Over 500,000 people in the United States and over 8 million people worldwide are dying every year from cancer. As people live longer, the incidence of cancer is rising worldwide and the disease is expected to strike over 20 million people annually by 2030. This open course is designed for people who would like to develop an understanding of cancer and how it is prevented, diagnosed, and treated. The course introduces the molecular biology of cancer (oncogenes and tumor suppressor genes) as well as the biologic hallmarks of cancer. The course also describes the risk factors for the major cancers worldwide, including lung cancer, breast cancer, colon cancer, prostate cancer, liver cancer, and stomach cancer. We explain how cancer is staged, the major ways cancer is found by imaging, and how the major cancers are treated. In addition to the core materials, this course includes two Honors lessons devoted to cancers of the liver and prostate. Upon successful completion of this course, you will be able to: - Identify the major types of cancer worldwide. (Lecture 1) - Describe how genes contribute to the risk and growth of cancer. (Lecture 2) - List and describe the ten cellular hallmarks of cancer. (Lecture 3) - Define metastasis, and identify the major steps in the metastatic process. (Lecture 4) - Describe the role of imaging in the screening, diagnosis, staging, and treatments of cancer. (Lecture 5) - Explain how cancer is treated. (Lecture 6) We hope that this course gives you a basic understanding of cancer biology and treatment. The course is not designed for patients seeking treatment guidance – but it can help you understand how cancer develops and provides a framework for understanding cancer diagnosis and treatment.
The Metastatic Process
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Del curso dictado por Johns Hopkins University
Introduction to the Biology of Cancer
1433 calificaciones
De la lección
Metastasis: The Real Killer
The lethal agent of cancer is metastasis. This week, we'll take a good look at this deadly event, TNM staging, the metastatic process, and an ecological paradigm.
Conoce a los instructores
Kenneth J. Pienta, M.D.The Donald S. Coffey Professor of Urology
The James Buchanan Brady Urological Institute
Okay, so we will now discuss how metastasis actually occurs,
which is the metastatic process.
So how does metastasis actually happen?
I have distilled the metastatic process into eight major steps, which is,
primary tumor growth, angiogenesis, epithelial-to-mesenchymal transition or
EMT, invasion, intravasation,
survival in circulation, extravasation and dormancy and secondary tumor growth.
We're going to go over each of these steps individually so you know what they are and
in which order they occur and how they work.
And at the end of this section we'll put it all together and
hopefully it will be easier to see how they all work together.
So first thing's first, there must be a primary tumor that grows to the point
where it's large enough to metastasize.
As you've heard from Doctors Emmond and
Zarif in previous lectures, a normal cell generally becomes a cancer cell due to
an accumulation of mutations that change it, so it begins to grow uncontrollably.
These cells also gain other hallmarks of cancer,
such as lack of growth suppression, changing metabolism,
resistance to cell death, and avoiding immune destruction among others.
All of these hallmarks allow for a tumor to get larger and
also change itself over time to become more aggressive and more invasive.
You can see here on the diagram,
a single cell with a mutation begins to grow into something called hyperplasia,
which is just an increase of proliferation and division in these cells.
This is not yet cancer.
As time goes on, cells begin to change enough so that they are referred to
as cancer, but if it has not invaded yet then it is referred to as cancer in situ.
Which means that it remains in its original place.
This is a benign tumor, in other words.
Eventually, the cancer becomes invasive and more and
more aggressive until it metastasizes.
However, it is important to point out here that some tumors
reach metastatic capability.
Some grow very large and never leave the primary tumor site and
therefore be cured simply by removing the tumor surgically.
But once the tumor metastasizes, it becomes much more difficult to treat.
The next stop in the metastatic process is the angiogenesis,
which is simply the formation of new blood vessels.
Which are composed of vascular endothelial cells as you see in the picture.
Tumor cells which in the picture are the cells with black nuclei divide and
grow more quickly than normal cells, the ones with blue nuclei.
And they often require more nutrients and oxygen as a result.
Tumor cells also grow geographically farther away from blood vessels
because of their fast growth rate and therefore they need more oxygen.
So new blood vessels form from already existing blood vessels and
reach to the tumor cells.
This can continue as the tumor grows larger and larger.
Because this process is not natural, these new blood vessels are often poorly made
and leaky and therefore become easy for the tumor cells to get into.
This provides an outlet for tumor cells to get into the bloodstream and
become metastatic.
So before I was talking about how tumor cells can become more
aggressive over time.
