Review the Concepts

1. Despite differences in origin, cancer cells have several features in common that differentiate them from normal cells. Describe these.

2. What characteristics distinguish benign from malignant tumors?

3. Which important characteristic of tumor cells did Otto Warburg discover?

4. Because of oxygen and nutrient requirements, cells in a tissue must reside within 100 µm of a blood vessel. Based on this information, explain why many malignant tumors often possess gain-of-function mutations in one of the following genes: βFGF, TGF-α, and VEGF.

5. Ninety percent of cancer deaths are caused by metastatic rather than primary tumors. Define metastasis. Explain the rationale for the following new cancer treatments: (a) batimastat, an inhibitor of matrix metalloproteases and of the plasminogen activator receptor, (b) antibodies that block the function of integrins, integral membrane proteins that mediate attachment of cells to the basement membrane and extracellular matrices of various tissues.

6. What is the importance of the EMT during metastasis?

7. What hypothesis explains the observations that incidence of human cancers increases exponentially with age? Give an example of data that confirm the hypothesis.

8. Distinguish between proto-oncogenes and tumor-suppressor genes. To become cancer promoting, do proto-oncogenes and tumor-suppressor genes undergo gain-of-function or loss-of-function mutations? Classify the following genes as proto-oncogenes or tumor-suppressor genes: p53, ras, BCL-2, JUN, MDM2, and p16.

9. Describe how mutations in genome maintenance factors promote tumorigenesis. Why would inactivation of a mis-match repair gene cause colon cancer?

10. Hereditary retinoblastoma generally affects children in both eyes, while spontaneous retinoblastoma usually occurs during adulthood only in one eye. Explain the genetic basis for the epidemiological distinction between these two forms of retinoblastoma. Explain the apparent paradox: loss-of-function mutations in tumor-suppressor genes act recessively, yet hereditary retinoblastoma is inherited as an autosomal dominant.

11. Explain the concept of loss of heterozygosity (LOH). Why do most cancer cells exhibit LOH of one or more genes? How does failure of the spindle assembly checkpoint lead to loss of heterozygosity?

12. Many malignant tumors are characterized by the activation of one or more growth-factor receptors. What is the catalytic activity associated with transmembrane growth-factor receptors such as the EGF receptor? Describe how a point mutation that converts a valine to glutamine within the transmembrane region of the HER2 receptor leads to activation of the relevant growth-factor receptor.

13. Describe the common signal transduction event that is perturbed by cancer-promoting mutations in the genes encoding RAS and NF-1. Why are mutations in RAS more commonly found in cancers than mutations in NF-1?

14. Describe the mutational event that produces the MYC oncogene in Burkitt’s lymphoma. Why does the particular mechanism for generating oncogenic MYC result in a lymphoma rather than another type of cancer? Describe another mechanism for generating oncogenic MYC.

15. Pancreatic cancers often possess loss-of-function mutations in the gene that encodes the Smad4 protein. How does this mutation promote the loss of growth inhibition and highly metastatic phenotype seen in pancreatic tumors?

16. Why are mutations in the INK4 locus so dangerous?

17. Explain how epigenetic changes can contribute to tumorigenesis.

18. Several strains of human papilloma virus (HPV) can cause cervical cancer. These pathogenic strains produce three proteins that contribute to host-cell transformation. What are these three viral proteins? Describe how each interacts with its target host protein.

19. Loss of p53 function occurs in the majority of human tumors. Name two ways in which loss of p53 function contributes to a malignant phenotype. Explain how benzo(a)pyrene can cause loss of p53 function.