Download LESSON 3.3 WORKBOOK How can the immune system

LESSON 3.3 WORKBOOK
How can the immune system
behave as a carcinogen?
DEFINITIONS OF TERMS
Inflammation – the immune
response to infection, injury, or
irritation that results in pain, redness, and swelling.
Transforming viruses – a virus
that promotes the change in size,
shape, and growth of a cell such
that it behaves like a transformed
cell.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 3.3
In the previous lesson we learned how errors of DNA replication cause mutations
and transform cells. We learned that mutagens able to mutate DNA can be
carcinogens. However not all carcinogens are mutagens; some increase the
frequency of random DNA mutations by causing cells to hyperproliferate. In this
lesson we will learn how chronic inflammation can behave like a carcinogens
stimulating cells to hyperproliferate and increasing the chance they will acquire
mutations that will lead to transformation.
Pathogens and inflammation in cell transformation
In the previous lesson we learned about how mutagens can directly modify DNA sequences and promote
cell transformation. However, not all carcinogens are mutagens, some carcinogens induce cells to
hyperproliferate and as a consequence increase the chances that cells will acquire mutations that lead to
transformation.
How does cell hyperproliferation lead to transformation? Cells that are hyperproliferating are less able
to repair errors in DNA replication and during mitosis. Hence the likelihood of them acquiring a relevant
mutation to a proto-oncogene or a tumor suppressor gene leading to transformation is also increased.
The two major ways that agents promote hyperproliferation is through viral infection or activation of
inflammation.
In Unit 1 we learned how Peyton Rous identified Rous Sarcoma virus as the cause of chicken tumors
nearly 100 years ago. But the mechanism by which viruses work has only recently been discovered. We
now know that as part of their life cycle viruses promote dividing cells to hyperproliferate so they can infect
more cells and produce more virus. As the cells hyperproliferate the rate at which mutations accumulate
accelerates and transformation results. Viruses that promote hyperproliferation and transformation are
therefore called transforming viruses. Normally viruses that use the host cell machinery to replicate their
MC Questions:
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1. Which of the following is a way that
carcinogens can transform cells?
(Circle all correct.)
aa. Directly mutate DNA.
bb. Activate hyperproliferation.
cc. Inhibit the immune system.
dd. Degrade stromal tissue.
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LESSON READINGS
genome weaken the cell so that it bursts and dies when virus exits the cell. Transforming viruses are able
to bury their genome in the host cells’
DNA, so that it is able to replicate without
killing its host or exposing itself to the
host’s immune system. Both DNA and
RNA viruses can be transforming, but the
strategies they use are different.
RNA viruses
RNA transforming viruses resemble
HIV. They replicate their genome using
reverse transcriptase and then insert the
DNA version of their genome into the
cell’s genomic DNA, as retrotransposons
do too. Cell transformation can occur
Figure 1: Transforming viruses (tumor virus)
can replicate their own genome by replicating the
either because the virus genome itself
cell they are infecting, rather than replicating their
encodes regulatory sequences that
genome in a traditional way and causing cell lysis.
promote over-expression of protooncogenes, or because the virus genome
carries an oncogene itself, like the Rous Sarcoma virus does – it carries the oncogene src.
Another way that RNA viruses can promote transformation is by inserting their genome within the protein
coding sequence of a tumor suppressor gene. This will disrupt the expression of the tumor suppressor
genes, and will also make the cell prone to hyperproliferate, leading to transformation.
This strategy of viral replication leading to cell transformation is so effective that sometimes viruses
STEAL host proto-oncogenes! As we learned in Unit 1, the Rous Sarcoma Virus (RSV) forms tumors
in chickens because it carried the src oncogene, which it had stolen from some host chicken way back
in evolutionary history. The src proto-oncogene found in normal chicken cells inhibits the cell cycle, but
the src oncogene carried by RSV has been mutated so that whenever the virus infects a chicken cell it
activates cell proliferation and forms tumors (called sarcomas). Again, this enables the virus to replicate
itself without being detected by the chicken immune system.
