Cancer

=Cancer= By: Aditya P., Aujan M., and Zachary J. Overview, How Do Cancer Cells Avoid Death?, Processing Nutrients, Why do cancer cells grow uncontrollably?, Invading Tissues, How Do Cancer Cells Bypass the Immune System?, Mutations, Types of Mutations, Genetic Basis of Cancer, Types of Tumors, Treatment, Review Questions, Sources

(1) Cancer is a genetic disease that results in the uncontrolled growth of cells into a malignant neoplasm (tumor). The failure of cell division control is the result of a mutation of a gene.Some genes code for the production of enzymes used to check for mutations in replicated DNA during the cell cycle. When a mutation is found, these enzymes stop the cell cycle until the mutation is repaired.Genes that help prevent the manufacturing of mutated cells are called tumor suppressing genes. Proto-oncogenes that regulate the control of the cell cycle can also mutate, becoming oncogenes, which lead to cancer.

Cancer is a disease that can affect anyone around the world from people in America down to people in Indonesia. It starts at the most basic level; within the DNA of a person’s cell. More than 90% of the time the cancer mutation is a result of external environmental factors while less than 10% of the time it is inherited. The deletion or duplication of nucleotides in a genetic sequence can lead to a mutation and many mutations transform a normal cell into a cancerous one. Once the cell’s life cycle is disrupted, the cancerous cells begin to grow at a rapid rate which results in the development of a tumor. (2)
 * Overview:**

Normal cells respond to the signals throughout the body that call for cell growth and division but cancer cells don’t respond to the signals so without any regulations or restraints, the cancer cells keep growing at startling rates. This whole time the cancer cells are growing in the presence of growth inhibitory hormones. (2) (6) Carcinogens- cancer causing agents that cause a mutation to the cell's DNA. Composed of two major groups, chemicals and radiation. Viruses- viruses insert their DNA into genetic material of the infected cells. As a result, the proto-oncogenes of a cell can be comprimised. Replication Mutations- Majority of genetic mutations occur during S phase when DNA is replicated. During replication of DNA, mutations can occur to proto-oncogenes causing them to become ineffective (oncogenes).

**How do cancer cells avoid death?**
Another way that a cancer can form is when a cell that is supposed to die doesn’t die (apoptosis- programmed cell death). Cells are supposed to die if they are either too old or damaged so it makes proteases (enzymes that break down proteins and the peptide bonds in the protein foods to free up the amino acids needed by the body) and other enzymes to break its parts down. Once a cell is broken down into smaller pieces, another cell engulfs the remains. (2)

There are a few ways that cancer cells can avoid apoptosis. The first way is typically used by skin cancer cells which cause melanoma; these cells avoid apoptosis by inhibiting the expression of the gene encoding Apaf-1(Apoptic Peptidease Activating Factor 1). This gene encodes a cytoplasmic protein that initiates apoptosis. (2)

Cancer cells (especially lung and colon cancer cells) avoid apoptosis by secreting elevated levels of a decoy soluble molecule that binds to FasL (Fas Ligand) so that FasL can’t bind to FasR which is it’s intended target and therefore the cytotoxic t cells can’t kill the intended cells. FasL is a transmembrane protein which when it binds to its receptor, FasR, it causes apoptosis. (2)

Another way that cancer cells can avoid apoptosis is by using BCL-2. BCL-2 is a human proto-oncogene located on chromosome 18. B-cells, like all other cells, die after a few days of completing their job using apoptosis. High levels of the BCL-2 protein protects the cell from apoptosis by preventing the activation of the caspases (another name for the protein cutting enzymes that strategically cut the protein into pieces; the executioners of apoptosis) that carry out the process. (2)

**Processing Nutrients**
If cancer cells want to grow, they need nutrients just like regular cells. The cancer cells that make up a tumor attract blood vessels to grow into the tumor mass. The blood vessels nourish the tumor providing it with nutrients, glucose, and oxygen and evacuating the metabolic wastes and carbon dioxide; this process is called angiogenesis.

Why do cancer cells grow uncontrollably?
Normal cells have a limited lifespan as well as a limited number of times they can divide and increase in number. These are both determined by telomeres which are found at the ends of the chromosomes. The telomeres are sequences at the ends of the chromosomes and they prevent end-to-end fusions with other chromosomes, protecting each other’s chromosomal DNA. When normal cells go through their division and growth stages, their telomeric DNA gets shorter and shorter until they can no longer protect the ends of chromosomal DNA. As a result the telomeres start fusing and therefore the chromosomes start fusing in those cells and those cells die. In order to avoid death, cancer cells turn on an enzyme called telomerase which extends the length of the telomeres making them longer and longer and enabling the cancer cells to go through many cycles of growth and division without problems with the telomeres. (2)

Cancers kill people because they invade tissues and disrupt their functions and develop the ability to migrate to different sites in the body. Most of the cancer related deaths are because the cancer cells spread and establish colonies in other parts of the body while invading and metastasizing (spreading). (2)
 * Invading Tissues**

