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Progression in Neoplastic Development
Folder Title: Progress(NoTP)
Updated: March 01, 2015
See “Multi-step Tumorigenesis, Chapter 11, Biology of Cancer, pp 399 - 462
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
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.
Progressive Steps in Neoplastic Cell Development:Cancer In situ and Invasive Cancer
Anaplastic Cells
Figure 11.8a The Biology of Cancer (© Garland Science 2007)p. 407
Progression from Intestinal Adenoma to Invasive Malignant Carcinoma
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
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 hostb.Exposure to carcinogensc.Diet and Life-Styled.Hormonal status
Note decline in incidence rate in the “Super-Old”
Effect of Age on Appearance of Carcinomas(Figure 11.1, p. 400, First Edition)Enlarged version of previous slide
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
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.
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.
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
Properties or Characteristics Affected by Progression in Cancer
Karyotype• Chromosome Numbers• Chromosome Structures (Visible Microscopically, or
Detectible by Molecular Biology)Growth Rate and ImmortalizationTransplantability into Experimental AnimalsMorphology, Histology, CytologyRegulation: • Hormone Dependence and Independence• Response to Growth Control SignalsDifferentiation and Degree of "Dedifferentiation"Invasion and MetastasisDrug Responsiveness
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
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
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?
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 situCIN = Cervical Intra-epithelial neoplasia.DCIS = Ductal carcinoma in situ
UV-Associated Activation of Telomerase in Progression to Skin Cancer. Ueda et al., Cancer Research,57:373(1997).
Telomerase + p53 Mutation Clonal Expansion
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 anomaliesFusion of normal and transformed cellsFailure to repair damaged DNASelective Survival of Aberrant Cells• Evolution toward increased autonomy
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?
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?
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 Genep53 = Major cancer suppressor gene
(See Also Sidebar 11.1, p. 434Relating p53 loss to RAS mutations in the same cancer cell.)
*EMBO J. 1983; 2(12): 2281–2283. PMCID: PMC555446Localisation of the human N-ras oncogene to chromosome 1cen - p21 by in situ hybridisation.M Davis, S Malcolm, A Hall, and C J Marshall
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 apoptosisEscape from need for exogenous mitogens (cell division signaling)AngiogenesisDetachment and Invasiveness
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 apoptosisControls cell cycle entry and cell growthImmortalization
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
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)DietLife-style
ExerciseWeight
Vitamin D Intake
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
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 oncogeneRas = rat sarcoma associated oncogene
Figure 11.24b The Biology of Cancer (© Garland Science 2007)
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
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
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)
caused by
smoking (estimate
d)
non-tobacco related
(estimated)
Global cigarette
consumption
Surgeon General’s Report on Smoking and Cancer: 1964
50Years!
~25Years
Recognition that smoking causes Lung cancer. Post WWII Jump in lung cancer in veteransreceiving cigarette rations during the war
AvoidableDeaths: 1964
to 2014;~50 to 75Million!
On Commercial Interests, Public Health, and Long Lag Phases
45-year lag phase: Start of wide-spread
cigarette use &explosion of lung cancer
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
1900-1945 1945 - 1964 1964Luther Terry,
S.G.
1964 – 1996C. Everett Koop, S.G.
1990(For Males)
2012
CO2 and Climate Change
1765 - 1830 1860 - 2013 1824 -1896Fourier & Arrhenius
? ? Uncertain of whether it
can be controlled
Public Health Problems, Lag Phases, and Effective Responses
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.
Arthur Godfrey Chesterfield’s Ad, April 1953
http://www.flickr.com/photos/capricornonevintage/5590122667/lightbox/
http://www.ratemyprofessors.com/ShowRatings.jsp?tid=396550
Site for Evaluating BIO501 and BIO 447
17 Responses in 10 years 2004 to 2013Approximate number of students in both courses over 10 years:
1,900
2004 to 2011 (Inclusive) 10 ResponsesGood 2Average 2Poor 6
2012 & 2013 7 ResponsesGood 6Average 1
Any constructive comments could be helpful and can be used to improve the courses and to plan for their future.
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