Wo r k b o o k
Lesson 3.3
The list of retroviruses that have stolen proto-oncogenes is long. In normal cells these proto-oncogenes
act at every stage in the transmission of a growth signal from the surface of the cell via a receptor through
transduction proteins to the nucleus. In each case the normal proto-oncogene found in a cell inhibits
some aspect of proliferation, while the oncogene stolen by the virus has been mutated to stimulate
proliferation, thereby increasing virus infectivity. Given how well this strategy works in a number of different
MC Questions:
2. Which of the following explains why
viruses transform cells? (Circle all
correct.)
aa. Faster replication cycle.
bb. Escape from immune system.
cc. Not have to find a new host.
dd. Easier to kill cells.
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3. Which of the following is a way that
RNA viruses can transform cells?
(Circle all correct.)
aa. Integrate into tumor suppressor
gene.
bb. Express protein that degrades
tumor suppressor genes.
cc. Express its own oncogene.
dd. Promote expression of protooncogene.
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LESSON READINGS
animals, it is very surprising that only one retrovirus has been found that causes cancer in humans.
Clearly there are aspects of this biology in humans we still don’t understand.
DNA viruses
DEFINITIONS OF TERMS
Inflammatory response –
same as inflammation. The
immune response to infection,
injury, or irritation that results in
pain, redness, and swelling.
Wo r k b o o k
Lesson 3.3
Most RNA viruses have very small genomes; in contrast, because DNA is more stable than RNA, DNA
viruses can have relatively large genomes containing more genes. Hence, while transforming RNA
viruses have to either ‘modify proto-oncogenes/tumor suppressor genes or ‘steal’ host oncogenes,
transforming DNA viruses can just carry along genes that promote cell proliferation and allow them to
avoid immune detection. DNA tumor viruses can also promote hyperproliferation by inactivating tumor
suppressor proteins, most notably the Rb protein. As we learned in Unit 2 Rb is one of the most important
regulators of the cell cycle, because it controls the R transition point. Recall that Rb serves as a gatekeeper to control the cell cycle because once cells have passed the R point they are committed to the cell
cycle and no longer need extracellular growth signals.. The main goal of DNA tumor viruses is to inhibit
the Rb protein by any means necessary, thereby forcing the cell to enter the cell cycle. DNA viruses,
such as human papillomavirus (HPV) have proteins such as E7, which destroy Rb. This function of the E7
protein is seen in 99.7% of all cervical cancers.
The immune system and cell transformation
Pathogens such as the transforming viruses can transform cells directly, but other pathogens as well as
many carcinogens can promote cell transformation indirectly, by activating the inflammatory response of
the immune system. Inflammation is the immune system’s front line defense against pathogens, damaged
cells or irritants, and is associated with swelling, pain, redness, and heat. During inflammation, blood
vessels at the site of damage/infection will open up and allow immune cells to enter the tissue. These
immune cells increase the blood flow at the site of damage, which causes the increases in redness and
heat. These blood vessels are also more leaky, and release contents such as immune cells, proteins,
and water (which increases swelling and pain caused by swelling). As we shall learn in the next Unit,
the growth of leaky blood vessels at the site of damage/infection allows cancer cells to spread into the
bloodstream and metastasize to other organs.
But inflammation not only promotes the ability of cancer cells to metastasize to other organs, it can also
lead to transformation of normal cells to tumor cells. For example, many types of stomach and liver
cancers are due to infection with pathogens. Stomach cancer is caused by the bacterium H. pylori, while
liver cancers caused by infections from the hepatitis B and C virus as well as the liver fluke (a type of
parasitic worm). These pathogens activate cancer by promoting tissue inflammation. Other carcinogens
that activate inflammation include: alcohol, radiation, and environmental pollutants.
MC Questions:
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4. True or false: Src protein encoded in
the genome of a virus can cause cell
transformation.
aa. True.
bb. False.
