Becoming a circulating tumor cell (CTC) and evading immune detection

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Understanding Cancer Metastasis

533 classificações

Johns Hopkins University

Understanding Cancer Metastasis

533 classificações

Over 500,000 people in the United States and over 8 million people worldwide are dying from cancer every year. 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. Everyone has been, or will be touched by cancer in some way during their lifetime. Thanks to years of dedication and commitment to research we’ve made enormous advances in the prevention and treatment of cancer, But there is still a lot of work to be done. In this course, physicians and scientists at the Johns Hopkins School of Medicine explain how cancer spreads or metastasizes. We’ll describe the major theories of metastasis and then describe the biology behind the steps in metastasis. The course also describes the major organs targeted by metastasis and describes how metastases harm the patient.

Na lição

Survival in the Circulation and Extravasation

We'll now take a close look at cancer survival within the circulation, the role of the circulatory system in metastasis, the genetic determinants of metastatic potential, signalling mechanisms, chemokines, the dock and lock hypothesis, and extravasation.

Introduction to Survival in the Circulation and Extravasation1:08

Glossary of Terms2:05

The Circulation4:03

How cancer cells survive while in circulation4:31

Becoming a circulating tumor cell (CTC) and evading immune detection10:50

Homing to a new site in the body and extravasation8:12

Conheça os instrutores

Kenneth J. Pienta, M.D.
The Donald S. Coffey Professor of Urology
The James Buchanan Brady Urological Institute
Jelani Zarif
Prostate Cancer Researcher
The James Buchanan Brady Urological Institute
Sarah Amend
Prostate Cancer Researcher
The James Buchanan Brady Urological Institute
Haley Axelrod
Prostate Cancer Researcher
The James Buchanan Brady Urological Institute
Kenneth Valkenburg
Prostate Cancer Researcher
The James Buchanan Brady Urological Institute

Welcome back.

Now that we have discussed the lymphatics and metastasis suppressor genes,

we will now discuss become a circulating tumor cell and evading immune detection.

Normally, if an epithelial cell is sloughed off and

accidentally enters the bloodstream it will die.

In the last section, we covered that and that form of cell death is known anoikis.

Other methods of death include immune cell destruction because

the immune cells undergoes surveillance of the circulation at all times.

And if there are foreign cells or

foreign bodies the immune system will clear them out by phagocytosis.

Another method in which a cell that gets in the circulation can die

is by shear blood pressure which can cause extreme cell lysis.

Especially, going from the venous system into the heart and

back out of the heart, so a cell must survive that as well.

So cancer cells or CTC evade all three of these forms of cell death.

That is anoikis, immune surveillance and shear blood pressure.

And they are able to enter the circulation, and

go undetected for a period of time.

And this is a active area of research right now, so

a CTC is short for a circulating tumor cell.

And it is a cell that has entered the bloodstream and, or lymphatics, and

has the ability to survive for a period of time while in the circulation.

CTCs have been shown to exist as a single cell or,

as a hetero-cellular cluster of cells that can travel throughout the human body.

On the left, you can see a breast cancer that is localized and upon magnification,

you can see that the primary tumor typically is hetero-cellular as well.

And these cells can enter into the bloodstream directly or

through the lymphatics and then into the bloodstream.

As a single cell or a CTC cluster And then metastasis to a distant

site such as the lungs as a single cell or as a hetero-cellular cluster.

Again, a circulating tumor cell has the ability to evade anoikis

as lost metastasis suppressed genes and

fit to withstand blood pressure to get to the lungs.

One piece of evidence that shows that have valuable CTC

are the sales that eventually form a test is this data shown here.

The more CTCs that are present in the blood of a cancer patient,

the worse that cancer patients prognosis is unfortunately.

This graph shows that when fewer than 5 CTCs were found in 7 milliliters of blood

of a breast cancer patient, those patients median survival was about 22 months.

However, when 5 or

more CTCs were found the median survival dropped to about 11 months.

In fact, the detection of CTCs is a very hot area in cancer research

because it can be used as a diagnostic and screening marker for metastatic disease.

You can imagine how difficult this is, though, in seven millilitres of blood.

There are about 50 to 60 million white blood cells on average

in the cancer cell can be hard to find in that volume.

Typically, cancer researchers only find about five CTCs in their volume.

While it is difficult in requires impressive biotechnology techniques to do

it, this is an area under investigation that we believe can help patients.

