Chapter 13

1. Introduction of Cancer Biology  Chapter 13 Cancer—Principles and overview By Robert A. Weinberg Member, Whitehead InstituteProfessor of Biology, MITHis research is in the area of oncogenes and the genetic basis of human cancer. 許勝傑博士 長庚大學生物醫學生物醫學系助理教授 20110609

2. Cancer is a disease of cells that proliferate at inappropriate times and locations in the body.

3. 13.1 Tumors are masses of cells derived from a single cell • Cancers progress from: • a single mutant cell • to a tumor • then to metastasis • Tumors are clonal. • Tumors are classified by cell type.

4. Tumors are classified into four major groups (neoplasms) Carcinomas (epithelial/ lung, pancreas, skin) Sarcomas (fibroblast/ bone, muscle) Leukemias, lymphomas, myelomas (hematopoietic) Neuroblastomas, glioblastomas, neuromas (neuroectodermal)

5. 13.2 Cancer cells have a number of phenotypic characteristics • Unlike normal cells, cancer cells do not stop dividing when they contact a neighboring cell when such cells are propagated in a Petri dish.

6. 13.2 Cancer cells have a number of phenotypic characteristics • Cancer cells have a greatly reduced requirement for growth factors to sustain growth and proliferation. • Unlike normal cells, cancer cells in culture do not require attachment to a physical substrate in order to grow. • The trait of anchorage independence

7. Unlike normal cells in culture, which halt division after a certain number of growth-and-division cycles: • cancer cells are immortal • they do not stop dividing after a predetermined number of generations • Cancer cells often have chromosomal aberrations, including changes in chromosome number and structure.

8. 13.3 Cancer cells arise after DNA damage • Agents that cause cancer may do so by damaging DNA. • Mutations in certain genes cause a cell to grow abnormally. • Ames devised a test to determine the carcinogenicity of chemical agents.

9. Cancers usually arise in somatic cells.

10. 13.4 Cancer cells are created when certain genes are mutated • Oncogenes promote cell growth and division. • Tumor suppressors inhibit cell growth and division. • Cellular genomes harbor multiple proto-oncogenes.

11. 在1911年，Peyton Rous從雞的身上萃取出病毒注射到健康的鳥類後，發現有腫瘤的發生，因此此病毒稱為Rous sarcoma virus。這是第一個成功萃取出引導癌症的反轉錄病毒(cancer-causing retrovirus)。如同所有的反轉錄病毒，Rous sarcoma virus 擁有簡單的基因構造，主要有三個基因(gag, pol and env)譯出病毒所需的蛋白質，除此之外，Rous sarcoma virus擁有第四種基因v-src(for viral sarcoma)，所譯出的蛋白質會導致腫瘤細胞型態的發生。 • Tumor viruses carry oncogenes. The Nobel Prize in Physiology or Medicine 1966

12. HPV E7 peptide binds Rb/ release E2F  cell cycle progression

13. 13.5 Cellular genomes harbor a number ofprotooncogenes • Gain-of-function mutations can activate protooncogenes. • Overexpression of proto-oncogenes can cause tumors. • Translocations can create hybrid proteins that are oncogenic. Genetic alterations can convert proto-oncogenes into potent oncogenes.

14. 13.6 Elimination of tumor suppressor activity requires two mutations • Both copies of a tumor suppressor gene must usually be inactivated to see a phenotype. • Mechanisms that result in loss-of-heterozygosity (LOH) are often responsible for the loss of the remaining normal copy of the tumor suppressor gene. • Cancer susceptibility can be caused by the inheritance of a mutant copy of a tumor suppressor gene.

15. 13.7 The genesis of tumors is a complex process • Cancer is a multistep process that requires four to six different mutations to reach the tumor state. • Tumorigenesis progresses by clonal expansion, where increasingly abnormal clones of cells outgrow their less mutant neighbors.

16. 13.8 Cell growth and proliferation are activated by growth factors • Cell signaling requires extracellular factors, receptors, and other proteins that transmit the signal to the nucleus. • Extracellular signals may be: • growth promoting or • growth inhibiting • Many genes encoding cell signaling molecules are proto-oncogenes and tumor suppressor genes.

17. 13.8 Cell growth and proliferation are activated by growth factors

18. 13.9 Cells are subject to growth inhibition and may exit from the cell cycle • Cells that have differentiated have reached their final specialized form. • Differentiated cells are usually postmitotic. • Thus, differentiation reduces the pool of dividing cells.

19. 13.9 Cells are subject to growth inhibition and may exit from the cell cycle • Cells can commit suicide by apoptosis. • Apoptosis eliminates healthy cells during development and at other times in an organism’s lifetime. • Apoptosis eliminates damaged cells that can pose a threat to the organism. • Mutations that compromise a cell’s ability to carry out apoptosis can result in malignancy.

20. 13.10 Tumor suppressors block inappropriate entry into the cell cycle • Cells decide whether or not to divide at the restriction point. • pRb is a tumor suppressor that can prevent passage through the restriction point.

21. 13.10 Tumor suppressors block inappropriate entry into the cell cycle • pRb can be inactivated by: • mutations • sequestration by oncoproteins • hyperactivity of the Ras pathway

22. 13.11 Mutation of DNA repair and maintenance genes can increase the overall mutation rate • DNA repair proteins keep the spontaneous mutation rate low. • Defects in DNA repair genes increase the basal rate of mutation in the cell. • Mutations in checkpoint proteins compromise chromosome integrity.

23. 13.12 Cancer cells may achieve immortality • Cancer cells avoid senescence by inactivating tumor suppressor genes. • Cancer cells reach a crisis (危機) point at which many of them die off. • Cells that survive the crisis are immortalized.

24. 13.12 Cancer cells may achieve immortality • Telomeres become shorter each generation unless telomerase is activated. • When telomeres become too short to protect the chromosomes, the chromosomes fuse. • This provokes crisis. • Most cancer cells activate telomerase transcription, thereby escaping death.

25. 13.13 Access to vital supplies is provided by angiogenesis • Tumor growth is limited by access to nutrients and waste removal mechanisms. • Tumors can stimulate blood vessel growth (angiogenesis), which enables them to expand.

26. 13.14 Cancer cells may invade new locations in the body • Some cells from a primary tumor can gain entrance to blood and lymphatic vessels (intravasation). • The process of intravasation often requires breaking through barriers of neighboring tissue. • Cells that survive the trip through the blood vessels may colonize other organs. • Metastasis, or colonization of other tissues, usually results in death of the individual.

27. Summary • Cancer • Properties of cancer • Causes of cancer (viral infection, DNA damage and genetic mutations). • Oncogenes and tumor suppressors. • Multi-step and complex Making Cancer History