.  These cancers are

105
00:00:18,000 --> 00:00:18,000
called carcinomas.
And you might have heard,
for example, a subset of carcinomas
called adenocarcinomas.
Adenocarcinoma is what I showed you
with respect to the colon cancers.
Adenocarcinoma of the breast.
Adenocarcinoma of the lung.
These are carcinomas that have a
glandular appearance.
And there are other kinds of
carcinomas as well.

106
00:18:32,000 --> 00:00:18,100
Those are the cancers.
And the benign tumors of these

107
00:18:38,000 --> 00:00:18,100
tissues, especially of the class
that gives rise to adenocarcinomas

108
00:18:44,000 --> 00:00:18,100
are called adenomas.
There are also tumors of your

109
00:18:50,000 --> 00:00:18,100
connective tissues like you
cartilage or your muscles

110
00:18:56,000 --> 00:00:19,000
or your tendons.
These are called sarcomas.

111
00:00:19,000 --> 00:00:19,000
And you've probably heard of
myosarcomas.  Those are tumors of
the muscle.  And there are different
types of myosarcomas.
And then there are tumors of the
blood system.
tumors are present,
tumor cells are present within the
blood itself.  And I showed you an
example of that.
Or lymphomas.  And here it's
defined as tumors which stay within
lymph organs like lymph nodes or
spleen or thymus.
They haven't made their way out
into the blood,
but they are still tumors of the
blood cells.

112
00:19:23,000 --> 00:00:19,100
These are called leukemias if the

113
00:20:02,000 --> 00:00:20,000
OK.  So we know a lot about what
these tumors look like based on

114
00:00:20,000 --> 00:00:20,000
visual inspection.
We also know what they look like
based on histological analysis.
This is a progression series
actually taken from a mouse model of
cancer generated in my lab.
appearance of the lung here.
And this circle you can see
hyperplasia, too many cells.
Cells, if you were to see them up
close, look pretty much like their
neighbors, but there are just too
this case.  These are benign tumors.
They don't have the features of the
more aggressive malignant cells.
And you can see them here.  They
all look pretty much the same.
And if you saw them next to a
normal cell they would look pretty
much like those.

115
00:20:20,000 --> 00:00:20,000
It's a tumor of the lung.  You
might be able to see the lacey

116
00:20:38,000 --> 00:00:20,100
many of them.  These progress into
lumps, masses called adenomas in

117
00:20:59,000 --> 00:00:21,000
But these can progress into
adenocarcinomas,

118
00:00:21,000 --> 00:00:21,000
more advanced tumors.
These are true cancers.
And you can tell that based on the
fact that the nuclei,
if you compare one cell to another,
looks very different, and the cell
shape looks very different from one
to the other.  So there's
heterogeneity.
And what you cannot see here is
that the tumors are also much more
proliferative.
They are dividing.
The cells are dividing much more
frequently.  So,
again, histologically we can
characterize what these
tumors look like.
the class is that we understand,
at least to a degree, what these
arrows represent,
what happens to a normal cell on the
way to hyperplasia or to an adenoma
or to an adenocarcinoma.
these transitions,
allow a normal cell to develop into
a cancer cell.
And so in that sense we consider

119
00:21:33,000 --> 00:00:21,100
What I'm going to tell you about
from this point really to the end of

120
00:21:50,000 --> 00:00:21,100
And the answer is defects to genes.
Defects to many genes underlie

121
00:00:22,000 --> 00:00:22,000
cancer as a genetic disease.
Now, cancer actually is also a more
traditional genetic disease in some
instances.  There are people who are
genetically predisposed to
developing cancer.
And I'm actually going to tell you
about them next time.
the development of cancer in them is
a genetic disease.
How do we know that?
Why do we think that?
Well, we think that for a number of
reasons.  And one of them,
which we've appreciated for more
than a hundred years is that the
chromosomes of cancer cells are
screwed up.  They look different
than normal cells.
I've actually shown you this slide
before.
This is a karyotype of a normal cell,
46 chromosomes,
23 pairs.  These are highlighted by

