A Window Into the Cell - AP Biology



Part 3. When Cells Go Wild – the Uncontrolled Nature of Cancer Cells

Having an understanding of the cell cycle, including mitotic cell division, has been one of the main foci of cancer treatment research. Why? Scientist are trying to better understand the mechanisms which tightly regulate the process of cell division in order to pinpoint faulty machinery that results in the development of uncontrolled cell division, cancer. Research has shown that there are two types of mutation that can disrupt cell division and lead to cancer. Proto-oncogenes are genes that code for growth factors which stimulate or jumpstart the cell cycle. Mutations of proto-oncogenes leave the cell cycle turned on. Tumor-suppressors genes code for the proteins that inhibit the cell cycle. Mutations of tumor suppressors turn off genes that allow the slow down of the cell cycle, DNA repair and cell death.

A mutation in a proto-oncogene creates an oncogene. Oncogenes are cancer-causing genes, which overstimulate cell division and allow the cell to override the G1 checkpoint. Many well-known oncogenes lie in the ras gene family. Mutation of the rasK is found in about 25% of lung cancers, 50% of colon cancers, and 90% of pancreatic cancers. Another well-known oncogene is HER2 involved in 20% of breast cancer tumors.

In contrast, a mutation in a tumor-suppressor gene results in failure of the inhibitory proteins to halt cell division. Some tumor-suppressor gene mutations may also inhibit the ability of proteins to detect and repair DNA damaged during cell division. Cell division is then encouraged and future mutations go unchecked. The p53 tumor-suppressor has been implicated in more human cancers than any other gene. Normally, the p53 gene checks the DNA and when damage is detected, makes the decision whether to fix the mistake or, when unable to correct it, commit cellular suicide. When p53 is mutated it allows the cell cycle to continue with DNA unchecked, allowing for the accumulation of numerous future mutations.

When a cell undergoes combinations of these types of mutations, the cell is allowed to grow unchecked creating a large mass of cells termed a tumor. When the tumor remains encapsulated and non-invasive to surrounding organ function it is called a benign tumor. These tumors are referred to as non-cancerous. If cells within the tumor acquired tumor-suppressor mutations that inhibit proteins to check DNA, there is the opportunity for many new mutations to occur. These future mutations increase the virulence of the tumor allowing it to become invasive, unencapsulated, and, at times, able to spread to distant locations within the body. At this point the tumor would be called a malignant tumor. Malignant tumors are cancerous.

Cancer Simulation Game

In the following activity the role of mutation in the development and progression of cancer will be simulated. During the activity each member of the group will take turns rolling four dice. Based on the series of numbers rolled, the individual will accumulate various mutations. Each of these mutations will affect the individual’s final cancer diagnosis. It is important to realize that this simulation uses single mutations to demonstrate tumor formation and development of many cancer characteristics. In reality, changes reflect the interplay of various mutations. Also actual cancer development does not fit a “typical” sequence. Mutation is a random event unique to the individual.

1. Form a group of four or five students. Each member of the group needs to obtain four dice.

2. Each member of the group is to simultaneously roll their individual set of four dice once and record the resulting series of numbers within the first column labeled Number Series Rolled within Table 4. When recording the series of numbers rolled write the numbers in increasing numerical order. This first series of numbers rolled indicates the mutations you were born with. Repeat this step until each member has rolled and recorded the resulting number sequences a total of fifteen times within Table 4.

3. Once all number series have been recorded, use the key found in Table 3 to determine the consequence, if any, of the particular number series rolled. Then in Table 4 place a check within the appropriate box.

4. When finished, examined the check marks made in Table 4. Were check marks made in the last four columns? If the answer is yes, start with the first check mark made in one of the last four columns. Did accumulating both a proto-oncogene and tumor suppressor mutation precede this check mark? If no, continue to ask this question for each of the additional check marks found in the last four columns. If (or when) yes, place a dark underline under this entire row. Disregard any check marks made in the last four columns above this line. This line indicates the moment in which a malignant tumor developed.

5. Fill in the group’s final cancer characteristic information on the Overall Class Cancer Characteristics overhead. When all groups have filled in their data, record the results into Table 5. Observe trends in the cancer characteristics of the entire class.

1. Did you have cancer at birth (after round one)?

2. How many people in your group had cancer at birth (after round one)?

3. How many mutations did you have at birth?

4. How many mutations did the other people in your group have at birth? , , ,

5. Can you have mutations that lead to cancer without getting cancer?

6. If you are born without inherited mutations, can you develop cancer later in life? Why?

7. If you are born with mutations that can lead to cancer, can you pass these mutations to your children? Why or why not?

