2. Tumorigenesis and Cancer Development Pin Ling ( 凌 斌 ), Ph.D. ext 5632; lingpin@mail.ncku.edu.tw References: 1.Chapter 23 Cancer in “Molecular Cell Biology” (Lodish et al., 5th edition) 2.Chapter13 Cancer in “Cells” (Benjamin et al., 1 st edition)

3. Outline 1.Overview of Tumorigenesis to Cancer -Progression, Types, & Properties 2.The Genetic Basis of Cancer 3.Metastasis 4. Cancer Stem cells 5. Cancer metabolism

4. Key Concepts about Cancer-I 1. All cancer cells share certain fundamental properties. 2. Various types of cancers have their distinctive traits & behaviors. => Different therapies 3. Cancer cells and normal cells still share a lot of properties. => Difficult to kill cancer cells w/o hurting normal cells 4. The Goal of Cancer therapy => increase targeting specificity.

5. Overview of Tumor formation to Cancer Adapted from “Cells” Cancer is a complex and progressive disease.

6. Cancer incidence is related to age

7. Adapted from “Cells” Phenotypical Properties of Normal and Cancerous Cells

8. Adapted from “Cells”

9. Lung cancer cells in liver

10. Four Major Types of Tumors Classified by the cell type from which neoplasms arise Caricnomas – the most frequent, transformed Epithelial cells lining organ cavities and surfaces; e.g. Lung, Colon, Breast, Prostate, ….etc. Sarcomas – Mesenchymal tissues (Fibroblasts & related cell types); e.g. Bone, Muscle, …etc Hematopoietic Cells & Organs – eg. Leukemias, Lymphomas, Myelomas, … etc Neuroectodermal cells – e.g. neuroblastomas, glioblastomas, melanomas, ….etc

11. Outline 1. Overview of Tumorigenesis to Cancer -Progression, Types, & Properties 2. The Genetic Basis of Cancer - Oncogenes & Tumor Supressor Genes 3. Metastasis 4. Cancer Stem cells 5. Cancer metabolism

12. Key Concepts about Cancer-II 1.Early in the 20 th century => Cancer as the result of viruses. 2.In the mid to late 20 th century concept of cancer => A complex & progressive genetic disease that requires a series of genetic mutations (at least 4-6, most >10). 3.Cellular genomes contain multiple proto-oncogenes & tumor suppressor genes. 4.Genetic mutations on these critical genes lead to dysregulated cell growth & division. 5. Cancers mostly arise from genetic mutations in somatic cells.

13. Acquired Abilities for Cancer Progression: Cancer Hallmarks 2000 vs 2011

14. Chromosome disorder in cancer cells

15. Somatic vs Germline Mutation

16. Tumor Viruses & Oncogenes-History 1.Avian and murine retroviruses (Rous in 1911) and DNA tumor viruses gave the first experimental handle on specific cancer causing genes. 2.Viruses were a way to achieve experimentally reproducible cancers before molecular techniques developed. 3. Isolation of tumorigenic viruses in the laboratory allowed cancer causing genes to be isolated.

17. The Discovery of Tumor-Inducing Viruses (Rous Sarcoma Virus)

18. Retroviruses & Oncogenes-History II 1.Early 1970s RSV=> Retrovirus containing v-Src as an oncogene for tumorigenesis 2.In 1975 scientists found a normal version of v-Src in healthy cells 3.This normal version of v-Src, called c-Src, was defined a proto-oncogene, playing an essential role in cell growth. 4.RSV picked up c-Src => mutation => RSV w/v-Src => tumor-inducing virus

19. The Discovery of Cellular Oncogenes

20. Schematic structures of c-Src vs v-Src

21. The Strategy for Identification of Cellular Oncogenes

22. Identification of Ras Oncogene Chiaho Shih, PhDRobert A. Weinberg, PhD

23. Mien-Chie Hung, PhD Identification of Her2/Neu Oncogene

24. Mechanisms of Oncogene Activation 1.Overexpression 2.Point mutation 3.Translocation

25. Many Cellular Proto-Oncogenes Cell growth & proliferation Proteins

26. Oncogenes vs. Tumor Suppressor Genes 1.Oncogenes promote cell growth & division. 2.Oncogene activation: (1) Overexpression & amplification, (2) Point mutation, (3) Translocation 3.Tumor viruses carry oncogenes. 4.Tumor suppressors inhibits cell growth & division. 5.Both copies of a tumor suppressor gene need to be mutated to see a phenotype.