122
00:22:30,000 --> 00:00:22,100
But even for people who are not
genetically predisposed to cancer,

123
00:00:23,000 --> 00:00:23,000
stains that allow us to distinguish
one chromosome from another.
So chromosome one stains yellow,
chromosome two stains red, and so on
and so forth.  And this is the
karyotype of a cancer cell.
It's different in many ways.
Name me two.
I heard there was mumbling but I
didn't hear anybody.  Say again.
many chromosomes.
I didn't count them up,
but there is more than double the
proper number of chromosomes in this
cancer cell.  So chromosome number
defects are quite common in cancer
cells.  But also structure,
and I've boxed two of them here,
the structure of chromosomes in
cancer cells are different.
This chromosome has undergone what
we call a translocation in which a
piece of one chromosome has been
joined to a piece of a
different chromosome.
And we now know that when that

124
00:23:22,000 --> 00:00:23,000
I didn't hear anybody.

125
00:23:34,000 --> 00:00:23,100
The number and shape of chromosomes.
Good.  So clearly there are too

126
00:00:24,000 --> 00:00:24,000
happens it's reflective of a
mutation that either is inactivating
or activating a gene that's present
at the point of translocation.
And this chromosome has undergone a
truncation, a deletion.
Genetic material has been loss.
And this, again, indicates that
there was a gene present there that
the tumor cell wanted to get rid of
in the development of the cancer.
So chromosomal abnormalities are
quite common, which was a first clue
that cancer is a genetic disease.
which came along as early as the
1920s, is that many carcinogens,

127
00:24:34,000 --> 00:00:24,100
The second indication,

128
00:24:58,000 --> 00:00:25,000
and what I mean by that is agents
that cause cancer.

129
00:25:05,000 --> 00:00:25,000
Many carcinogens are mutagens,

130
00:25:17,000 --> 00:00:25,100
agents that cause what?  Yeah?

131
00:25:31,000 --> 00:00:25,100
Not all.  But there is a very high
correlation between things that will

132
00:25:35,000 --> 00:00:25,100
cause cancer and things that will
cause mutation in simple

133
00:25:39,000 --> 00:00:25,100
mutation assays.

134
00:25:50,000 --> 00:00:25,100
And you can do assays to determine
the carcinogenicity or mutagenicity

135
00:00:25,000 --> 00:00:26,000
of an agent of interest.

136
00:26:08,000 --> 00:00:26,000
Carcinogenicity assays are done
typically in experimental animals,

137
00:00:26,000 --> 00:00:26,000
mice or rats.  And one takes the
animal and exposes it to agent X.
It might be injected into the
animal or it might be painted on the
skin of the animal.
And then one waits a period of time
and asks the question did the animal
develop a tumor?

138
00:26:34,000 --> 00:00:26,100
And if so the agent is a carcinogen.
And you can actually determine how

139
00:26:38,000 --> 00:00:26,100
strong a carcinogen is,
how strong a carcinogen it is by

140
00:26:43,000 --> 00:00:26,100
determine the dose,
the amount of the agent needed to

141
00:26:47,000 --> 00:00:26,100
produce a tumor.
There are also mutagenicity tests.

142
00:26:52,000 --> 00:00:27,000
And this is typically done in

143
00:00:27,000 --> 00:00:27,000
bacteria.  So one takes a bacterial
strain and asks whether the agent
can cause mutations in that strain.
And usually to do this one takes a
bacterial strain that already has a
mutation, a bacteria that is
histidine deficient,
which means that it's not able to
synthesize its own histidine
and amino acid.
Petri dish that lacks histidine,
you haven't added histidine to the
media, will it grow?
No.  It's histidine minus,
it cannot make its own, if you don't
provide it, cells cannot grow,
so you get no colonies.
However, if I now add agent X,

144
00:27:30,000 --> 00:00:27,100
That means that if you take that
bacteria strain and plate it onto a

145
00:28:01,000 --> 00:00:28,000
which I think might be a mutagen,
to these bacteria, if it is a

146
00:28:06,000 --> 00:00:28,000
mutagen it might mutate the
defective histidine gene and turn it

