Teacher Notes for Understanding the Biology of Cancer

Teacher Notes for Understanding the Biology of Cancer Dr. Ingrid Waldron, University of Pennsylvania, 20161

This analysis and discussion activity can be used to introduce students to the biology of cancer or to reinforce and deepen student understanding of the biology of cancer. This activity also provides the opportunity to review some aspects of molecular and cellular biology.

This activity is designed for high school students or for college students in a non-majors biology course. To answer the questions in this activity, students will need to read for understanding and apply what they have learned to explain various aspects of cancer biology. The information in the Student Handout and the recommended web reading is presented at a level appropriate for students who have been introduced to a basic understanding of mitosis, genetics, and transcription and translation.2 If you prefer to introduce your students to cancer biology in another way, you can edit the Student Handout to omit unneeded explanatory material.

Learning Goals Introduction to Biology of Cancer  Cancer develops in a series of stages with increasing abnormalities in the regulation of cell division and other cell characteristics. Some important stages in the development of cancer are:  hyperplasia (an increased accumulation of cells resulting from abnormally high rates of cell division)  in situ tumor or benign tumor (an accumulation of cells that are abnormal and divide excessively, but remain confined within the original tissue)  cancer or malignancy (an accumulation of abnormal cells that divide excessively and have invaded adjacent tissues and can enter blood vessels or lymph vessels and spread to other parts of the body).  The development of cancer is due in large part to mutations in the genes that code for proteins involved in the normal regulation of the rate of cell division. Multiple cancer-causing mutations must accumulate in the same cell line in order to produce an invasive or malignant cancer.  Proto-oncogenes code for proteins that contribute to normal stimulation of cell division. An oncogene is a mutated proto-oncogene that codes for an abnormal protein that stimulates excessive cell division. Thus, oncogenes contribute to the development of cancer.  Tumor suppressor genes include genes that code for proteins that inhibit cell division. Mutated tumor suppressor genes that code for inactive proteins contribute to the development of cancer.  Some mutated cancer-causing genes are inherited, but most cancer-causing mutations occur in a person's body cells during his or her lifetime. The rate of cancer-causing mutations is increased by exposure to carcinogens (including chemical mutagens and radiation, which can damage DNA molecules).  Mutations are rare events and it takes a long time to accumulate multiple cancer-causing mutations in the same cell line. This explains why there is a long lag (typically decades) between initial exposure to a carcinogen and development of a cancer. This also explains why cancer is much more common in older people.  These basic biological processes contribute to the development of all types of cancer. However, different types of cancer have different characteristics, including differences in prognosis and differences in the environmental exposures that increase the risk of developing a

1 These Teacher Notes and the related Student Handout are available at http://serendip.brynmawr.edu/exchange/bioactivities/cancer .

2 The hands-on, minds-on activities available at http://serendip.brynmawr.edu/sci_edu/waldron provide useful introductions to these background topics; these activities are more in-depth than needed as background for this cancer activity. particular type of cancer.

Review of Some Aspects of Molecular and Cellular Biology  Genes code for proteins. A mutated gene codes for a different version of the protein, and this can result in different characteristics.  Cells respond to a chemical messenger when molecules of the chemical messenger bind to protein receptor molecules on or in the cell. This binding activates or inhibits a sequence of molecules inside the cells to produce an effect such as stimulation or inhibition of cell division.  The body is in dynamic equilibrium. For example, cells that are damaged are constantly replaced by cell division. The rate of cell division is regulated by growth factors so that, normally, the rate of production of new cells balances the rate of death of damaged cells (or the rate of production of new cells meets the requirements for growth).