8. If you accumulate mutations later in life by being exposed to carcinogens, can you pass these mutations to your children? Why or why not?

______

9. What are four ways your body can cope with mutations in order to prevent them from leading to cancer?

10. How do mutations of proto-oncogenes disrupt the normal cell cycle? Which checkpoint is involved?

11. How do mutations of tumor suppressor genes disrupt the normal cell cycle? Which checkpoint(s) are involved?

12. Why can’t you get a malignant tumor until after a proto-oncogene and tumor suppressor gene have mutated?

______

13. Why can’t anigoenesis, contact inhibition, or metastasis occur until after a proto-oncogene and tumor suppressor gene have mutated?

14. How would exposing everyone in the class to cigarette smoke over many years change the total numbers you got in Table 5?

15. What is the average number of rounds it took the people in your group to develop a malignant tumor? How old would the average person be when he gets a malignant tumor if every round represents 5 years of life?

16. How many people in your group could have organ failure from cancer (hint: which vocabulary word in Table 3 leads to organ failure)?

17. Whose cancer in your group would be considered the worst in terms of staging (hint: metastasis, invasion of nearby tissues and larger-sized tumors are characteristic of later-stage cancers. Which columns in Table 4 indicate metastasis, the ability to grow large tumors and invasion of nearby tissue)?

Table 3. Consequence of Series of Numbers Rolled

|Numbers Rolled (in any |Consequence |

|order) | |

|Any combination of numbers |No mutation has occurred. |

|not found below | |

|A pair |A mutation has occurred within a cell’s proto-oncogene. An oncogene has resulted allowing over |

|Ex. 2251 or 3324 |stimulation of the cell’s cell cycle. Potentially, this cell may be destroyed by the immune system or a |

| |benign tumor may form. |

|A Run of Three |A mutation has occurred within one of a cell’s tumor-suppressor genes. The resulting inhibitory protein |

|Ex. 1232 or 2342 |no longer suppresses the cell’s division and allows its DNA to go unchecked. Potentially, this cell may |

| |be destroyed by the immune system or a benign tumor may form. |

|Three of a kind |A mutation has occurred within a single tumor cell. The cell’s gene that is responsible for promoting |

|Ex. 4442 or 5553 |blood vessels formation causes angiogenesis to occur. During this process the cell secretes substances |

| |that encourage blood vessels to form a close network surrounding the developing tumor. The tumor will |

| |now develop access to the nutrients and oxygen needed for significant growth and development. The |

| |development of angiogenesis can lead to the failure of surrounding organs. |

|Run of 4 |A mutation has occurred within a single tumor cell. The cell’s gene, that requires a cell to stop |

|Ex. 1234, or 2345 |dividing when it contacts its neighboring cells, has mutated. The result of this mutation is contact |

| |inhibition. The cells can pile on top one another without restraint to form large tumors. |

|2 Pair |Two mutations have occurred with cells of the tumor: The first mutation has occurred within a gene that |

|Ex. 2233 or 4411 |requires a cell to maintain contact with an underlayer of cells, anchorage dependence. The result of |

| |this mutation is the ability of the cell to dislodge from the original tumor. The second mutation has |

| |occurred within a gene that controls the production of an enzyme called proteinase. The result of this |

| |mutation is the ability of the cell to produce proteinase, which breaks through tissue enabling the cell |

| |to gain access to a blood vessel. The cell is now able to travel and metastisis occurs. |

|Four of a Kind |A mutation has occurred within a single tumor cell gene that controls the production of telomerase. In a|

|Ex. 3333 or 2222 |normal cell there are sequences at the end of DNA strands called telomeres. After each cell division the|

| |length of these sequences is shortened. After approximately fifty divisions the shortened length of the |

| |telomeres signals a cell to stop dividing. The result of this mutation is the ability to produce |

| |telomerase, which maintains the length of telomeres so cells basically become immortal, able to divide |

| |continuously. |

Table 4. Individual Data Record

|Round |Number Series |Types of Mutations |

| |Rolled | |

| |

|2 | | | | |

|1 | | | | |

|2 | | | | |

|3 | | | | |

|4 | | | | |

|5 | | | | |

|6 | | | | |

|TOTAL: | | | | |

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