147
00:28:11,000 --> 00:00:28,000
into a normally functioning
histidine gene such that if I now

148
00:28:16,000 --> 00:00:28,000
plate these bacteria that have been
treated with the mutagen I may get

149
00:28:21,000 --> 00:00:28,000
some colonies.
And you're still using a his-minus

150
00:28:26,000 --> 00:00:28,100
plate here.
And the number of colonies that I

151
00:00:28,000 --> 00:00:28,100
get is an indication of the strength
of the mutagen.
Lots of colonies,
strong mutagen.  Fewer,
not so strong.  And what I'm saying
is that there's a strong correlation
between things that pass this assay
and things that pass that assay,
another indication that cancer might
be caused by mutations to DNA.
Now some things that we know for
sure are carcinogens.
They pass this carcinogenicity test
very, very strongly.

152
00:29:00,000 --> 00:00:29,000
Fail in this simple mutagenicity
test.  Why?  How can that be?

153
00:00:29,000 --> 00:00:29,000
They clearly are cancer-causing.
But if you mix them with bacteria
in isolation here you don't get any
increased mutation frequency.
What's different?  What's different
about this situation versus
this situation?  Yes?
their native form are not mutagenic.
We call them promutagens.  However,
when acted on by the body in the
process of metabolism they

154
00:29:42,000 --> 00:00:29,100
Excellent.  Precisely correct.
There are certain agents which in

155
00:00:30,000 --> 00:00:30,000
become mutagens.
The body senses that these are
actually dangerous compounds and
will try to detoxify them,
typically by adding hydroxyl groups
to them to make them more
water-soluble so that they can be
secreted or excreted by the body.
But in the process of making them
more water-soluble they go through
an intermediate form which turns out
to be highly mutagenic.
benzo(a)pyrene.
This is an agent found in cigarette
And what happens is that the body,
in an attempt to add hydroxyl groups
different ring positions of this
molecule, as an intermediate towards

156
00:30:32,000 --> 00:00:30,100
And that's illustrated here for a
very powerful carcinogen known as

157
00:30:40,000 --> 00:00:30,100
smoke, for example.
This agent is not highly mutagenic

158
00:30:45,000 --> 00:00:30,100
on its own, but in this type of test
it is highly carcinogenic.

159
00:30:54,000 --> 00:00:30,100
to make it more water-soluble,
will actually introduce epoxides in

160
00:00:31,000 --> 00:00:31,000
making it more hydroxylated.
And these epoxides are very
And the Ames Test takes the
compound, the agent that you're
trying to test the mutagenicity of,
and rather than adding it directly
back to bacteria it's mixed first
with an extract of the liver.
Many of the enzymes that do this
detoxification are present in your
liver.  Cytochrome P450
enzymes, for example.

161
00:31:07,000 --> 00:00:31,000
interactive with DNA and therefore
mutagenic.  So the body turns

162
00:31:12,000 --> 00:00:31,000
something that actually wasn't
mutagenic into something that is

163
00:31:17,000 --> 00:00:31,000
mutagenic.  And therefore this test,
this mutagenicity test has been

164
00:31:22,000 --> 00:00:31,000
modified, principally based on the
work of a bacteriologist at Berkeley

165
00:31:27,000 --> 00:00:31,100
named Bruce Ames.
And so we now call it the Ames Test.

166
00:32:02,000 --> 00:00:32,000
In which case the compound becomes
modified, or might become modified.

167
00:00:32,000 --> 00:00:32,000
And through that modification
becomes mutagenic.
And then the agent gets tested in
the standard bacterial
mutagenicity test.
disservice in thinking it's actually
trying to help you.
There are still other agents which
are not mutagens,
even in the Ames Test,
but are clearly carcinogens.
Asbestos, for example.  That stuff
in packing material that's now been
banned exposure to which gives
people, or can give people
mesotheliomia,
a tumor of the lining of the lungs.

168
00:32:26,000 --> 00:00:32,100
OK.  So we can now expand our list
of things that are mutagenic through

169
00:32:30,000 --> 00:00:32,100
exposing them to some of the body's
own enzymes.