Learning Goals from National Standards In accord with the Next Generation Science Standards3 and A Framework for K-12 Science Education4:  Students will gain understanding of two Disciplinary Core Ideas:  LS3.A: Inheritance of Traits – Each chromosome consists of a single very long DNA molecule, and each gene on the chromosome is a particular segment of that DNA. The instructions for forming species' characteristics are carried in DNA.  LS3.B: Variation of Traits –Although DNA replication is tightly regulated and remarkably accurate, errors do occur and result in mutations, which are also a source of genetic variation. Environmental factors can also cause mutations in genes, and viable mutations are inherited.  Students will engage in Scientific Practices:  Constructing Explanations – Students should be able to:  Construct their own explanations of phenomena using their knowledge of accepted scientific theory and linking it to models and evidence.  Use primary or secondary scientific evidence and models to support or refute an explanatory account of the phenomenon.  Offer causal explanations appropriate to their level of scientific knowledge.  Obtaining, Evaluating and Communicating Information – Students should be able to:  Read scientific… text, including tables, diagrams, and graphs, commensurate with their scientific knowledge and explain the key ideas being communicated.  The Extension Activities proposed at the end of these Teacher Notes engage students in additional scientific practices.  This activity provides the opportunity to discuss the Crosscutting Concept, Stability and change.  This activity helps to prepare students for Performance Expectation HS-LS3-2, Make and defend a claim based on evidence that inheritable genetic variations may result from… mutations.

Biology Background and Instructional Suggestions To maximize student participation and learning, I recommend that you first have your students answer the questions in each section individually or in pairs and then have a whole class discussion after each section. In each discussion, you can probe student thinking and help them develop a

3 Next Generation Science Standards (http://www.nextgenscience.org/) 4 A Framework for K-12 Science Education: Practices, Crosscutting Concepts, and Core Ideas (http://www.nap.edu/catalog.php? record_id=13165 ).

2 sound understanding of the concepts and information covered before moving on to the next group of related questions.

It will be crucial for your students to understand that cell division is the same as cell proliferation. Also, it may be helpful to give your students examples of how the rate of cell division is adjusted to meet body needs. For example, if part of the liver has been damaged, the remaining liver cells have a substantially increased rate of cell division. If a person is injured, platelets (cell fragments that participate in clot formation) release protein growth factors that stimulate neighboring cells to divide to repair the injury.

To help your students understand the molecular and cellular biology of cancer you may want to show them the Cell Cycle Animations, available at http://science-education.nih.gov/supplements/nih1/cancer/activities/activity2_animations.htm

Cancers are tumors that have invaded adjacent tissues and spread to other parts of the body, so it is difficult or impossible to completely remove a cancer by surgery. Chemotherapy and radiation can be used to try to kill remaining cancer cells, and these types of treatments have contributed to improved prognosis for many types of cancer. A cancer can kill a person by interfering with the function of tissues and organs needed for survival. For example, cancer in the lungs can prevent a person from getting enough oxygen. Cancers can also produce substances that cause severe weight loss. Some in situ or benign tumors can also cause serious illness and death; for example, a brain tumor can take up so much room in the skull that it compresses the brain and interferes with brain function. Many scientists prefer to reserve the word cancer for tumors that have become invasive or malignant, but other scientists use the expression "in situ cancer" instead of the more correct "in situ tumor".

Proto-oncogenes code for proteins involved in stimulating cell division needed for growth or to replace cells that have been damaged. Specifically, proto-oncogenes code for growth factors, growth factor receptors, signaling enzymes inside the cell, and transcription factors which stimulate the synthesis of mRNA transcribed from specific genes that code for proteins that stimulate cell division. You may want to discuss with your students the origin of the peculiar name "proto- oncogenes" for genes that code for proteins that play important roles in normal control of cell division. The mutated versions of these genes, called oncogenes (cancer-causing genes) were discovered first; this led to the discovery of the normal versions of these genes, which were then called proto-oncogenes.

Mutations are sometimes characterized as loss-of-function mutations (which code for inactive proteins) or gain-of-function mutations (which code for proteins that are more active than normal). Since oncogenes code for proteins that stimulate excessive cell division, the mutation from a proto- oncogene to an oncogene is considered a gain-of-function mutation. Gain-of-function mutations usually produce dominant alleles. In contrast, if both copies of a tumor suppressor gene have loss- of-function mutations, this can contribute to the development of cancer. For example, an inactive tumor suppressor protein cannot inhibit excessive cell division. If only one copy of a tumor suppressor gene is mutated, the normal allele on the homologous chromosome usually can produce enough normal protein to maintain normal control of cell division. Therefore, a loss-of-function mutation in a tumor suppressor gene is typically recessive. The principle that loss-of-function mutations are usually recessive applies to other types of genes as well.