Because the cancer cells no longer look like normal cells or respond to signals that control normal cellular functions, they need to avoid detection from an alert immune system. Scientists have found that cancer cells can evade the immune system by changing their genetic code. As you know, genetic code within each cell is held in the chromatin. Chromatin proteins called histones possess a code of their own which can influence the control of genes. Some cancer cells have the ability to alter this histone code and by doing this, the remove the molecular tags on cells that the immune system relies on to recognize the cancer. Without these tags the cancer cells are invisible to the immune system. (5)
 * How do cancer cells bypass the immune system?**

Genetic Basis of Cancer
-Since cell division is very rapid, the cell undergoes cell division before the cell is fully mature and can fully perform its functions. Thus, if cancerous cells are immature, they do not function properly and reproduce in an uncontrolled manner. These mutations occur after birth, so cancer is not considered a hereditary disease. Cancer is due to the uncontrolled growth of a cell. This occurs because of a mutation in the DNA sequence of the gene. As a result, the cell begins to replicate at an accelerated and uncontrolled rate. This new cell mass is called a neoplasm (tumor). As the tumor grows in size at an uncontrollable rate, it can become detrimental to the area it's affecting. Tumor Suppressing Genes - every cell's DNA contains genes that code for proteins/enzymes that inhibit cell division. These genes often code for proteins/enzymes that repair damaged DNA. When these genes are mutated, the chance for uncontrolled cell division increases as does the chance that other cell-causing mutations will accumulate. Proto-Oncogenes - these are normal genes that promote and regulate the cell cycle by stimulating normal cell growth and division. When these genes mutate, they become Oncogenes. Oncogenes - derived from the greek word for tumor, "onco", an oncogene is a mutated gene that codes for proteins/enzymes that regulate the cell cycle. Since the gene is mutated, it's constantly producing proteins/enzymes that initiate and stimulate unrestrained cytokinesis. These mutated genes cause the cell to ultimately become a cancer cell. (3) ras proto-oncogene and p53 tumor suppressor gene: Both ras and p53 proteins are part of the signal transduction pathways that are fundamental in cell signaling. Mutated in about 30% of cancers, the ras gene works based on a G Protein signal transduction pathway. At the end of this transduction pathway the cellular response entails the creation of a protein that stimulates the cell cycle. What is dangerous about a mutation in the ras gene is that it can increase cell division where even the growth factor is limited. This effectively allows the ras protein to signal without the use of the growth factor. The p53 gene which is mutated in 50% of cancers, acts as a transcription factor for several genes; often titled the "guardian angel of the genome", a normal non-mutated p53 gene is expressed when cellular DNA is damaged. The p53 protein binds DNA which then stimulates another gene to produce a protein called p21 that interacts with a cell division-stimulating protein (Cdk2). When p21 and Cdk2 work together, the cell can’t pass through the next stage of cell division. P53 that has mutated can no longer bind DNA in an effective way and as a consequence the p21 is unable to act as a stop signal for cell division and the formation of tumors occurs. Three different actions result from this detection of defected DNA: cellular repair, cellular destruction, and halt the cell cycle. (1), (8)

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Mutations
Mutations occur when the genetic material of a cell is tampered with. In specific, point mutations are changes to a specific portion of a gene. Point mutations may be transmitted to offspring allowing the trait to be found in successive generations. Point mutations are harmful because they can lead to the generation of a dysfunctional protein/enzyme. They change a gene's protein product into a more resilient/active product. Mutagens are a physical or chemical agent that causes a mutation in the DNA (i.e.- X-rays, UV rays). Mutagens fall into sever categories: Base Analogs - similar to normal DNA bases, but pair incorrectly during replication. Another type can insert themselves within the DNA sequence, thus changing the shape of the DNA helix.

Types of Mutations
Substitutions: Base Pair Substitution - replacement of one nucleotide and its complimentary pair with another complimentary pair. Some of these mutations are referred to as silent mutations because the change doesn't affect the protein's function. On occasion, it can lead to an improved protein, which can enhance the survival of a species in certain situations. Missense Mutation - a mutation in which an altered genetic codon still codes for a specific amino acid, but this amino acid doesn't make sense with the functionality of the protein. Nonsense Mutation - a mutation that causes the production of a stop codon. Insertions/Deletions: Adding/Losing Nucleotide Pairs - this type of mutation is more harmful than substitutions because of the fact that mRNA is coded in a series of three nucleotide bases. The loss or gain of one of these nucleotide bases would cause the entire sequence of triplets to shift over, thus causing a shift in the reading frame. Frameshift Mutation - a mutation where nucleotides inserted or deleted do not come in a multiple of three, thereby altering the reading frame, and producing a protein that is almost always useless. (1)

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Types of Tumors
There are two types of tumors or neoplasms: benign and malignant. Benign neoplasms are a mass of cells whose cellular composition doesn't differ from normal cells in surrounding tissues. Nuclear division of benign neoplasms is similar to the rate of normal cells. The neoplasms are surrounded by connective tissue and the cells don't metastasize. Because the rate of cellular division is just slightly accelerated, the tumor will grow slowly. Malignant neoplasms are neoplasms whose DNA has mutated and therefore differs from that of the surrounding tissue. These neoplasms resemble immature and undifferentiated cells. The growth of these cells is greatly acclerated; as a result, the growth of the neoplasm is uncontrolled and disorderly. The neoplasm then breaks out of the connective tissue capsule and can spread throughout the body. Malignant cells usually contain chromosomes that have been degraded and are joined incorrectly to another strand. As a result, a proto-oncogene may be placed next to a promoter. Malignancies are classified by the type of tissue they originate from: Carcinoma- this is the most common type of tumor. It originates from epithelial tissues and spreads through the body via the lymphatic system. Sarcoma- this type of tumor originates from the muscle and its connective tissues, and spreads through the body via the blood stream. Leukemia- this is the cancer of the bone marrow that results in the production of abnormal blood cells that don't perform their physiological function properly.