CTCs have also been shown to associate with several other cell types.

One of these cell types are platelets.

Platelets are a nuclear cells that are involved with clotting vessel injuries.

They are found in large numbers in the blood and contribute to angiogenesis.

CTCs can interact with platelets via

tumor cell inducted platelet aggregation or TCIPA.

TCIPA activates platelets and

allows them to attach to CTCs and shield them from Immune destruction.

Platelets also have the ability to transfer

Major Histocompatibility Complex Proteins onto CTCs, so

that the immune system does not detect them.

This allows for evasion of the immune system.

Another cell type that has been shown experimentally to associate with CTCs

are M2 Macrophages.

M2 Macrophages are a type of white blood cell that is important for wound healing.

And these cell types have been shown experimentally to allow a cancer cell

to undergo epithelial mesenchymal transition as well as intravasate.

In experimental models in vitro,

isolated CTCs have been shown to have the proclivity to recruit cells

belonging to a myloid lineage using factors known as cytokines.

This association with myeloid cells allow CTC cells to

suppress the cell proliferation of T-cells which will target

any foreign cells by listening in the nearer response.

But this cells of regulate programmed death ligand 1 a notable checkpoint

ligand which blocks T-cell proliferation and

allows cancer cells to survive within the circulations.

CTCs can interact with the host of others cell types while in the bloodstream

Highlighted in this illustration are platelets associated with

circulating tumor cells, monocytes associated with circulating tumor cells.

And also highlighted in this illustration is that circulating tumor cells can

have a expression of programmed death ligand 1.

Which binds to PD1 on T-cells and allows CTCs

to evade immune destruction by factor T-cells.

Let's take a closer look at the programmed death ligand 1 signaling,

shown in this illustration are two cell types.

Tumor Cells and Myeloid Cells can express programmed death ligand 1 or

programmed death ligand 2.

They bind to PD1 on T-Cells or

B-Cells and can cause B-Cells to

stop proliferating by down regulating the Psychiatric Kanis Pathway.

This is a very hot area of scientific investigation,

clinically specially with a lot of check point and

hemorrhoids in the bodies that are available to cancer patient.

Survival during systemic circulation.

Once cells get into the blood stream they face an uphill battle.

They have to survive the circulation of the blood from the vein in which they

enter from whatever organ it may have originated from to the heart,

back out the lungs, back to the heart.

And then, throughout the arterial system where it could go anywhere and

wind up anywhere.

Sometimes, a circulating tumor cell, may just stop in the lungs and never really

into the systemic arterial system and could just develop lung metastasis.

During the transit throughout the CTCs must survive various forms of cell death,

which we've highlighted previously.

Currently, this is again a very hot area and is under investigation

to try to find CTCs from patients.

In our laboratory, we are able to detect circulating tumor cells

in blood from prostate cancer patients using prostate cancer markers.

This is what we do here at Johns Hopkins University School of Medicine.

We are able to obtained seven millilitres of blood from patients that consent and

what we do is we used markers.

They are found only on cancerous cell types from prostate cancer.

And are not on blood cell types to determine the number of

circulating tumor cells in a given sample.

Here, we use HOXB13 and

NKX3.1, both of which are expressed in prostate cancer cells.

We use DAPI, which Stains for nuclei and that's blue.

And we use a host of white blood cell marker such as CT45 to

discern a CTC from a white blood cell and shown as one CTC.

And here's another from the same patient from a different bottle of blood,

so we're able to detect a small amount of CTCs in the blood.

From another cancer patient,

we obtained 7 milliliters of blood and

looked for HOXB13, NKX31.

Pan Cytokeratin positive, CD45 negative cells.

And then when we did a merge on the left side of the screen

you can see cells that are HOXB13 positive, NKX3.1.

Pan Cytokeratin positive and

white blood cell marker negative shown here and

also in the bottom we are able to brightly see a CTC, that is NKX3.1.

HOXB13, Pan Cytokeratin positive, but white blood cell marker negative.

So recap for this section,

a CTC is a cancer cell that has the ability to survive while in circulation.

They can exist as a single cell or heterocellular clusters.

CTCs can associate with a host of different cell types,

notably immune cells while in circulation.

This association helps CTCs in various ways to evade immune destruction.

Finally, immune checkpoints expressed on T-Cells allow them to target foreign cells

In the blood.

However, CTCs and their entourage

can express programmed death-ligand 1 which allow immune circumvention.

Now, for a quiz.

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