One way they do this is by becoming more mobile, and
this is accomplished by the cells undergoing a transformation or
transition, from an epithelial like cell, to a mesenchymal like cell.
This process is called the epithelial to mesenchymal transition or EMT for short.
EMT is natural during processes like development and
wound healing because these processes require that cells become able to move.
But most cells should not move, they should stay put and
perform whatever function it is that they have.
Most cancers originate from epithelial cells,
which are cuboidal in shape, stationary and have strong intercellular interactions
with the extracellular matrix and their neighboring cells.
The extracellular matrix or ECM is a collection of secreted molecules that
form a structure that provide support for epithelial cells, tissues, and organs.
The ECM basically keeps everything in place where it should be, and
protects cells from leaking out all over the place.
Loss of contact with the ECM is one of the major ways for a cell to undergo EMT.
This mesenchymal state that it turns into,
causes cells to become more stretched out and allows them to move around.
When cells lose contact with the ECM, they're able to move around,
which is not desirable.
Imagine liver cells that no longer stay put in their natural place, but
start moving.
And once cells start moving around they can start to invade neighboring tissue and
get into the bloodstream.
And that's actually the next couple steps here.
So as cells become more aggressive and more mobile, they also gain cellular
properties that allow them to break through the protective ECM and
break out into neighboring tissue and gain access to blood vessels more easily.
Please note that there is a difference between being able to move and
being able to invade.
Invasion requires the ability of a cell to secrete enzymes that actually chew through
the molecules of the ECM to create a hole that mobile cells can go through.
Importantly, invasion is that last straw to make a diagnosis of cancer.
If invasion is seen in a histological test, cancer becomes the diagnosis
because the cancer cell has the ability to possibly metastasize.
So invasion pushes the severity of the cancer to a higher level.
Once a cancer cell has invaded, the next logical step is for
it to get into the bloodstream.
This process is called intravasation.
In other words, cancer cells intravasate into a blood vessel
usually by pushing their way through the vascular endothelial cells.
Depending on the leakiness of the blood vessel, some cancer cells can slough off
or basically fall into the blood stream through small holes in the blood vessel.
In general, cells that are passively sloughed off are likely less aggressive
than the ones that actively push their way into the blood vessel.
You can now understand how the process of angiogenesis could promote cancer cells to
get into the blood stream more readily.
I also need to tell you that cancer cells can get into the bloodstream through
the lymphatic system.
Cancer cells can intravasate into lymphatic vessels as
well as blood vessels.
Lymphatic vessels drain into lymph nodes as we've discussed already, but
then they drain into the venous system.
Veins carry blood to the heart which then pump blood to the entire body.
So if a cancer cell gets into a lymph node, it could potentially get into
the bloodstream without ever having intravasated into a blood vessel.
Once cells get into the bloodstream they face an uphill battle.
They have to survive the circuitous route of blood from the vein in which they
entered, from whatever organ they may have originated from, to the heart,
back out to the lungs, back to the heart again.
And then through the arterial system where it could go anywhere and
wind up anywhere in the body.
Although sometimes a circulating tumor cell, or a CTC,
may just stop in the lungs and never really enter the systemic arterial system,
and these could develop lung metastasis.
During the transit throughout the circulation,
CTCs must survive various sources of death.
Normally if an epithelial cell is sloughed off and
accidentally enters the bloodstream, it dies.
First, as we've discussed,
epithelial cells are supposed to be attached to others cells and the ECM.
If they lose this attachment, they are programmed to undergo cell death.
So that's the first source of death that a CTC must avoid.
But because it has undergone EMT, it is able to avoid this death.
Secondly, the immune system is constantly surveying the blood in search for
cells that are not supposed to be there.
Epithelial cells fit this bill and
they usually display certain molecular markers on the cell surface
which tell immune cells to kill them under certain conditions.
CTCs avoid this immune surveillance and
survive and this is actually an active area of cancer research right now.
How can we re-activate immune cells to kill cancer cells?
All right, the third source of death that CTCs must avoid
is the strong shearing force of the blood pressure.
In the veins the amount of pressure is not as serious, but
once blood is being pumped from the heart, it undergoes a significant increase in
pressure which most epithelial cells would not withstand.
CTCs however are able to survive this force and survive.
Some cancer cells do indeed succumb to these three forms of death, but
the ones that do not become viable CTCs and are the ones that form metastasis.
One piece of evidence that shows that viable CTCs
are the cells that eventually form metastasis is this.
