Cancer

=Hannah Binney, Melissa Yuan, David Zhang=

**Our Powerpoint (click for narrated video)**
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What is Cancer? YouTube Video =media type="youtube" key="LEpTTolebqo" height="315" width="560"= = Characteristics of Cancer = Cancer is a very wide group of diseases that results in an unchecked division of cells. Healthy cells typically have numerous molecular controls to restrict cell growth and reproduction. Once cells no longer respond to control signals, they divide uncontrollably and begin to form a large mass of cancer cells, called a tumor. There are several broad categories of cancer: **Carcinoma:** Cancer that begins in the skin or epithelial tissues that line cavities and organs (e.g. breast cancer, lung cancer, colon cancer). This is the most common kind of cancer and makes up 80-90% of all cases. (10) **Sarcoma:** Cancer that begins in the connective tissue, bone, cartilage, fat, muscle, or blood vessels. **Leukemia:** Cancer that begins in blood-forming tissues like the bone marrow and result in the production of many abnormal blood cells. **Lymphoma and Myeloma:** Cancers that begin in the cells of the immune system. **Central nervous system cancers:** Cancers that begin in the tissues of the brain and spinal cord. (9)



= Tumor Growth = A tumor begins with a single cell that begins reproducing inappropriately. All resulting cells show the same characteristics. Fewer than 10 mutations can cause a cell to become cancerous (i.e., more likely to reproduce than it normally would be). The tumor then enters a stage called **hyperplasia**, during which the cell and its descendants grow and divide too often. This increases the risk of another mutation in one of the progeny, which further increases that cell's tendency to divide too quickly. The next stage is called **dysplasia**, during which the cell which has mutated further divides excessively and looks abnormal. One of these abnormal cells experiences another mutation. This cell and its progeny is abnormal in growth and appearance. These cells may form an //in situ// tumor that may be contained indefinitely within the originating tissue (**benign** tumor). Further mutations to these tumor cells may allow the tumor to invade adjacent tissues. The tumor may throw off cells into the blood or lymph, meaning that the tumor is **malignant**. Malignant tumors metastasize, meaning that they establish new tumors in other parts of the body. Tumors are dangerous because they can threaten the functions of tissues and organs. (3)



= Changes in Physical Properties of Cancer Cells = The defining characteristic of cancer cells is their ability to grow and divide even in the absence of appropriate signals or in the presence of inhibitory signals. However, other physical properties are characteristic of cancer cells and can both aid in diagnosis and help explain the behavior of tumors. **Cytoskeletal changes:** Distribution and activity of microfilaments and microtubules in cancer cells may change, affecting the ways that the cell interactions with other cells. **Cell adhesion and motility:** Cancerous cells do not adhere well to other cells and the extracellular matrix. They also do not exhibit contact inhibition, meaning that they grow even when surrounded by other cells. Contact inhibition is an important mechanism that prevents cells from spreading rapidly throughout the body, so the absence of this control mechanism allows metastasis to occur. **Nuclear and genetic changes:** The shape and organization of the nucleus in cancerous cells is different, allowing for diagnosis of cancer and determination of the tumor stage. Cancer cells may also have chromosomal abnormalities and extra copies of certain genes (gene amplification). **Enzyme production:** Cancer cells secrete enzymes that dissolve barriers to migration (lamina) and enable them to migrate to other tissues. (4) **Immortality:** Normal cells divide about 50 times and then die. Cancerous cells can divide indefinitely if they have enough nutrients. (5) **Abnormal apoptosis:** Cancer cells have a high level of a protein called survivin the inhibits apoptosis and prevents the body from effectively controlling cancer growth. **Lack of differentiation:** Normal cells are differentiated and therefore capable of one particular function. Cancer cells are unspecialized. **Reduced need for growth factors:** In normal cells, cyclin combines with kinase only in the presence of growth factors. Oncogenes allow these reactions to occur with a smaller amount of growth factors, allowing cancer cells to replicate in an abnormal fashion. **Angiogenesis:** Cancer cells release a growth factor that encourages blood vessels to produce branches that grow into the cancerous tissue. **Immune system reaction:** Cancer cells have mutated "self" markers that allow the immune system to recognize them as "other." They are therefore destroyed by the immune system. (6)



= = = The Genetics of Cancer =

= **Overview** = Cancer is caused by mutations that alter genes that normally regulate the cell growth and division, or the cell cycle (1). The transformation from a normal cell to a cancerous cell usually requires more than one mutation. Gene mutations can either be inherited, which occurs in only 10% of cancer cases, or acquired during a person's lifetime through random spontaneous mutation or environmental factors such as chemical carcinogens or physical mutagens (2).

