DNA and the Cell Cycle › Cell Cycle

Cancer - Mutations & Model of Development

Notes

Cancer - Mutations & Model of Development

Sections

CANCER

  • Cells reproduce in defiance of restraints
  • Cells invade and colonize territories reserved for other cells

Benign tumors

Reproduce without restraint but are noninvasive

Malignant tumors

Reproduce and metastasize

Proto-oncogene

Gene whose protein product stimulates normal cell growth and division

Oncogene

Mutated gene that has hyperactive function that can lead to cancer

Tumor suppressor gene

Gene whose protein product inhibits cell division and whose mutation can lead to cancer if it leads to decreased function

4 TYPES OF CANCER CAUSING MUTATIONS

Proto-oncogene

  1. Gene moves to new location
  • Could lead to excess protein production
  1. Gene is duplicated
  • Could lead to excess protein production
  1. Mutation in gene's control element
  • Could lead to excess protein production
  1. Mutation in gene itself
  • Could lead to hyperactive or degradation resistant protein

MULTISTEP MODEL OF CANCER DEVELOPMENT

  • Cancer is caused by an accumulation of mutations, not just one

Example: colon cancer pathway

  1. Loss of tumor suppressor function (adenomatous polyposis coli gene)
  • Can lead to a polyp (benign growth)
  1. Activation of ras oncogene and
  2. Loss of another tumor suppressor gene
  • Can lead to an adenoma (larger benign growth)
  1. Loss of p53 tumor suppressor and
  2. Addition mutations that allow for invasion and metastasis
  • Can lead to carcinoma (malignant tumor)

Full-Length Text

  • Here we will learn about cancer, a disease of uncontrolled cell growth.
  • First, start a table to denote some key concepts about cancer.
  • Denote that the hallmarks of cancer are that the cells reproduce in defiance of restraints and that they invade and colonize the territories reserved for other cells.
  • Denote that there are two types of tumors:
    • Benign, which reproduce without restraint but are noninvasive, and
    • Malignant, which reproduce and metastasize (spread to secondary sites).

Now, let's include some important definitions:

  • Denote that a proto-oncogene is a gene whose protein product stimulates normal cell growth and division.
  • Denote that an oncogene is mutated so that it has hyperactive function which can lead to cancer.
  • Finally, denote that tumor-suppressor genes inhibit cell division and their mutation leaves them with decreased function which can lead to cancer.

We'll begin by looking into four types of mutations that can lead to cancer.

  • Draw a stretch of DNA.
  • Indicate that a section of this DNA is a proto-oncogene.
  • Indicate an earlier section is a control element (such as the promoter or enhancer) for this gene.
  • Draw the protein product of this gene and indicate the normal amount of this protein is produced.
  • Indicate that the first type of mutation is one in which the gene moves to a new location which is now under the control of a new control element.
  • Draw a stretch of DNA.
  • Redraw the proto-oncogene.
  • Draw a new control element.
  • Draw excess protein underneath the gene to show that if this new control element is more active than the old one, it can lead to increased production of the proto-oncogene protein product.
  • Also write that alternatively if the proto-oncogene fuses to another gene that is more actively transcribed it would lead to the same end-result of increased proto-oncogene protein product.
  • Indicate that the second type of mutation is one in which the gene is duplicated.
  • Draw a stretch of DNA.
  • Draw three copies of the proto-oncogene.
  • Draw excess protein underneath the gene to show that this situation can also lead to increased production of the protein.
  • Indicate that another type of mutation is one in which there is a mutation within the control element.
  • Draw the stretch of DNA.
  • Draw the proto-oncogene.
  • Draw the control element.
  • Draw a mutation within the control element to show that this situation can also lead to increased production of the protein.
  • Finally, indicate that the fourth type of mutation is one in which there is a mutation within the gene itself.
  • Draw the stretch of DNA.
  • Draw the proto-oncogene.
  • Draw the control element.
  • Draw a mutation within the proto-oncogene.
  • Draw the mutated protein product and indicate that this type of mutation can lead to hyperactive or degradation resistant proteins.

Next, we will learn about the Multistep Model of Cancer Development, a well-supported theory on the development of cancer in which cancer is caused by an accumulation of mutations, not just one. To illustrate this, we will look at a possible pathway for colorectal cancer, one of the better understood cancers.

  • Draw the colon.
  • Draw a magnified section of the colon wall.
  • Indicate that these are normal colon epithelial cells.
  • Next, redraw the colon wall.
  • Draw a small polyp forming on the wall.
  • Write that this is a small, benign growth.
  • Write that the first step is often a mutation that results in the loss of a tumor suppressor such as the adenomatous polyposis coli (APC) gene.
    • Mutations in this gene are found at high frequencies in both early-stage and late-stage cancers, indicating it is often an early mutation.
    • The loss of a tumor-suppressor allows a cell to begin to reproduce more than its neighbors.
  • Now, redraw the colon wall.
  • Draw an adenoma, which is larger than a polyp.
  • Write that this is a larger benign growth.
  • Write that step 2 is often the activation of a ras oncogene (such as KRAS), in this case a mutation within the gene creates a hyperactive form of the protein.
  • Write that step 3 could be the loss of another tumor suppressor.
    • These extra mutations will lead to increased cell growth and reproduction.
  • Redraw the colon wall.
  • Draw a carcinoma.
    • It has metastasized throughout the colon wall.
  • Write that this is now a malignant tumor.
  • Write that step 4 is the loss of the p53 tumor suppressor.
    • p53 is a protein that activates several genes which inhibit the cell cycle.
    • It is so important that it has been called the "guardian of the genome."
  • Write that step 5 is additional mutations which allow for invasion and metastasis.

UNIT CITATIONS:

  1. Campbell, N. A. & Reece, J. B. Biology, 7th ed. (Pearson Benjamin Cummings, 2005).
  1. Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K. & Walter, P. Molecular Biology of the Cell, 5th ed. (Garland Science, 2008).
  1. Alberts, B., Bray, D., Hopkin, K., Johnson, A., Lewis, J., Raff, M., Roberts, K. & Walter, P. Essential Cell Biology, 3rd ed. (Garland Science, 2010).
  1. Lodish, H., Berk, A., Kaiser, C. A., Krieger, M., Scott, M. P., Bretscher, A., Ploegh, H. & Matsudaira, P. Molecular Cell Biology, 6th ed. (W. H. Freeman and Company, 2008).
  1. Marieb, E. N. & Hoehn, K. Human Anatomy & Physiology, 10th ed. (Pearson, 2016).
  1. Polinsky, K. R. Tumor Suppressor Genes. (Nova Publishers, 2007).
  1. Coleman, W. B. & Tsongalis, G. J. The Molecular Basis of Human Cancer. (Springer Science & Business Media, 2001).