Because the development of cancer depends on the accumulation of multiple mutations in a single cell line, a mutation that results in an increased mutation rate (e.g. a mutated gene that codes for an 3 inactive DNA repair protein) can contribute to the development of cancer. One very important type of tumor suppressor gene becomes active if the cell's DNA is damaged; this type of tumor suppressor gene codes for a protein transcription factor that activates other genes which code for proteins that stop cell division temporarily (to allow time for DNA repair) or induce the cell to commit suicide (if the DNA damage is severe). If both copies of this tumor suppressor gene are mutated and code for inactive proteins, this allows the accumulation of other mutations which contributes to the development of a cancer.

There is typically a lag of decades between exposure to a carcinogen and the diagnosis of cancer because mutations are rare events and it takes a long time to accumulate multiple cancer-causing mutations in the same cell line. In addition, it takes a long time for a tumor to grow to be big enough to be clinically detected. The same reasons explain why cancer is much more common in older people than in younger people. It takes less time for white blood cell cancers to develop because fewer mutations are needed to develop a malignancy since white blood cells already have the ability to move in the blood and invade other tissues. The development of solid tumors typically requires 5- 15 mutations, but white blood cell cancers can develop with fewer than 5 mutations.

A variety of factors increase the risk of cancer by directly or indirectly increasing the risk of mutations.5 Most carcinogens (cancer-causing agents) are mutagens. (A few carcinogens act by increasing the rate of cell division, either by causing damage and the need to replace cells (e.g. alcohol) or by stimulating growth (e.g. hormonal effects on the breast); each cell division carries a small risk of an error in copying the DNA, so an increased rate of cell division results in increased risk of mutations.) UV light and other types of radiation increase the risk of cancer by damaging DNA and thus causing mutations.6

Different external factors influence different tissues in the body, which explains why different types of cancer have different risk factors. You may want to mention that each of the risk factors listed (in the table on page 3 of the Student Handout) increases the risk for more than one type of cancer. For example, smoking increases the risk of multiple types of cancer of the respiratory system, as well as cancer of the kidney and bladder. Inherited mutations of BRCA1 and BRCA2 account for roughly 5% of breast cancers and roughly 10% of ovarian cancers among white women in the US and also increase the risk of some other types of cancer such as pancreatic cancer and prostate cancer. Scientists do not really understand why BRCA1 and BRCA2 primarily affect the risk of breast and ovarian cancer. You may also want to mention that more than one behavior or characteristic can increase the risk of a particular type of cancer. For example, the risk of breast cancer is influenced by hormonal exposures, including more years of menstrual cycling due to early menarche and/or late menopause.

It should be noted that there are significant differences within each type of cancer listed. This point is illustrated by breast cancer. BRCA mutations contribute to some cases of breast cancer, but not others. Some breast cancers are sensitive to estrogen and others are not. One-fifth of new breast cancer diagnoses in the US are ductal carcinoma in situ, and the five-year survival rate for ductal 5 Environmental factors may also contribute to cancer risk by epigenetic changes (changes in the chemistry of a gene or associated proteins that result in changes in gene expression without causing a mutation, i.e. without changing the nucleotide sequence of the gene). This is just one example of the complexities of cancer biology that have been omitted from this introductory activity.

6 Scientists do not yet understand why people who work outdoors in the sun do not have increased risk of melanoma, but sunburns and high sun exposure during recreation and vacations are associated with increased risk of melanoma. Total sun exposure is associated with increased risk of another type of skin cancer which is less dangerous than melanoma.

4 carcinoma in situ is nearly 100%, whereas some other types of breast cancer have significantly poorer prognosis.

Some cancer-causing mutations can be inherited (e.g. the BRCA genes), but inherited genes only contribute to 10% or fewer of all cancers.7 Inherited genes can have a strong effect on risk, but are relatively rare, so inherited genes generally make a smaller contribution to cancer risk than somatic mutations (mutations in cells that are not in the germ line). Somatic mutations can be due to environmental carcinogens, carcinogens produced within the body (including byproducts of cellular respiration), or mistakes made during DNA replication. Thus, cancer is not usually inherited, even though cancer is always a genetic disease.