= **Types of Genes** = Three types of genes involved in regulation of the cell cycle are frequently also involved in cancer as well. **Proto-oncogenes** are normal cellular genes that code for proteins that stimulate natural, controlled growth and division in cells. **Oncogenes** are the cancer-causing genes; they can be found in viruses or as part of the normal genome, and they trigger cancerous characteristics. The third type of gene, **tumor-suppressor genes**, do not promote growth; instead, they are the "brakes" of the cell.Tumor suppressor genes normally encode for proteins and other products that inhibit cell division, preventing uncontrolled cell growth (1).

Proto-oncogenes can become oncogenes through three types of genetic changes. One genetic change is movement of DNA within the genome. Cancerous cells often have incorrectly rejoined chromosomes, so that fragments from one chromosome are translocated to another (1). A new, more active promoter may end up increasing trasncription of the proto-oncogene so that it creates too much growth-stimulation protein and becomes an oncogene. Another type of genetic change is gene ampliication, in which the number of copies of the proto-oncogene in the cell is increased. Again, the normal protein that stimulates cellular growth will be produced in excess. (1) The last possibility is that a point mutation changes the gene’s products to a more active or degradation-resistant version, so the growth-stimulating protein is difficult to control. (1) Different types of point mutations include frameshift, deletion, insertion, and substitution (1).

A specific example of a proto-oncogene is the **//ras// proto-ongene**, which is mutated in about 30% of human cancers (1). The //ras // gene, which is sometimes called the K-ras gene (2), produces the Ras protein, a G protein in a signal-transduction pathway that relays a growth signal from a growth factor receptor to a cascade of protein kinases and ends in the production of the Ras protein, stimulating the cell cycle (1). When the //ras// gene is hyperactive, the pathway may increase cell division even without an external signal (1). Or, a point mutation may cause the //ras// to be an oncogene that codes for a hyperactive Ras protein that may issue signals on its own (1). Both types of genetic change cause excessive cell division, a major characteristic of cancer cells. (1)



Tumor suppressor genes are necessary for controlling cell growth and division. If a mutation causes the decrease of the normal activity of a tumor-suppressor product, then cancer may occur due to an uncontrolled cell cycle. (1) Various protein products of tumor suppressor genes have different functions: some repair damaged DNA, so that mutations are not accumulated; some inhibit the cell cycle; and others control the adhesion of cells, as cell anchorage is often absent in cancerous tissues (1).

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A specific example of a tumor suppressor gene is the **//p53// gene**, which is mutated in about 50% of human cancers (1). The //p53// gene, sometimes called the "guardian angel of the genome," acts as a transcription factor for many genes, and its signal is damage to the cell's DNA. It helps prevent the cell from passing on mutated DNA in 3 major ways. First of all, it activates genes, such the //p21// gene, which produces products to halt the cell cycle by binding to cyclin-dependent kinases (1). The //p21// gene allows the cell time to repair the DNA. Also, //p53// can directly turn on repair genes (1). Lastly, the //p53// can activate apoptosis, or programmed cell death, if the damage is too great and irreparable (1).



In summary, proto-oncogenes become cancer-causing oncogenes when they are activated, while tumor suppressor genes can cause cancer when they become inactivated. (8) = media type="youtube" key="IeUANxFVXKc" height="315" width="560" =

**Heredity and Cancer** As mentioned above, mutations can be inherited or somatic (8). **Inherited mutations** are passed through the egg or sperm, and are found in every cell of the body. (6) Acquired mutations, which are also called **somatic mutations**, are much more common than inherited mutations. They occur in one cell and then are passed on to that cell's daughter cells, and any subsequent cells, when it divides (8). For a cell to become cancerous, it requires an average of 5-7 mutations in its DNA (2).



Certain types of cancer, only about 10%, are linked to inherited mutations. These types of cancer include breast cancer, ovarian cancer, colorectal cancer, prostate cancer, thyroid cancer, and melanoma skin cancer (11). Very specific inherited genetic mutations make people more likely to get these types of cancer. For example, women with mutations in the BRCA1 and/or BRCA2 genes have a much greater chance of getting breast or ovarian cancer (11).

= = = **Cell Repair Mechanisms, Natural Killer Cells, and Therapies** =

Major components of the immune system response to cancer cells are the natural killer (NK) cells. Natural killer cells better identify defective cells because they recognize a cancer cell’s deficient expression of HLA-class I molecules (the major histocomptability complex in humans) that are typically found on infected cells and express the presence of antigens, but are suppressed in cancer cells. NK cells identify the lack of HLA molecules and then initiate the apoptosis of HLA-lacking cells. NK cells are typically inhibited by surface proteins (Killer-cell immunoglobin-like receptors) and also require activating ligands from the target cell to cause apoptosis. Once both the ligands exist on the target cell and there is no presence of HLA, the natural killer cell initiates the lysis of the target cell. (13)



