1. Progression in Neoplastic Development
Folder Title: Progress(NoTP)
Updated: March 08, 2017
Folder Title: Progress
The genetic instability that is characteristic of neoplasia, and the resulting heterogeneity of neoplastic sub-populations within a growing neoplasm, leads to the gradual emergence of increasingly malignant phenotypes. Cancer is characterized by the gradual acquisition of increasingly neoplastic, invasive, and malignant qualities. This gradual acquisition is called Neoplastic "Progression".
See “Multi-step Tumorigenesis, Chapter 11, Biology of Cancer,
2nd Edition, pp

2. In the Second Third of Biology of Cancer: How Do Cancers Get that Way?
What are cancer cells like? (Cell Properties; Immortalization) Chapter 2 (Parts); Chapter 10 , pp
How do cancer cells interact and diverge? (Heterogeneity) Chapter 13: Heterotypic Interactions. pp 577 – 640)
How do cancer develop and change? (Progression) Chapter 11: Multi-step Tumorigenesis. pp
How do cancer cells and cancerous neoplasms grow? Chapter 5: Growth Factors and Receptors, pp
How do cancer cells become invasive and become able to spread? (Invasion and Metastasis) Chapter 14: Moving Out: Invasion and Metastasis, pp
What do we study in order to understand metastatic cancers? (Met Models) Chapter 14

3. Progressive Steps in Neoplastic Cell Development: Hyperplasia and Dysplasia

4. Progressive Steps in Neoplastic Cell Development: Cancer In situ and Invasive Cancer

5. 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

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

7. Effect of Age on Appearance of Carcinomas
(Figure 11.1, p. 400, First Edition) (See Figure 11.1, p. 440, 2nd Ed)
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:
Genetics of the host
Exposure to carcinogens
Diet and Life-Style
Hormonal status
Note decline in incidence rate in the “Super-Old”

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

9. Duration of exposure to carcinogenic agent is driving force in generating mesothelioma from asbestos exposure (Left panel) or skin cancer from solar exposure (Right Panel). Age at first exposure is not relevant.
Figure The Biology of Cancer (© Garland Science 2007) Figure 11.5, p. 444, 2nd Edition

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

11. 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.

12. 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

13. 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

14. Progressive Development of Aneuploidy in Mouse Sarcoma

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

18. 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

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

20. Why does losing something support the progression on cancer?
Loss of heterozygosity (LOH) (Loss of variations) in Chromosomes in Human Colon-rectal Cancer
Why is loss of alleles extra-ordinarily common in chromosomes 5, 6, 8, 17 and 18?
Why does losing something support the progression on cancer?
Figure The Biology of Cancer (© Garland Science 2007)

21. What is being lost during progression in chromosomes 5, 17 and 18?
Loss of Tumor Suppressor Genes (TSG) and Activation on Oncogenes in Progression in Colon Carcinoma
What is being lost during progression in chromosomes 5, 17 and 18?
Loss of “DCC” Gene. Function unknown
Loss of APC Gene
Loss of p53 gene
“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
LOH = Loss of Heterozygosity (Loss of alleles)
p. 409
Figure The Biology of Cancer (© Garland Science 2007)

27. 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) Aberrant intra-cellular signaling and aberrant cell cycle entry
Angiogenesis
Detachment and Invasiveness

32. Phenotypic effects of Lost or Mutated p53 Major Tumor Suppressor Gene
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

33. Two Turning Point Questions No Communicating Among Students
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No Communicating Among Students

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37. Clonal Origins of Leukemia in Human From a single Original Cell:
How can we tell?

38. ALL = Acute Lymphocytic leukemia
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
ALL = Acute Lymphocytic leukemia
T-ALL = T-Cell Acute Lymphocytic Leukemia
MLL = Mixed cell leukemia
NHL = Non-Hodgkins Lymphoma
AML = Acute Myelogenous leukemia
TEL = Telomerase
Figure 11.22b The Biology of Cancer (© Garland Science 2007)

39. Colon Cancers Appear at Different Times in Different Persons Negotiating the same progressive steps.
Why the difference?
Host genetics (e.g. familial APC gene defect)
Cooperation on Oncogenes: Myc and RAS
Diet
Life-style
Exercise
Weight
Vitamin D Intake

40. Introduction of myc or ras oncogenes into rat embryo fibroblasts in cell culture
Insertion of Oncogenes into Cells in Culture
Adenovirus early oncogene
Able to grow in suspension culture.
No foci of transformed cell colonies
Forms tumor cell colonies in cell cultures.
Gives tumors in syngeneic or immuno-suppressed mice
Able to grow in suspension culture.
Some colonies is dilute agar.
(Fig ; page 472, 2nd Edition)
Figure The Biology of Cancer (© Garland Science 2007)

41. Oncogene Collaboration in Mice with inserted (“transgenic”) oncogenes
Insertion of Oncogenes into Embryonic Mice: Tumor Appearance in Vivo
Oncogene Collaboration in Mice with inserted (“transgenic”) oncogenes
T50 = Time in Days to get 50% of the mice to develop mammary carcinomas .
Myc and ras oncogenes cooperate in generating mamarry cancer in vivo
Figure 11.24b The Biology of Cancer (© Garland Science 2007)

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

43. Sequence of steps in colon carcinoma
Codes growth inhibitory tumor suppressor product. (Also called SMAD4)
Code for growth promoting cancer-inducing oncogene products
Adenomatous polyposis coli gene
Figure 11.11a The Biology of Cancer (© Garland Science 2007)

44. Tumor Promoting Agents: Drivers of Cancer Progression

45. 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

46. Three Turning Point Questions No Communicating Among Students
Please clear desktops
No Communicating Among Students

50. Tobacco Use and Cancer Progression

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

52. Public Health Problems, Lag Phases, and Effective Responses
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
1964 Luther Terry, S.G.
1964 – 1996 C. Everett Koop, S.G.
1990 (For Males)
2012
CO2 and Climate Change
Fourier & Arrhenius ?
Uncertain of whether it can be controlled

53. 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

54. → ←
                                                                                                   
→ → ⤡
CapricornOneVintage
Arthur Godfrey Chesterfield’s Ad, April 1953
End of Cancer Progression Presentation

55. 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
“Cancer Cell Phenotypes, in Fifty Shades of Grey”
Science Perspective in Cancer

56. 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
“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.

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

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

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