1. Progression in Neoplastic Development Folder Title: Progress(NoTP) Updated: March 01, 2015 See “Multi-step Tumorigenesis, Chapter 11, Biology of Cancer, pp 399 - 462

2. What If Different Cancer Cells within the Cancer in a single patient respond differently from one another? Handout: Science, February 1, 2013; Volume 339, pages 528-529 “Cancer Cell Phenotypes, in Fifty Shades of Grey” Science Perspective in Cancer

3. What If Different Cancer Cells within the Cancer in a single patient respond differently from one another? Handout: Science, February 1, 2013; Volume 339, pages 528-529 “Cancer Cell Phenotypes, in Fifty Shades of Grey” Science Perspective in Cancer Distinct Clonal Populations within a single tumor respond to signals and to chemotherapy differently from one another leading to differential clonal evolution and clonal survival. These differences are not based solely on genetic heterogeneity. Epigenetic differences and tumor micro-environment affect clonal heterogeneity. Other unknown factors may support heterogeneity. See accompanying research article conclusions, pp 543 to 548.

4. Progressive Steps in Neoplastic Cell Development: Hyperplasia and Dysplasia Anaplasia

5. Progressive Steps in Neoplastic Cell Development: Cancer In situ and Invasive Cancer Anaplastic Cells

6. Figure 11.8a The Biology of Cancer (© Garland Science 2007) p. 407 Progression from Intestinal Adenoma to Invasive Malignant Carcinoma

7. Definitions and Concepts of Progression in Neoplasia Transitions in Cancer Development: Hyperplasia Dysplasia Anaplasia Pre-neoplastic nodules Carcinoma (or other histogenetic type) in situ Malignant neoplasia Gradual Acquisition of Fully Neoplastic Character "Acquisition of permanent, irreversible, qualitiative changes in one or more characteristics of a neoplasm“ = Progression ProgDef

8. Effect of Age on Appearance of Carcinomas (Figure 11.1, p. 400, First Edition) A series of successive steps must be achieved before a cancer can appear. Each of these steps may take 10 or 15 years to complete. The rate of completing these steps can be accelerated by: a.Genetics of the host b.Exposure to carcinogens c.Diet and Life-Style d.Hormonal status Note decline in incidence rate in the “Super-Old”

9. Effect of Age on Appearance of Carcinomas (Figure 11.1, p. 400, First Edition) Enlarged version of previous slide

10. Figure 11.3 The Biology of Cancer (© Garland Science 2007) Slope of 5 in Log Death Rate vs Linear Age in Years in Carcinomas: ~ Five steps needed to generate full-blown carcinoma

11. Figure 11.4 The Biology of Cancer (© Garland Science 2007) Duration of exposure to carcinogenic agent is driving force in generating mesothelioma from asbestos exposure. Age at first exposure is not relevant.

12. Patterns of Progression in Neoplasia Permanent, irreversible changes; independent of other tumor cells in the developing neoplasm Different characteristics within the tumor progress separately and independently Pathways and sequences of steps vary in unpredictable and divergent ways Progression need not be associated with tumor growth Progression converges toward similar end-product neoplastic cells, but by diverse routes.

13. Implications and Consequences of Progression in Cancer For the biology of carcinogenesis As an underlying cause for long latent periods For screening human populations for cancers For defining the "Biology of a Cancer" For cancer diagnosis For cancer treatment

14. Properties or Characteristics Affected by Progression in Cancer Karyotype Chromosome Numbers Chromosome Structures (Visible Microscopically, or Detectible by Molecular Biology) Growth Rate and Immortalization Transplantability into Experimental Animals Morphology, Histology, Cytology Regulation: Hormone Dependence and Independence Response to Growth Control Signals Differentiation and Degree of "Dedifferentiation" Invasion and Metastasis Drug Responsiveness

15. Progressive Development of Aneuploidy in Mouse Sarcoma

16. Figure 1.11b The Biology of Cancer (© Garland Science 2007) Fluorescent in situ hybridization (FISH) of normal metaphase human chromosomes using chromosome specific DNA probes with different fluorescent dyes Normal Karyotype