170
00:32:34,000 --> 00:00:32,100
In this sense,
the body is actually doing you a

171
00:00:33,000 --> 00:00:33,000
It's not a mutagen.
However, you test it,
it's not a mutagen.  Alcohol,
which is clearly associated with
liver cancer, is not a mutagen.
These agents we think act as
irritants.  They case damage to
tissue which causes the cells to
have to increase their proliferation
to repair the tissue,
and that is inherently a mutagenic
process.  And so these things can
act as carcinogens in that
very indirect way.
OK.  Now there are many things in

172
00:33:34,000 --> 00:00:33,100
our environment that
are carcinogens --

173
00:33:38,000 --> 00:00:33,100
-- that we get exposed to either

174
00:33:48,000 --> 00:00:33,100
passively or deliberately.
Sunlight, for example, is a

175
00:33:52,000 --> 00:00:33,100
carcinogen and a mutagen.
It causes damage to DNA, causes

176
00:33:56,000 --> 00:00:34,000
mutation, increases your
risk of skin cancer.

177
00:34:00,000 --> 00:00:34,000
Other things that we do to ourselves.
Certain dietary carcinogens we

178
00:00:34,000 --> 00:00:34,000
impose on ourselves.
But what's the biggest carcinogen
that we impose on ourselves?
Smoke.  Tobacco smoke.
cancer in this country per year?
Anybody want to hazard a guess?  10,
00?  100,000?  175,
00.  175,000 people per year die of
lung cancer each year.
And more than 150,000 of them it's
because of smoking.

179
00:34:14,000 --> 00:00:34,000
And obviously tobacco smoke is

180
00:34:21,000 --> 00:00:34,000
associated with one particular type
of cancer, although it's not limited

181
00:34:26,000 --> 00:00:34,100
to lung cancer.
Any idea how many people die of lung

182
00:35:05,000 --> 00:00:35,000
Lung cancer is the number one cancer
killer.  It kills more people in

183
00:00:35,000 --> 00:00:35,000
this country than breast cancer,
colon cancer and prostate cancer
combined.  And it's completely
preventable, or almost completely
preventable through a change of
habit, failure to smoke.
So let me just emphasize the
importance of this.
among men and women and the
incidence of cancer,
lung cancer in this country among
men and women.
You can see that early on,
in the early part of the century
smoking was  uncommon and lung
cancer was uncommon.
But as people began to smoke this
frequency increased and then years
later the incidence of lung cancer
increased dramatically.  It
takes a little while.
You've got to expose yourself to

184
00:35:28,000 --> 00:00:35,100
These are curves that show the
smoking frequency in this country

185
00:00:36,000 --> 00:00:36,000
these carcinogens for a period of
time for this process to have its
effect, but eventually that smoking
exposure leads to the development of
lung cancer.  You can see that women
started smoking a little bit later,
but they quickly caught up.  And now
the lung cancer incidence in women
is also extremely high.
Lung cancer among women is the
leading cause of cancer deaths.
It's now surpassed breast cancer as
the leading cancer killer of women.
The statistics about smoking in this
country, despite these facts,
are remarkable.  47 million adults
smoke.  Roughly one in four men,
and almost as many women smoke.

186
00:37:06,000 --> 00:00:37,000
Even more amazing to me than that,
in 2002, I don't have more recent

187
00:00:37,000 --> 00:00:37,000
statistics than that,
but in 2002 the percent of high
school students who responded to a
survey about whether they
smoked was what?
What do you think?
High school students.
28%.  So this is not just people
who have been smoking a long time,
who started when they didn't know
any better.  Kids who get exposed to
the message about smoking and lung
cancer from an early age are not
paying attention.
So the problem is not going away.
These folks obviously have a
dramatically increased risk of dying
from lung cancer.

188
00:38:01,000 --> 00:00:38,000
And it's not just lung cancer.
Smoking increases your risk of

189
00:00:38,000 --> 00:00:38,000
heart disease,
of stroke, of emphysema.
I read a startling statistic when I
was preparing this.
Of all the people who are alive
today on this planet,
500 million of them will die early
due to tobacco usage.
exposure to tobacco products.
So if you learn nothing else from
this class this year,
if you now smoke, stop.
If you don't smoke, don't start.
OK.  So carcinogens in our
environment and carcinogens that we
exposure ourselves to are important.
No doubt about it, they can be a
cause of cancer.