There is a substantial random component to whether a mutation occurs in any given cell and whether the multiple mutations needed for the development of cancer accumulate in a given cell line. The importance of this random component is illustrated by the observation that women with breast cancer typically develop cancer in only one of their breasts and not the other. Random variation in the occurrence of somatic mutations is also a major reason why it is common for only one of a pair of identical twins to develop a cancer.

Additional Questions for Reviewing Relevant Cellular and Molecular Biology and Genetics You may want to incorporate some or all of the following questions in the Student Handout or in your discussion to make sure your students remember and understand the relevant basic biology.  Explain why cell division is the same thing as cell proliferation.  What is transcription? What do transcription factors do?  How are monozygotic twins formed in development, and why are they called identical twins? How are dizygotic twins formed in development? How do studies comparing monozygotic and dizygotic twins help us estimate the contributions of genetic factors to phenotypic characteristics such as the occurrence of cancer?

Extension Activities Both of these extension activities are designed to give students experience with the practices of science, as recommended by A Framework for K-12 Science Education: Practices, Crosscutting Concepts, and Core Ideas (available at http://www.nap.edu/catalog.php?record_id=13165 ).

One suggested extension activity engages students in the scientific practice of "Developing and Using Models", including the goals that students should be able to:  "Construct drawings or diagrams as representations of events or systems…"  "Discuss the limitations and precision of a model as the representation of the system, process, or design and suggest ways in which the model might be improved to better fit available evidence… Refine a model in light of empirical evidence or criticism to improve its quality and explanatory power."

Specifically, this extension activity asks students to draw the steps by which a cancer develops. I suggest that you encourage your students to start with figure 3 on the first page of the "Understanding Cancer" Web Reading assigned on page 1 of the Student Handout; they can modify this figure to provide a more complete model of our current understanding of the development of cancer by incorporating concepts such as carcinogens, cell division, mutations, oncogenes, proto- oncogenes, and tumor suppressor genes. In discussing the pros and cons of your students' model

7 Although BRCA1 and BRCA2 mutations make a substantial contribution to inherited risk of breast cancer, most of the inherited risk identified in twin studies is due to other genes. 5 diagrams as representations of reality, you will want your students to evaluate clarity and accuracy and you may also want to include questions such as whether these models can account for important features of the development of cancer, e.g. the long lag between exposure to a carcinogen and the diagnosis of cancer.

Another suggested extension activity engages students in the scientific practices of "Asking Questions" and "Obtaining, Evaluating and Communicating Information", including the goals that students should be able to:  "Distinguish a scientific question… from a nonscientific question…."  "Ask probing questions that seek to identify the premises of an argument, request further elaboration…"  "Read scientific… text, including tables, diagrams, and graphs, commensurate with their scientific knowledge and explain the key ideas being communicated."  "Engage in critical reading of… media reports of science and discuss the validity and reliability of the data, hypotheses and conclusions."

As students ask questions about cancer that are not readily answered based on the information you have available, you can keep a record of these questions. You can also ask students what else they would like to know about cancer. Then students can use web resources and any relevant print material you have to search for answers to these questions. The following websites are informative, reliable and written at an appropriate level for high school students.

"Understanding Cancer", available at http://www.ncbi.nlm.nih.gov/books/NBK20362/ (see especially the "cancer" link), is an excellent resource from the National Cancer Institute

Cancer Help UK, available at http://cancerhelp.cancerresearchuk.org/ , provides clear and reliable information about the biology of cancer, specific types of cancer and cancer treatment.

"Learn about Cancer" by the American Cancer Society, available at http://www.cancer.org/Cancer/index , provides useful basic information about cancer, causes, and many specific types of cancer.

"Cancer" by the Mayo Clinic, available at http://www.mayoclinic.com/health/cancer/DS01076, provides a good overview of the clinical aspects of cancer; this website also provides accurate and informative clinical information about multiple specific types of cancer.