17. Figure 1.11c The Biology of Cancer (© Garland Science 2007) Aneuploid karyotype of human breast cancer cell. Note “scrambling” of colors demonstrating chromosomal reciprocal translocations Aneuploidy During Tumor Progression

18. Turning Point Questions Please clear desktop No communication verbal or electronic

19. What is Happening During Those Years When Changes are Accumulating? Why does the frank neoplasia outgrowth take so long? Can we slow down the rate of progression to forestall the disease or stop it altogether?

20. Figure 11.7 The Biology of Cancer (© Garland Science 2007) p. 406 Representative Times to Full Neoplastic Progression for Cancers of Various Histogenetic Sites of Origin CIS = carcinoma in situ CIN = Cervical Intra-epithelial neoplasia. DCIS = Ductal carcinoma in situ

21. UV-Associated Activation of Telomerase in Progression to Skin Cancer. Ueda et al., Cancer Research,57:373(1997). Telomerase + p53 Mutation Clonal Expansion

22. Basis or Source of Progression Patterns Acquired, Self-perpetuating genetic lability Cytological anaplasia at the chromosome level. Genetic instability inherent in the original cell lineage that became transformed. Genetic instability induced in the transformed cells. Immortalization and gradual accrual of additional genetic anomalies Fusion of normal and transformed cells Failure to repair damaged DNA Selective Survival of Aberrant Cells Evolution toward increased autonomy

23. Figure 7.14 The Biology of Cancer (© Garland Science 2007) Loss of heterozygosity (LOH) in Chromosomes in Human Colon-rectal Cancer Why is loss of heterozygosity extra-ordinarily common in chromosomes 17 and 18? Why does losing something lead to cancer? How can losing cancer genes lead to increased cancer?

24. Figure 11.9 The Biology of Cancer (© Garland Science 2007) p. 409 Loss of Heterozygosity (LOH) and Oncogene activation in Progression in Colon Carcinoma What is being lost during progression in chromosomes 17 and 18?

25. Figure 11.10 The Biology of Cancer (© Garland Science 2007) p. 409 Loss of Tumor Suppressor Genes (TSG) in Progression in Colon Carcinoma “DCC” Gene = Deleted in Colon Carcinoma. Identity not known. “APC” = Adenomatous polyposis coli gene (Cancer suppressor gene) “K-ras” = Oncogene activated, transduced, or mutated, first identified in virally-induced rat sarcoma. (On chromosome 1*) TSG = Tumor Suppressor Gene p53 = Major cancer suppressor gene (See Also Sidebar 11.1, p. 434 Relating p53 loss to RAS mutations in the same cancer cell.) *EMBO J. 1983; 2(12): 2281–2283. PMCID: PMC555446 Localisation of the human N-ras oncogene to chromosome 1cen - p21 by in situ hybridisation. M DavisM Davis, S Malcolm, A Hall, and C J MarshallS MalcolmA HallC J Marshall

26. Phenotypic effects of activated or mutated RAS Oncogene: See Oncogenes Later and Also Legend to Figure 11.43, p. 459 Widely acting oncogene: Acts immediately below the cell membrane in transducing growth factor signaling from outside the cell and transmitting it to the nucleus. Effects of RAS: Susceptibility to apoptosis Escape from need for exogenous mitogens (cell division signaling) Angiogenesis Detachment and Invasiveness

27. Phenotypic effects of Lost or Mutated p53 See Oncogenes and Suppressor Genes Later and Also Legend to Figure 11.43, p. 459 Major Tumor Suppressor Gene Effects of p53: Susceptibility to apoptosis Controls cell cycle entry and cell growth Immortalization

28. Figure 11.11a The Biology of Cancer (© Garland Science 2007) Sequence of steps in colon carcinoma Adenomatous polyposis coli gene Codes growth inhibitory tumor suppressor product on Chromosome 18. Loss of inhibitor promotes cancer growth Oncogenes: Turn on cancers Suppressor Gene