The more CTCs that are present in the blood of the cancer patient
the worse that patient's prognosis is.
This graph shows that when fewer than five CTCs
on average were found in 7 milliliters of a breast cancer patient's blood,
those patients median survival was about 22 months.
However, when five or
more CTCs were found, median survival dropped to only about 11 months.
In fact, the detection of CTCs is a hot area of cancer research, because it can be
used as a diagnostic, and potentially a screening marker of metastatic disease.
You can imagine how difficult this is though.
In 7 millilitres of human blood,
there are about 50 million white blood cells on average.
And cancer researchers are trying to find roughly five CTCs in that volume.
It is quite difficult and
it requires impressive biotechnological techniques to do.
Okay, so moving on to the next step which is extravasation,
which is the opposite of intravasation, where cells get into the blood.
So extravasation is the process of cells getting back out of the blood at
a secondary site.
One way this happens is that cells get stuck in tiny capillaries,
which are very small blood vessels inside an organ, and
then they squeeze there way out into the surrounding tissue.
Another way is that molecular factors that are secreted into the bloodstream by
the cells in the tissue attract the CTC to exit the bloodstream and
move towards those vectors.
CTCs have protrusions that allow them to adhere to the side of
a blood vessel wall and stick.
Because blood keeps flowing, the cancer cell rolls along the interior surface of
the vessel until it eventually is able to squeeze itself through the endothelial
cells into the surrounding tissue.
Once a cell has successfully extravasated, it is no longer referred to as a CTC but
rather as a disseminated tumor cell, or DTC.
So we've discussed that a CTC must traverse the entire circulatory system and
is therefore able to wind up anywhere in the body.
But sometimes cancer cells tend to wind up in the same location in many different
patients.
For example, breast cancer tends to metastasize to the bone,
but never to the peritoneum.
Stomach cancer on the other hand, almost always metastasizes to the peritoneum, but
very rarely to the bone.
So how can this be when it seems as though there should be an even chance for
any type of cancer cell to wind up any where in the body.
Well the answer to that question is actually not fully known at this point.
And it's an active area of cancer research.
But there is a lot of data that supports the seed and
soil hypothesis made by Stephen Paget in a ground breaking paper in 1889,
the distribution of secondary growths in cancer of the breast.
This hypothesis says that cancer cells, which is the seed in this analogy,
home to, or metastasize to certain secondary sites because they thrive better
in that environment, or the soil, that that particular organ has to offer.
So for example,
if prostate cancer metastasizes, it is almost always found in the bone marrow.
But you will never find a prostate metastasis growing in the pancreas
for instance.
So if this hypothesis is correct then the bone marrow is a more attractive
environment or soil for the prostate cancer cells to grow in than the pancreas.
Once a cancer cell extravasates and becomes a DTC, or disseminated tumor cell,
it can begin to grow a metastatic tumor in a secondary site.
This tumor follows many of the same hallmarks as primary tumors
dividing uncontrollably, resisting cell death,
avoiding immune to surveillance, changing metabolism, etc.
The larger the secondary tumor becomes, the more problems it causes.
And we discussed that previously when we talked about how metastatic cancer can
kill people.
It can cause bleeding, embolisms, hypercalcemia, etc.
If there are multiple metastatic tumors throughout the body,
this enhances all of those problems.
Now one thing that can happen to a DTC in a secondary site is that it become
dormant, which means that it can survive, but not proliferate or divide.
And basically just stays put as a single cell or groups of cells for a long time.
They basically hibernate.
For how long?
Well, there is evidence that suggests that a dormant DTC
can reside in a patient's bone marrow for years and even decades.
Sometimes these dormant DTCs don't cause any issues.
A single cell can't really do much harm.
But dormant DTCs can become activated and pushed toward proliferation and
can become a metastatic tumor at any time.
And what causes this reactivation from dormancy is unknown and
is also an active area of cancer research.
So this slide is just a summary of the metastatic process, and
we've gone over all of these steps.
And I'll just summarize it for you here.
Cancer cells can grow into a tumor, cause new blood vessels to grow,
which is angiogenesis, undergo physical changes, that's just EMT, and
invade through the ECM.
And get into the bloodstream, which is intravasation.
CTCs must survive circulation until they extravasate into a secondary site.
Once there as a DTC, they can either grow into a metastatic tumor or go dormant.
I hope I have conveyed the metastatic process to you.
And in the next section of the module we'll talk about
cancer ecology as an analogy for the cancer metastatic process.
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