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5. Which of the following inflammatory
responses promotes progression of
cancer? (Circle all correct.)
aa. Activation of pain receptors.
bb. Increase of blood flow.
cc. Growth of blood vessels.
dd. Killing of damaged cells.
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LESSON READINGS
DEFINITIONS OF TERMS
Cytokines – signaling proteins
released by immune cells that
affect the behavior of other cells.
Tumor necrosis factor α
(TNF-α) – a signaling molecule
secreted primarily from immune
cells, but also from other cells,
that is the primary activator of
inflammatory response.
Chronic infections – an
infection that is persistent and
never fully cleared by the immune
system.
Adipose cells – cells that are
specialized to store fat in the
body.
Inflammation promotes cell transformation in two ways. By killing off infected or damaged cells, the
inflammatory response destroys tissue structure, exposing stem and progenitor cells to other carcinogens
that can mutate DNA directly. Inflammation can also cause secretion of important signaling proteins called
cytokines, which are essentially signals from immune cells that instruct other cells how they should
behave. These cytokines can induce hyperproliferation. One of the most potent cytokines in inflammation
is tumor necrosis factor α (TNF-α). TNF-α is a signaling molecule that is primarily intended to recruit
immune cells at a site of infection. TNF-α is intended to signal only to immune cells, however liver and
stomach carcinomas can also receive TNF-α signals, leading to activation of the NF-кB pathway. In Unit
2 we learned that the TNF-α/NF-кB pathway which
promotes the growth and survival of cells, is often
active in tumor cells.
Pathogens such as H. pylorii, hepatitis B and C
viruses, and liver flukes cause chronic inflammation,
because the infection is never fully cleared, despite
the continuous activation of inflammatory response.
Another chronic inflammatory state is seen in individuals who are obese. Adipose cells, the cells that store
fat in the body, increase in size and number during
obesity. These cells also constantly secrete TNF-α, so
increase numbers of adipose cells may promote the
chronic inflammation that can lead to cancer.
Altogether, carcinogens that promote inflammation or
hyperproliferation of cells are responsible for promoting cell transformation by increasing the chance that
random DNA mutations will occur.
MC Questions:
6. Which of the following is an outcome
of TNF-α signaling? (Circle all
correct.)
aa. Recruitment of immune cells.
bb. Recruitment of adipose cells.
cc. Activation of NF-кB.
dd. Clearance of pathogen from
infected tissue.
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Figure 2: Prolonged infection by
Hepatitis B or C viruses or excessive
alcohol consumption leads to progression of disease and liver cancer caused
by inflammation.
7. Why is obesity associated with
cancer? (Circle all correct.)
aa. Obese people have weak
immune systems.
bb. Obese people secrete more
TNF-α.
cc. Obese people experience
chronic inflammation.
dd. Obese people more susceptible
to transforming virus infection.
Wo r k b o o k
Lesson 3.3
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STUDENT RESPONSES
Smoking while drinking alcohol has been shown to increase the risk of developing cancer more than smoking alone. Can you
explain a way in which smoking and drinking could increase the chances of cell transformation more than smoking alone?
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Remember to identify your
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Wo r k b o o k
Lesson 3.3
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TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 3.3
DEFINITION
Adipose cells
Cells that are specialized to store fat in the body.
Chronic infections
An infection that is persistent and never fully cleared by the immune system.
Cytokines
Signaling proteins released by immune cells that affect the behavior of other cells.
Inflammation
The immune response to infection, injury, or irritation that results in pain, redness, and swelling.
Inflammatory response
Same as inflammation. The immune response to infection, injury, or irritation that results in pain, redness,
and swelling.
Tumor necrosis factor α
(TNF-α)
A signaling molecule secreted primarily from immune cells, but also from other cells, that is the primary
activator of inflammatory response.
Transforming viruses
A virus that promotes the change in size, shape, and growth of a cell such that it behaves like a transformed
cell.
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