29. Colon Cancers Appear at Different Times in Different Persons Negotiating the same progressive steps. Why the difference? Host genetics (e.p. familial APC gene defect) Diet Life-style Exercise Weight Vitamin D Intake

30. Figure 11.22b The Biology of Cancer (© Garland Science 2007) Appearance of identical leukemia clones in monozygotic twins: Initial transformed cell lineage generated in utero in one twin and transferred to the other via shared placenta before birth

31. Figure 11.23 The Biology of Cancer (© Garland Science 2007) Introduction of myc or ras oncogenes into rat embryo fibroblasts in cell culture: Oncogene Cooperation Able to grow in suspension culture. No foci of transformed cell colonies Able to grow in suspension culture. Some colonies is dilute agar. Forms tumor cell colonies in cell cultures. Gives tumors in syngeneic or immuno- suppressed mice Myc = myelocytomatosis virus introduced oncogene Ras = rat sarcoma associated oncogene

32. Figure 11.24b The Biology of Cancer (© Garland Science 2007) Oncogene Collaboration in Mice with inserted (“transgenic”) oncogenes T 50 = Time in Days to get 50% of the mice to develop mammary carcinomas. Myc and ras oncogenes cooperate in generating mamarry cancer in vivo

33. Tumor Promoting Agents: Drivers of Cancer Progression

34. Effects of Progression on Treatment Selection and progression to increased autonomy and "dedifferentiation " Poorly differentiated cells may becme increasingly difficult to affect with treatment Poorly differentiated cells may become increasingly aggressive Emergence of Drug-Resistance Selection of pre-exisiting variants with ability to survive treatment Generation of variants by treatment Emergence of immune unresponsiveness

35. Figure 11.43 The Biology of Cancer (© Garland Science 2007) p. 459 hTert = Telomerase catalytic subunit Cancer Cell Genotypes and Phenotypic Expression (For a “Generic” Cancer)

36. caused by smoking (estimate d) non- tobacco related (estimated) Global cigarette consumption Surgeon General’s Report on Smoking and Cancer: 1964 50 Years! ~25 Years Recognition that smoking causes Lung cancer. Post WWII Jump in lung cancer in veterans receiving cigarette rations during the war Avoidable Deaths: 1964 to 2014; ~50 to 75 Million! On Commercial Interests, Public Health, and Long Lag Phases 45-year lag phase: Start of wide-spread cigarette use & explosion of lung cancer

37. Initiation of Dangerous Behavior Appearance of the Problem Recognition of the Problem and Its Causes Public Acceptance of that Recognition and Program for Responding Control of the Causative Agent: No Further Increase in Cause of the Problem Control of the Problem: Leveling off of the Increase in Damage Lung Cancer and Cigarettes 1900-19451945 - 19641964 Luther Terry, S.G. 1964 – 1996 C. Everett Koop, S.G. 1990 (For Males) 2012 CO2 and Climate Change 1765 - 18301860 - 20131824 -1896 Fourier & Arrhenius ??Uncertain of whether it can be controlled Public Health Problems, Lag Phases, and Effective Responses

38. On the Influence of Carbonic Acid in the Air upon the Temperature of the Ground Svante Arrhenius Philosophical Magazine and Journal of Science Series 5, Volume 41, April 1896, pages 237-276.

39. Arthur Godfrey Chesterfield’s Ad, April 1953 http://www.flickr.com/photos/capricornonevintage/5590122667/lightbox/

40. http://www.ratemyprofessors.com/ShowRatings.jsp?tid=396550 Site for Evaluating BIO501 and BIO 447 17 Responses in 10 years 2004 to 2013 Approximate number of students in both courses over 10 years: 1,900 2004 to 2011 (Inclusive) 10 Responses Good 2 Average 2 Poor 6 2012 & 20137 Responses Good 6 Average 1 Any constructive comments could be helpful and can be used to improve the courses and to plan for their future.