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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: ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ 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. ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ 95 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. ________________________________ ________________________________ ________________________________ 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. ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ 96 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: ________________________________ ________________________________ ________________________________ 4. True or false: Src protein encoded in the genome of a virus can cause cell transformation. aa. True. bb. False. ________________________________ ________________________________ ________________________________ ________________________________ 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. ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ 97 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. ________________________________ ________________________________ ________________________________ 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 ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ 98 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? _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ ____________________________________________________________________________________________________ Remember to identify your sources _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ Wo r k b o o k Lesson 3.3 _____________________________________________________________________________________________________ ___________________________________________________________________________________________ 99 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. 100