Transcript Progress(NoTP).

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:
Hyperplasia and Dysplasia
Anaplasia
Progressive Steps in Neoplastic Cell Development:
Cancer In situ and Invasive Cancer
Anaplastic Cells
Progression from Intestinal Adenoma to Invasive Malignant Carcinoma
Figure 11.8a The Biology of Cancer (© Garland Science 2007)
p. 407
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)
Note decline
in incidence
rate in the
“Super-Old”
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
Effect of Age on Appearance of Carcinomas
(Figure 11.1, p. 400, First Edition)
Enlarged version of previous slide
Slope of 5 in Log Death Rate vs Linear Age in Years in Carcinomas:
~ Five steps needed to generate full-blown carcinoma
Figure 11.3 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.
Figure 11.4 The Biology of Cancer (© Garland Science 2007)
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 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
Progressive Development of Aneuploidy
in Mouse Sarcoma
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)
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)
Turning Point Questions
Please clear desktop
No communication
verbal or electronic
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?
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
Figure 11.7 The Biology of Cancer (© Garland Science 2007)
p. 406
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 anomalies
Fusion of normal and transformed cells
Failure to repair damaged DNA
Selective Survival of Aberrant Cells
• Evolution toward increased autonomy
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 7.14 The Biology of Cancer (© Garland Science 2007)
Loss of Heterozygosity (LOH) and Oncogene activation in
Progression in Colon Carcinoma
What is being lost during progression in chromosomes 17 and 18?
p. 409
Figure 11.9 The Biology of Cancer (© Garland Science 2007)
Loss of Tumor Suppressor Genes (TSG) in Progression in Colon Carcinoma
(See Also Sidebar 11.1, p. 434
Relating p53 loss to RAS mutations in
the same cancer cell.)
“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*)
*EMBO J. 1983; 2(12): 2281–2283.
TSG = Tumor Suppressor Gene
PMCID: PMC555446
Localisation of the human N-ras
p53 = Major cancer suppressor gene
oncogene to chromosome 1cen - p21 by
p. 409
Figure 11.10 The Biology of Cancer (© Garland Science 2007)
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 apoptosis
Escape from need for exogenous mitogens (cell division signaling)
Angiogenesis
Detachment 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 apoptosis
Controls cell cycle entry and cell growth
Immortalization
Sequence of steps in colon carcinoma
Oncogenes:
Turn on cancers
Suppressor
Gene
Adenomatous
polyposis
coli gene
Figure 11.11a The Biology of Cancer (© Garland Science 2007)
Codes growth inhibitory tumor
suppressor product on
Chromosome 18.
Loss of inhibitor promotes cancer
growth
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
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 11.22b The Biology of Cancer (© Garland Science 2007)
Introduction of myc or ras oncogenes into rat embryo
fibroblasts in cell culture: Oncogene Cooperation
Myc = myelocytomatosis virus introduced oncogene
Ras = rat sarcoma associated 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 immunosuppressed mice
Figure 11.23 The Biology of Cancer (© Garland Science 2007)
Able to grow in
suspension culture.
Some colonies is
dilute agar.
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)
Tumor Promoting
Agents:
Drivers of Cancer
Progression
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
Cancer Cell Genotypes and Phenotypic Expression
(For a “Generic” Cancer)
Figure 11.43 The Biology of Cancer (© Garland Science 2007)
hTert = Telomerase catalytic subunit
p. 459
On Commercial Interests, Public Health, and Long Lag Phases
Surgeon General’s Report
on Smoking and Cancer: 1964
~25
50
Years
Years!
Global cigarette
consumption
caused by
smoking
(estimated)
Avoidable
Deaths: 1964
to 2014;
~50 to 75
Million!
non-tobacco
related
(estimated)
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
Public Health Problems, Lag Phases, and Effective Responses
Initiation of
Dangerous
Behavior
Appearance
of the
Problem
Recognition
of the
Problem and
Its Causes
Lung
Cancer
and
Cigarettes
1900-1945
1945 - 1964
1964
Luther Terry,
S.G.
CO2 and
Climate
Change
1765 - 1830
1860 - 2013
1824 -1896
Fourier &
Arrhenius
Public
Control of
Control of
Acceptance of
the
the
that
Causative
Problem:
Recognition
Agent: No
Leveling off
and Program
Further
of the
for
Increase in
Increase in
Responding
Damage
Cause of the
Problem
2012
1964 – 1996
1990
(For Males)
C. Everett
Koop, S.G.
?
?
Uncertain of
whether it
can be
controlled
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
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17 Responses in 10 years 2004 to 2013
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Average 1
7 Responses
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