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Tumorigenesis and Cancer Development

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). Outline.

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Tumorigenesis and Cancer Development

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  1. 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., 1st edition)

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

  3. 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.

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

  5. Cancer incidence is related to age

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

  7. Adapted from “Cells”

  8. Lung cancer cells in liver

  9. 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

  10. 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

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

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

  13. Chromosome disorder in cancer cells

  14. Somatic vs Germline Mutation

  15. Tumor Viruses & Oncogenes-History • Avian and murine retroviruses (Rous in 1911) and DNA tumor viruses gave the first experimental handle on specific cancer causing genes. • 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.

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

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

  18. The Discovery of Cellular Oncogenes

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

  20. The Strategy for Identification of Cellular Oncogenes

  21. Identification of Ras Oncogene Chiaho Shih, PhD Robert A. Weinberg, PhD

  22. Identification of Her2/Neu Oncogene Robert A. Weinberg, PhD Mien-Chie Hung, PhD

  23. Mechanisms of Oncogene Activation • Overexpression • Point mutation • Translocation

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

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

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

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

  28. 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

  29. Rb blocks the cell cycle progression

  30. Many TSGs keep the Genome Stability

  31. Tumor Suppressor Genes in Inherited Cancer Susceptibility Syndromes

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

  33. Telomeres Protect Chromosomes Stability

  34. Telomerase Extends Telomeres

  35. Telomerase activity is required for immortalizating tumor cells

  36. 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

  37. 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.

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

  39. Chemokines and Tumor Growth & Metastasis

  40. 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

  41. Key Concepts about Cancer-IV • Stem cells and cancer cells share some common properties, e.g. self-renewal, survival, ..etc. • Tumors often originate from transformation of normal stem cells. • 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.

  42. Signaling Pathways in Stem Cell Development & Transformation

  43. Development of Cancer Stem Cells

  44. Models of Heterogeneity in Cancer Cells

  45. Strategies for Cancer Therapy

  46. 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

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

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

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

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

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