1. 1 Dr. Karen Schmeichel January 22, 2009 BIO 290 Special Topics in Biology: Cancer Biology Lecture #4 “Profile of a Cancer Cell”

2. 2 Business Items: Quiz return Cancer Diagnosis & First Journal Entry (due 1/29/09) First Speaker 1/29/09 (WDIC) Prep for Discussion of “Models”

3. 3 Objectives:  Last Comments on Early Terminology  Introduce Hallmarks of Cancer  Investigate Cellular Proliferation -- How to study -- Molecular Basis

4. 4 How Does Cancer Kill?

5. 5 Fig. 1-6 Tenacity of Cancer Types is Measured By 5 yr Survival Rates

6. 6 Conventions in Tumor Nomenclature Malignant Tumor Type: Cellular OriginPrevalence Carcinoma (solid) Epithelial90% Sarcoma (solid) Supporting tissues (bone, cartilage, blood vessels, fat, muscle, fibrous tissue) 1% Lymphoma (solid) & Leukemias (bloodborne) Lymphatic and Blood Origin 9%

7. 7 Conventions in Tumor Nomenclature Prefix Of Cell type Involved + Cancer Type = Clinical Nomenclature Lipo + Sarcoma = Liposarcoma (malignant) Lipo + oma = Lipoma (benign)

8. 8 Complexities at Sites of Origin Organs can be comprised of multiple cell types, each one of which can be site of origin: Ex., Skin *BCC *SCC

9. 9 Hallmarks of Cancer

10. 10 A “Chinese Menu” Analogy

11. 11 Features of Proliferation Profile of a Cancer Cell:

12. 12 Propensity to Grow & Form Tumors: 3 Assays

13. 13 1.Detecting cancer by injecting cells into mice Basu et al.Breast Cancer Research 2005 7:R422

14. 14 2. Growth of Cells in Cultures Normal cells undergo “Density-Dependent Inhibition of Growth”

15. 15 Fig. 2-1 Cancer cells tend to pile up in monolayer cultures

16. 16 Mouse fibroblasts infected with Src Hartley and Rowe 1966 PNAS 55:780 Focus

17. 17 Normal Cell Growth is Regulated by Cell-ECM Anchorage

18. 18 3. Anchorage independent growth is a cancerous feature (Fig 2-3)

19. 19 Soft Agar Assay NormalMalignant

20. 20 Soft Agar Assay: Higher Resolution MCF-7 Cells ± PLC  overexpression Leung et al. 2004. Mol. Cancer 3:15

21. From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings. Fig. 2-2 Anchorage Independence Correlates with Focus Formation

22. 22 Cancer Features to Measure: Propensity to grow & form tumors Form foci in cultures Anchorage-independent growth Telomeres

23. 23 Profile of a Cancer Cell: Normal Cells Tumor Cells Cells divide 50-60 x then degenerate or die Cells divide indefinitely “Immortal”

24. 24 Fig. 2-4 Young Fibroblasts Old Fibroblasts

25. 25 HeLa Cells: HeLa = Henrietta Lacks 1951 Cervical Cancer Tumor cells placed in culture Routine Use to this day A BC

26. 26 Why do cancer cells grow indefinitely in culture? Telomere Restoration

27. 27 5’ 3’ RNA Primers: removed / processed after replication Remember back to DNA Replication…. The Telomere Problem

28. 28 The problem lies with the gap that remains after RNA primer is removed

29. 29 Fig. 2-5 Repeated Cell Division Leads to Telomere Shortening

30. 30 Cancer Cells Are Characterized By High Telomerase Activation + Telomerase

31. 31 We’ve considered how to test for cancerous growth, but what triggers it?

