Review The Concepts

1. What characteristics distinguish benign from malignant tumors? With respect to gene mutations, what distinguishes benign colon polyps from malignant colon carcinoma?

2. 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) batima-stat, an inhibitor of matrix metalloproteinases and of the plas-minogen activator receptor, (b) antibodies that block the function of integrins, integral membrane proteins that mediate attachment of cells to the basal laminae and extracellular matrices of various tissues, and (c) bisphosphonate, which inhibits the function of bone-digesting osteoclasts.

3. Because of oxygen and nutrient requirements, cells in a tissue must reside within 100 ^m 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: bFGF, TGFa, and VEGF.

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

5. 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 follow ing genes as proto-oncogenes or tumor-suppressor genes: p53, ras, Bcl-2, telomerase, jun, and p16.

6. 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 epidemiologic 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.

7. 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?

8. 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 the following events lead to activation of the relevant growth factor receptor: (a) expression of the viral protein gp55, (b) translocation that replaces the extracellular domain of the Trk receptor with the N-terminal region of tropomyosin, (c) point mutation that converts a valine to glutamine within the transmembrane region of the Her2 receptor.

9. 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?

10. What is the structural distinction between the proteins encoded by c-src and v-src? How does this difference render v-src oncogenic?

11. 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.

12. 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 of pancreatic tumors?

13. 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 the mechanism by which the following agents cause loss of p53 function: (a) human papillomavirus and (b) benzo(a)pyrene.

14. DNA-repair systems are responsible for maintaining ge-nomic fidelity in normal cells despite the high frequency with which mutational events occur. What type of DNA mutation is generated by (a) UV irradiation and (b) ionizing radiation? Describe the system responsible for repairing each of these types of mutations in mammalian cells. Postulate why a loss of function in one or more DNA-repair systems typifies many cancers.

15. Which human cell types possess telomerase activity? What characteristic of cancer is promoted by expression of telomerase? What concerns does this pose for medical therapies involving stem cells?

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