Treatment
There is no cure for cancer, however, three treatment options exist for the disease: surgery, radiation, and chemotherapy. Patients with cancer are usually treated with a combination of the three methods in order to attempt to hinder metastasis. Surgery- entails the removal of neoplasm and immediate surrounding tissue. This method is most effective if it is done prior to metastasis. Radiation- an extremely precise process that uses x-rays and radio isotopes to destroy cancer causing cells while simultaneously sparing healthy cells. Chemotherapy- a method that poisons cancer cells with the usage of chemicals.

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Review Questions:
Multiple choice: Identify the choice that best completes the statement or answers the question.

1. Which of following are not beneficial to the cell’s prevention of cancer? a)proto-oncogenes b)oncogenes c)tumor-suppressor genes d)anti-oncogenes e)onco-mutagens

2. What is the most detrimental type of point mutation? a)insertion b)substitution c)deletion d) both a and c e) none of the above

3. The following events portray the acquirement and spread of cancerous cells. Place the events in the order from last to first then choose the answer that indicates that sequence. I. proto-oncogenes and tumor-suppressor genes are compromised II. metastasis III. environnemental cause initiates gene mutation IV. cells grow at an uncontrollable rate V. cells break out of surrounding tissue capsule

a) III, IV, V, I, II b) II, V, IV, I, III c) III, I, IV, V, II d) II, IV, V, I, III e) III, I, V, IV, II

4) Which of the following best describes the role of the enzyme telomerase? a) telomerase is responsible for creating the spindle fibers used in mitosis b) cancer reprograms telomerase to destroy sequences of genetic code c) this enzyme compromises the ras and p53 genes d) cancer reprograms telomerase which allows cells to grow uncontrollably e) telomerase is not a real enzyme and is not responsible for the development of cancer

5) This type of cancer originates from the epithelial tissues and spreads through the body via the lymphatic system. a) Leukemia b) Sarcoma c) Carcinoma d) Glioma e) Melanoma

6) All of the following are ways that cancer cells avoid apoptosis except: a) inhibiting the expression of the gene encoding apoptic-peptidease activating factor 1 b) secreting elevated levels of a decoy soluble molecule that binds to fast ligand c) utilizing BCL-2 to prevent the activation of caspases that initiate programmed cell death d) mutation of the ras gene e) none of the above

Matching: The choices may be used once, more than once, or not at all.

a) ras gene b) p53 gene c) benign neoplasm d) mutagen e) replication mutation ab) malignant neoplasm ac) telomerase ad) metastasis ae) k26 gene

7) A mass of cells whose cellular composition doesn't differ from normal cells in surrounding tissues.

8) Occurs to proto-oncogenes causing them to become ineffective.

9) The globalization of tumors to all parts of the body.

10) Example of a tumor suppressor gene. Essay: Answers must be in essay form. Outline form is not acceptable. Labeled diagrams may be used to supplement discussion, but in no case will a diagram alone suffice. It is important that you read each question completely before you begin to write.

1. Mutations occur when the genetic material of a cell is tampered with. Answer __all__ of the following.

a) Identify and discuss the two different types of mutations and their implications to the human genome. (Be sure to discuss the positives and negatives that can arise from mutation)

b) Choose one of the two types of mutations above and discuss how it would contribute to the development of cancer.

Sources: 1.[|Campbell/ Reece Biology (6th Edition)] A good source for basic information on cancer and mutations

2.[|Cancer Biology] The most comprehensive site about cancer around: has both information and animations that cater to a non- PHD based audience

3.[|Oncogene Diagram] A good diagram about oncogenes

4.[|Telomerase Diagram] A diagram that outlines the differences between telomeres of adult and embryonic stem cells

//5.[|Daily Mail- UK]// A rather recent article that discusses cancer and its implications to the immune system

//6.[|Causes Of Cancer Diagram]// A good diagram and article that outlines both the environmental and genetic causes of cancer

//7.[|Radiation Therapy Diagram]// A diagram depicting radiation therapy, one of the three types of cancer treatments

//8. [|P53 Tumor Suppressor Protien]// A useful article and diagram about the P53 gene

9. [|Cancer Growth Animation] A simple animation regarding the growth and development of cancerous tumors

10. [|HHMI Angiogenesis Video] A narrated animation that discusses and depicts the spread of cancerous cells throughout the body

11.[|Apoptosis Video] An animation that gives an in depth look at the process of apoptosis