32. 32 Proliferation Requires Mechanisms that enable Cross-Membrane Communication

33. 33 3 Classic Signaling Delivery Mechanisms

34. 34 Paracrine Ligands and the ECM in Development

35. 35 Growth Autonomy: Cancer Cells By Nature Display a Decreased Dependence on External Growth Factors

36. 36 Growth Factor Signaling at the Cell Level Receptor Growth Factor (usually a peptide) Nucleus Cell Growth

37. 37 Examples of Growth Factors FactorSourcePrimary Activity PDGF Platelets, endothelial cells, placenta Promotes proliferation of connective tissue (wound healing), glial and smooth muscle cells EGF Submaxillary gland Brunners gland Promotes proliferation of mesenchymal, glial and epithelial cells TGF-  common in transformed cells May be important for wound healing FGF Wide range of cells protein is associated with the ECM Proliferation of many cells; inhibits some stem cells; induces mesoderm to form in early embryos NGF Neuron’s targetNeurite outgrowth EPO KidneyProlif/diff of RBCs TGF  Activate T0helper and natural killer cells Anti-inflammatory, promotes wound healing IGF-I LiverProlif. Many cells IGF-II Varitey of cellsProlif many cells, usu. fetal

38. 38 Growth Factors are often “over-expressed” in cancers Uncontrolled Cell Growth

39. 39 OR-- Growth Factors Receptors are often “over-expressed” in cancers Uncontrolled Cell Growth

40. 40 Let’s Look Beneath The Membrane!! Other Proteins/Genes Are at Play Too

41. 41 Fig 2-6 In some cancer cells, GFRs can be activated in the absence of GF!

42. 42 Ras participates in GFR signaling relays Ras

43. 43 In cancer cells Ras is mutated such that it is no longer tethered to the membrane: Ras is always on Activated Ras

44. 44 Ties to the Cell Cycle How do Growth Factors and Their Signaling Cascades Stimulate Cell Growth?

45. 45 TUES 1/27: Ch 2: Profile of a Cancer Cell (finish) Cancer Models: Read 3 assigned papers, Review Model Summary and Checklist

46. 46 EGFR Signaling Through Ras From Lodish et al. Molecular Cell Biology

47. 47 EGFR Signaling Through Ras (cont’d) From Lodish et al. Molecular Cell Biology

48. 48 Ras Signaling Ends with a MAP Kinase Cascade From Lodish et al. Molecular Cell Biology

49. 49 Fig. 2-7 The Cell Cycle

50. 50 Fig. 2-8 Cell cycle: Driven By formation CDK-Cyclin complexes

51. 51 Fig. 2-9 Mitotic CDK-Cyclin activation also requires a series phosphorylation/dephosphorylation events

52. 52 Fig. 2-10: How Growth Factors Activate Cell Cycle

53. 53 Fig. 2-11 Control Points in the Cell Cycle

54. 54 Cell Death & Its Regulation Fig 1-19

55. 55 Apoptosis: A Normal Regulated Cellular Suicide Process Used to Clear Unneeded or Defective Cells

56. 56 Cell Death Is a Normal Component of Development

57. 57 Fig 2-13 Early Apoptosis

58. 58 Fig 2-13 Mid-Apoptosis

59. 59 Fig 2-13 Late-Apoptosis

60. 60 Photomicrographs of Apoptosis

61. 61 Fig. 2-13 Apoptosis is triggered by activation of caspase (protease) cascades

62. 62 Why Aren’t Cancer Cells Cleared By Apoptosis? Ex., p53 mutations

63. 63 Take-Home Points: Cancer cells display immortalized growth in culture due to their capacity to regenerate telomeres Cell Cycle is stimulated by a very complex series of signaling events that are normally regulated By the circulation of growth factors in the bloodstream growth factors control entry into the cell cycle by allowing for the transcription and translation of genes that activation CDK/Cyclin complexes Apoptosis is a normal cell death program that is impaired in cancer cells thus preventing their removal and promoting tumor persistence.

64. 64 Take-Home Points: Cancer is characterized by a combination of uncontrolled cell growth, loss of differentiation and acquired capacity for cancer cells to spread A simple nomenclature system is used to describe the origins/severity of tumor Cancer complexity is evident in the number of tissues and cell types involved Cancer tissues display characteristic cellular properties that facilitate grading of tumors by pathologists

65. 65 Hallmarks of Cancer