Cancer due to cell mutations from damage in DNA can often be fixed by the various DNA mechanisms in cells. DNA repair mechanisms involved in repairing cancerous cells include basic excision repairs and nucleotide excision repairs. Basic excision repairs target one mutated base in DNA: DNA glycosylase removes the damaged base and DNA polymerase replaces the base. (15)

More important in the repair of DNA in cancer cells is the nucleotide excision repair (NER). NER targets much larger damage to DNA, typically as a result from foreign stimuli, such as UV light. Lesions in DNA due to UV radiation can often cause skin cancer. Such damaged cells are repaired through the four discrete steps in NER. First, the damage in the DNA is detected, typically as large, distorted lesions in the DNA. Next, excision of the entire section of DNA occurs. DNA polymerase then restores the missing bases that were previously excised. Lastly, the newly synthesized DNA and the older DNA are fused back together. (14)

A broad range of synthetic antibodies, cytosines, interferons, interleukins, and other immune-system substances known as **biological response modifiers (BRMs)** can work to alter the interaction of the body’s immune system with cancerous cells. (17) These BRMs can initiate, boost, or restore the body’s ability to fight the disease.

Effects of BRMs are used to:
 * stop or suppress the division of cancer cells
 * make cancer cells more recognizable to the immune system
 * boost the cytotoxic abilities of T-cells and NK cells
 * block or reverse the process that turned a precancerous cell into a cancerous cell
 * and prevent cancer from spreading to other parts of the body.

Cancer is often a disease that requires therapies to treat and repair. When simple excision of the tumor from the body is not enough, one may resort to the common treatments of chemotherapy and radiation.

Chemotherapy uses the treatment of drugs to inhibit cell division and damage target cells. Chemicals released by the drugs enter the cytoplasm of target cells and are primarily effective at the inhibition of fast, uncontrolled division, such as that of cancer cells. This is because as a group of cells divide quickly there are more daughter cells with the chemo-drugs in the cytoplasm. Unfortunately, chemotherapy does not only target cancerous cells. (18) As a result, other body cells are also damaged and inhibited in the process (which is why a chemotherapy patient will lose hair cells). Another downside of chemotherapy is that older generations of cancer cells become less susceptible to chemotherapy. The more a cancer cell divides, the more its division control mechanisms degrade. Furthermore, cancer cells become more resistant to chemotherapy over time. In some instances the chemicals can be actively transported to outside the cell. (18)

In radiation therapy, high energy x-rays and gamma rays are used to shrink or destroy tumors. Radiation kills cancer cells by thoroughly damaging their DNA beyond all repair. Once the genetic code cannot be restored, the affected cells do not divide and eventually die. Like chemotherapy, however, radiation damages both healthy and cancerous cells. In certain situations, chronic side effects include memory loss, fibrosis, and infertility. (19)

= Multiple Choice Questions = 1. Which of the following types of cancer begins in cartilage, fat, or muscle? A. Leukemia B. Myeloma C. Sarcoma D. Carcinoma E. Microcarcinoma

2. How does the absence of contact inhibition allow for the formation of tumors? A. It allows cells to live for longer, permitting them to replicate without growth factors. B. It allows cells to grow uncontrollably, even when there is no room for them to do so. C. It allows cells to dissolve the lamina between tissues and migrate through the body. D. It prevents the immune system from recognizing cancer cells as “other.” E. It forces cells to undergo apoptosis, planned cell death.

3. In which of the following stages of tumor growth to cancer cells begin to look abnormal? A. Invasive cancer B. Dysplasia C. Hyperplasia D. In situ cancer E. Never

4. Which of the following is not a mutation that can cause a cell to become cancerous? A. Gene amplification <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">B. Translocation <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">C. Frameshift <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">D. Lateralization <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">E. Transposition

<span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">5. What is the normal role of a tumor suppressor gene in a cell? <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">A. Producing various G-proteins, such as the Ras protein <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">B. Killing cancerous cells <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">C. Controlling the cell cycle and cell division <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">D. Producing growth factors and cyclin-dependent kinases <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">E. Activating natural killer cells

<span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">6. Which of the following is not true of the ras gene? <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">A. It is nicknamed “the guardian angel of the cell cycle,” and is growth inhibiting <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">B. The product of it is a G protein <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">C. Many ras oncogenes have a point mutation that leads to a hyperactive Ras protein <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">D. In its normal state, it stimulates the cell cycle <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">E. In its hyperactive form, it can cause cells to become cancerous

<span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">7. What is a major reason that predispositions to certain cancers runs in some families? <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">A. One inherited mutation can affect multiple alleles. <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">B. Multiple genetic changes are required to produce a cancer cell, and any inherited mutations increase the chance of a cell becoming cancerous. <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">C. Some types of cancer, such as breast cancer, are the products of only one mutation in a oncogene, so any mutation will cause the cell to become cancerous. <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">D. Cancer can be a sexually transmitted disease. <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 15px; text-decoration: none; vertical-align: baseline;">E. Abnormal cell division is always caused by inherited mutations.