27. DNA Tumor Viruses & Tumor Suppressor genes-History 1.DNA tumor viruses (SV40, EBV, HPV, …) produce cancer-inducing proteins unrelated to growth- regulating proteins. 2.These viral proteins bind and perturb another set of cellular proteins => Tumor suppressors => Dyregulate cell growth & division. 3.Large T protein (SV40) => Rb & p53 E6 (HPV) => p53 E7 (HPV) => Rb

28. Robert A. Weinberg, PhD Wen-Hwa Lee, PhD Identification of 1st Tumor Suppressor Gene-Rb

29. 1. Two mutations to inactivate tumor suppressor 2. Cancer susceptibility is increased by the inheritance of a mutant copy of tumor suppressor gene. 3. Loss of heterozygosity by mitotic recombination

30. Rb blocks the cell cycle progression

31. Many TSGs keep the Genome Stability

32. Tumor Suppressor Genes in Inherited Cancer Susceptibility Syndromes

33. Acquired Abilities for Cancer Progression: Cancer Hallmarks 2000 vs 2011

34. Telomeres Protect Chromosomes Stability

35. Telomerase Extends Telomeres

36. Telomerase activity is required for immortalizating tumor cells

37. Outline 1. Overview of Tumorigenesis to Cancer -Progression, Types, & Properties 2. The Genetic Basis of Cancer - Oncogenes & Tumor Supressor Genes 3. Angiogenesis & Metastasis 4. Cancer Stem cells 5. Cancer metabolism

38. Key Concepts about Cancer-III 1. Tumor growth is limited by access to nutrients and waste removal. 2. Tumors stimulate blood vessel growth (Angiogenesis), which enables them to expand. 3. Some tumor cells can break neighboring tissues to move into blood and lymphatic vessels (Intravasation). 4. Tumor cells travel and colonize into other tissues (Metastasis). 5. Metastasis often lead to death of the individual.

39. Lymphoangiogenesis & Metastasis 1. VEGFR signaling is the key player. 2. Many primary tumors express VEGFR.

40. Chemokines and Tumor Growth & Metastasis

41. Outline 1. Overview of Tumorigenesis to Cancer -Progression, Types, & Properties 2. The Genetic Basis of Cancer - Oncogenes & Tumor Supressor Genes 3. Angiogenesis & Metastasis 4. Cancer Stem cells 5. Cancer metabolism

42. Key Concepts about Cancer-IV 1.Stem cells and cancer cells share some common properties, e.g. self-renewal, survival,..etc. 2.Tumors often originate from transformation of normal stem cells. 3.Cancer stem cells may exist among cancer cells and possess the unique ability to self-renew and survive. 4. Targeting cancer stem cells is the new strategy for cancer therapy.

43. Signaling Pathways in Stem Cell Development & Transformation

44. Development of Cancer Stem Cells

45. Models of Heterogeneity in Cancer Cells

46. Strategies for Cancer Therapy

47. Outline 1. Overview of Tumorigenesis to Cancer -Progression, Types, & Properties 2. The Genetic Basis of Cancer - Oncogenes & Tumor Supressor Genes 3. Angiogenesis & Metastasis 4. Cancer Stem cells 5. Cancer metabolism

48. Factors affecting cancer metabolism TW Mak et al., Nat Rev Cancer, 2011

49. Metabolisms: Normal vs Cancer cells TW Mak et al., Nat Rev Cancer, 2011

50. PKM2 effect on Glycolysis & the Pentose Phosphate Pathway TW Mak et al., Nat Rev Cancer, 2011

51. Paper Discussion-I (3/20) Papers related to following topics are suggested: 1.Cancer development: (1) Cancer metabolism, (2) Cancer stem cells, (3) Epigenetics in cancer, or (4) MicroRNAs in cancer 2.Inflammation & Cancer: (1) Inflammatory regulation in cancer, (2) TAM (Tumor-associated macrophages) in cancer, or (3) Others 3.Check your papers with me first

52. The End & Thank you

53. Models of Metastasis

54. Six Traits for Malignancy Promoted by Macrophages

55. Tumor Clonal Expansion

56. Oncogene Cooperation in Tumor Formation

57. Signaling Networks in Cancer