190
00:38:27,000 --> 00:00:38,100
500 million people who are alive
today would live longer if not for

191
00:39:02,000 --> 00:00:39,000
I call these exogenous or

192
00:39:35,000 --> 00:00:39,100
But they're not the only thing that
causes cancer.

193
00:40:00,000 --> 00:00:40,000
And these mistakes can be then in
critical genes which can ultimately

194
00:00:40,000 --> 00:00:40,000
lead to tumor development.
cell during various processes.
Sometimes it gets broken, and
sometimes those breaks are not
properly repaired.
And this can lead to some of the
defects that I've shown you on this
slide like the translocations where
different pieces get rearranged with
the wrong other piece.
the class and how the cells have an
intricate ability to properly
segregate their chromosomes,
that each daughter cell gets the
right number.  Sometimes that
process doesn't work properly so
that one cell gets too many
chromosomes or one cell gets too few.
These chromosomal imbalances can
also contribute to tumor
development.
Defects in DNA repair.

195
00:40:12,000 --> 00:00:40,000
Your DNA can sometimes get broken.
It gets moved around inside the

196
00:40:36,000 --> 00:00:40,100
Defects in chromosome segregation.
We talked about mitosis early in

197
00:41:04,000 --> 00:00:41,000
Your cells have all sorts of enzymes

198
00:00:41,000 --> 00:00:41,000
that will try to find damaged DNA
and fix it, but these enzymes
themselves can be mutationally
inactivated in the development of
cancer.  So now you've debilitated
the cell's ability to fix the damage
leading to an increased frequency of
damage, increased frequency of
mutation, increased cancer risk.
And importantly --

199
00:41:38,000 --> 00:00:41,100
-- production of indigenous mutagens

200
00:41:53,000 --> 00:00:41,100
in contrast to exogenous mutagens.
Your body actually produces things

201
00:41:57,000 --> 00:00:42,000
that are mutagenic.
And the biggest class of these are

202
00:00:42,000 --> 00:00:42,000
oxygen radicals such
as superoxide --
reactive to DNA,
can cause DNA breaks and base
changes, and cause mutation.
And your body produces these
naturally in the process of
metabolism.  You have enzymes that
will kind of keep the concentrations
of these down but,
nevertheless, they're present and
cause damage at a certain frequency
in all cells.  If that damage occurs
in the wrong cell at the wrong time
it can be cancer-causing.
So there are lots of ways that the
DNA of your cells can get mutated,
which then overall contributes to

203
00:42:11,000 --> 00:00:42,000
-- or hydrogen peroxide.

204
00:42:29,000 --> 00:00:42,100
And these radicals are highly

205
00:00:43,000 --> 00:00:43,000
the development of cancer.
Now, this doesn't happen all at once,
development from a normal cell to a
more advanced cancer cell as a
clonal evolution process.
A clonal evolution process whereby
abnormal cells arise in a population.
These now have a selected advantage
compared to their normal cells and
will grow, for example,
better than their normal cells,
divide faster than their normal
cells, make more of themselves.
The mutation that took place is now
present in all the daughter cells of
that abnormal cell.

206
00:43:06,000 --> 00:00:43,000
as I've tried to indicate to you.
It doesn't happen from normal cell

207
00:43:10,000 --> 00:00:43,000
to cancer cell in a single step.
We think that this process happens

208
00:43:14,000 --> 00:00:43,000
over time.  And in humans over
decades of time.

209
00:43:18,000 --> 00:00:43,000
Cancers often initiate maybe in
mid-life, but they don't present

210
00:43:22,000 --> 00:00:43,000
themselves as a clinically advanced
tumor until late in life.