8. Which of the following does not play a MAJOR role in the activation of natural killer cells on cancer cells? A. Presence of KIR ligand B. Presence of KIR ligand receptor C. Presence of Killer-cell immunoglobinlike receptors D. Lack of HLA-class I molecules E. Lack of HLA-class II molecules

9. Which of the following is not a discrete step of a nucleotide excision repair? A.Recognition of damaged DNA B. Addition of replacement bases C. Removal of damaged DNA segment D. Gap of missing DNA filled by DNA polymerase E. Fusing of old and new DNA

10. What is a common disadvantage between both radiation and chemotherapy? A. Both eventually destroy the entire body B. They do not only target cancer cells C. They require the entry of foreign substances into the cytoplasm of cells D.Both make patients radioactive E. They are not recommended treatments for cancer

=<span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 24px; text-decoration: none; vertical-align: baseline;">ESSAY QUESTION =

<span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 16px; text-decoration: none; vertical-align: baseline;">Mary has recently been diagnosed with cancer. She asks you, her doctor, what happened to her cells to cause them to become cancerous.

<span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 16px; text-decoration: none; vertical-align: baseline;">A.) Explain the roles of the following genes in the development of cancer:
 * <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 16px; text-decoration: none; vertical-align: baseline;">Proto-oncogenes
 * <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 16px; text-decoration: none; vertical-align: baseline;">Tumor suppressor genes

<span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 16px; text-decoration: none; vertical-align: baseline;">B.) Describe three of the following physical changes in cancer cells:
 * <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 16px; text-decoration: none; vertical-align: baseline;">Cytoskeletal changes
 * <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 16px; text-decoration: none; vertical-align: baseline;">Cell adhesion and motility
 * <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 16px; text-decoration: none; vertical-align: baseline;">Nuclear and genetic changes
 * <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 16px; text-decoration: none; vertical-align: baseline;">Enzyme production
 * <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 16px; text-decoration: none; vertical-align: baseline;">Immortality
 * <span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 16px; text-decoration: none; vertical-align: baseline;">Angiogenesis

<span style="background-color: transparent; color: #000000; font-family: Arial; font-size: 16px; text-decoration: none; vertical-align: baseline;">C.) Describe two different treatment options for cancer.

Helpful Links!
[|Interactive Cancer Animations and Videos] Cancer Animation

= = = **Sources** = (1) [|Campbell Biology Book, Chapter 19] An explanation of the molecular biology of cancer, especially the different types of cancer-causing genes. (2) [|Inside Cancer] The most in-depth source on cancer, with many various videos and animations. (3) [|Cell Biology and Cancer]

(4) [|CancerQuest] A detailed breakdown of the physical changes and properties of cancer cells. (5) [|Cell Reproduction: Mitosis and Cancer] An overview of how cell reproduction is related to cancer, complete with review questions. (6) [|Cancer] A very general introduction to cancer, including characteristics, genetics, and prevention. (7) [|National Cancer Institute] 61 great slides on understanding cancer. (8) [|Genetics and Cancer] A section on heredity and cancer, oncogenes and tumor suppressor genes, and genetic testing. (9) [|What is cancer?] A list of the types of cancer. (10) [|ChemCases] An excellent illustration of how cells become cancerous through mutations. (11) [|Heredity and Cancer Risk] A list of the types of cancer that can be linked to family history, and a brief explanation. (12) [|Types of Cancer] Another source on the different types of cancer, and a good paragraph debunking the myth that breast cancer only affects women. (13) [|Natural Killer Cells and Immunity Against Cancer] A scholarly article on how natural killer cells can attack cancerous cells. (14) [|DNA Damage & Repair: Mechanisms for Maintaining DNA Integrity] A description of how DNA repair mechanisms recognize and repair damaged DNA. (15) [|DNA Repair] General summary of DNA repair mechanisms. (16) [|Natural Killer Cells and Cancer] An in-depth description of the role of NK cells in tumor description, with a section explaining how they can be used for immunotherapy. (17) [|Biological Therapies for Cancer] Description of possible therapies for cancer, including interleukins, vaccines, and interferons. (18) [|Chemotherapy] Summary of types, effects, and mechanisms of chemotherapy. (19) [|Radiation Therapy for Cancer] Frequently asked questions about radiation therapy. <span style="display: block; font-size: 120%; height: 1px; left: 0px; overflow-x: hidden; overflow-y: hidden; position: absolute; top: -25px; width: 1px;">[]