Progression in Neoplastic Development

Folder Title: Progress

Updated: March 02, 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

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

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

Figure 11.8a The Biology of Cancer (© Garland Science 2007)p. 407

Progression from Intestinal Adenoma to Invasive Malignant Carcinoma

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

Progressive Development of Aneuploidy in Mouse Sarcoma

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

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

CIN = Cervical Intra-epithelial neoplasia.DCIS = Ductal carcinoma in situ

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 cellsImmortalization and gradual accrual of additional

genetic anomaliesFusion of normal and transformed cellsFailure to repair damaged DNASelective Survival of Aberrant Cells• Evolution toward increased autonomy

UV-Associated Activation of Telomerase in Progression to Skin Cancer. Ueda et al., Cancer Research,57:373(1997).

Telomerase + p53 Mutation Clonal Expansion

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?

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

Code for growth promoting cancer-inducing oncogene products

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

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

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

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

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)

Three Turning Point Questions

Please clear desktops

No Communicating Among Students

One step in cancer Progression showed the acquisition of Telomerase (Tel +). What pathological property would acquisition of telomerase activity confer on

the cancer cell?

Use one word or a very concise two or three words.

In Colon Carcinoma Progression we saw the sequential collaboration of a number of genes including DCC and RAS.

Which gene anomaly is a suppressor gene leading to colo-rectal cancer ?

Why did you choose that one?

In Colon Carcinoma Progression we saw the sequential collaboration of a number of genes including DCC and RAS.

Which gene anomaly is an oncogene leading to colo-rectal cancer ?

Why did you choose that one?

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.

When you see “CIS” or “DCIS” the “C” means carcinoma, and the “DC” means ductal carcinoma, but what does the “IS” mean?

You can either give the words that “IS” abbreviates or you can say what the “IS” tells you about the carcinoma.