211
00:43:26,000 --> 00:00:43,100
and that's because the process
requires lots of steps that require

212
00:43:30,000 --> 00:00:43,100
lots of time to accumulate.
And so we now consider tumor

213
00:00:44,000 --> 00:00:44,000
And within that now-expanded clone
of abnormal cells a second mutation
takes place which increases the
capacity of that cell to grow and
divide, survive,
move around compared to its
neighbors.  So now this cell and of
its descendents have two mutations.
And within that expanded clone a
third mutation can take place and so
and so forth.
We now think that cancers,
advanced cancers in human probably
have five, ten,
maybe twenty distinct mutations in
genes controlling important
processes.  What are those processes?
There are many.
We're going to emphasis,
in this class, just proliferation
and cell death.
I'll say a bit more about that in a
second.  But it's also important for
you to know that the cancer cells
also regulate factors that increase
the blood supply.

214
00:45:03,000 --> 00:00:45,000
Cancer cells turn on growth factors
that recruit blood vessels.

215
00:45:06,000 --> 00:00:45,000
If they didn't do so they would
never be able to progress.

216
00:45:10,000 --> 00:00:45,000
You cannot actually make a solid
tumor bigger than two millimeters in

217
00:45:14,000 --> 00:00:45,000
diameter without recruiting a new
blood supply.  And so the tumor

218
00:45:18,000 --> 00:00:45,000
cells turn on these factors to deal
with angiogenesis.

219
00:45:21,000 --> 00:00:45,000
They also turn on factors that
allow them to move around to a

220
00:45:25,000 --> 00:00:45,000
greater degree or separate
themselves from their neighbors to

221
00:45:29,000 --> 00:00:45,100
invade into the basement tissues,
the basement membranes.

222
00:45:33,000 --> 00:00:45,100
To turn on proteases,
for example, that chew up the

223
00:46:07,000 --> 00:00:46,000
So proliferation,
it's kind of obvious that in cancers

224
00:00:46,000 --> 00:00:46,000
there might be changes that lead to
more cell division.
And, indeed, the original
cancer-associated genes did this.
And many of the important
cancer-associated genes that we know
about are involved in promoting
increased cell division.

225
00:46:35,000 --> 00:00:46,100
But we also know that cell death or
apoptosis, which I briefly

226
00:46:40,000 --> 00:00:46,100
introduced you to in an earlier
lecture, is important in tumor

227
00:46:45,000 --> 00:00:46,100
development.  And do you find more
apoptosis or less apoptosis during

228
00:46:50,000 --> 00:00:46,100
tumor development?
Less.  There's decreased amounts of

229
00:46:55,000 --> 00:00:47,000
cell death in tumor cells compared
to normal cells.

230
00:47:00,000 --> 00:00:47,000
And this is due to mutations in
genes that regulate apoptosis,

231
00:00:47,000 --> 00:00:47,000
positive mutations that block
apoptosis, loss of function
mutations in genes that are normally
required for apoptosis.
And we think, therefore,
that the balance, if you think of
this as a scale where proliferation
is on one end and cell death
is on the other.
Whereas, this process is well
balanced in normal tissues,
what we call normal homeostasis,
you produce as many cells as you
need, you kill off as many cells as
you need in order to give rise to a
normal, average cell number.
In cancer this process is deranged.
And this can happen in one of two
ways, and typically in both.
There can be an increase in

232
00:00:48,000 --> 00:00:48,000
proliferation and a reduction in
cell death.  And we'll talk about
some of the factors that control
those specifically next time.
But the final way that we know that
cancer is a genetic disease is by
looking in the DNA of a tumor,
by looking at the genes themselves.
You know about genes.  You know
about gene sequences.
You know how to figure out what the
sequence of a gene is.
mutations.  And this is actually the
very first cancer gene found in the
context of human cancer.
It was found here at MIT by Bob
Weinberg's lab.
And when its DNA was sequenced
compared to the normal sequence
shown above it incurred a mutation,
a mutation which blocked the ability
of this protein to be properly
regulated leading to increased
proliferation.

233
00:48:31,000 --> 00:00:48,100
When this is done in a cancer cell
compared to a normal cell one finds

234
00:49:00,000 --> 00:49:03,000
And I'll tell you that
story next time.