17 Cell Cycle, Mitosis, And Cancer Pt 2

8/13/2019 17 Cell Cycle, Mitosis, And Cancer Pt 2

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Chapter 12, 19.6

The Cell Cycle,

Mitosis, and Cancer,part 2



How cells regulate their own division

Cell Cycle Control



Cell Cycle Control

Mitotic cell division is necessary…

Growth

Repair/Replacement

… but cell division must be carefully regulated

A loss of cell cycle control leads to the development of a

tumor (abnormal mass of cells)

Length of cell cycle varies significantly among

different cell types or with changing conditions

Intestinal cells – 2x per day

Nerve cells – nondividing; arrest in G0

www.cbp.pitt.edu/faculty/yong_wan/index.html

http://www.cbp.pitt.edu/faculty/yong_wan/index.html

http://www.cbp.pitt.edu/faculty/yong_wan/index.html



Cell Cycle ControlDiscovery of Mitosis Promoting Factor (MPF)



Cell Cycle ControlDiscovery of Mitosis Promoting Factor (MPF)

Mitosis Promoting Factor (MPF) – “start mitosis” signal

Dimer composed of:

Cyclin – protein whose concentration fluctuates throughoutthe cell cycle – builds during interphase; peaks during M

phase

Cyclin-dependent Kinase (Cdk) – catalyzes transfer of

phosphate group from ATP to target proteins(Phosphorylation triggers mitosis); active when bound to

cyclin



Cell Cycle ControlCyclin Concentration Regulates MPF Concentration



Cell Cycle

Control:Checkpoints



Damaged DNA Leads to Apoptosis

Apoptosis – programmed cell death

Plays role in:

shaping organisms

preventing tumor development

limiting spread of viruses



Cell Cycle Control: Checkpoints

What happens

when

checkpoints are

not functioning properly?



Cancer: The Loss of Cell Cycle Control

Cancer - growth disorder of cells

family of diseases characterized by uncontrolled

cell division

cancer cells do not respond normally to the cell

cycle control

cells divide excessively – develop tumors



Cancer



10 Leading Causes of Death as a Percentage of All Deaths

United States - 1900



10 Leading Causes of Death as a Percentage of All Deaths

United States - 2010

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm#fig1



2008 Estimated US Cancer Deaths

ONS=Other nervous system.

Source: American Cancer Society, 2008.

Men

294,120

Women

271,53026% Lung & bronchus

15% Breast

9% Colon & rectum

6% Pancreas

6% Ovary

3% Non-Hodgkinlymphoma

3% Leukemia

3% Uterine corpus

2% Liver & intrahepaticbile duct

2% Brain/ONS

25% All other sites

Lung & bronchus 31%

Prostate 10%

Colon & rectum 8%

Pancreas 6%

Liver & intrahepatic 4%bile duct

Leukemia 4%

Esophagus 4%

Urinary bladder 3%

Non-Hodgkin 3%lymphoma

Kidney & renal pelvis 3%

All other sites 24%

1 in 3 Americans

will be affected by

cancer in their

lifetime



Characteristics of Cancer Cells

Lack differentiation – not specialized, do not contribute

to functioning of tissue

Immortal – no limit on number of divisions

Abnormal nuclei – enlarged; abnormal number of

chromosomes

Do not undergo apoptosis – damaged cells do not

undergo programmed cell death



Characteristics of Cancer Cells

Form tumors – do not exhibit

contact inhibition

Undergo metastasis – travel to

new locations in the body

Undergo angiogenesis – growth

of blood vessels



Tumors

Tumor – abnormal mass of cells

Benign Tumor - abnormal mass of cells, remainsat original site in body, not invasive

Malignant Tumor - abnormal mass of cells,

capable of detaching from original tumor and

spreading into distant tissues (metastasis),

invasive; CANCER



Review:

Cancer: The Loss of Cell Cycle Control

Cancer - growth disorder of cells

family of diseases characterized by uncontrolled

cell division

cancer cells do not respond normally to the cell

cycle control

cells divide excessively – develop tumors



What Causes Loss of Cell Cycle

Control?

DNA mutations in genes carrying instructions for

the synthesis of proteins that control the cell cycle

Proto-oncogenes – provide “go ahead” signals; gain-of-function mutations (become overactive)

Example: Growth factors, receptors, signaling molecules

Tumor Supressors – provide “stop” signals; loss-of-

function mutations

* DNA mutations – change in genetic information



Proto-oncogenes Oncogenes

Proto-oncogene – normal gene with potential tobecome an oncogene; normal functions of a proto-oncogene products include:

Growth factors (“go ahead”) – “social control”

Growth factor receptors

Intracellular signaling molecules

Transcription factors (initiate protein production)

Oncogene –

gene thatcauses cancer (mutated

proto-oncogene;

overactive)



Receptor

DNA

Regulated Cell

Prol i ferat ion

Cell nucleus

Transcriptionfactors

Signalingenzymes

Growth factor(Ex. Hormone)

Proto-Oncogenes and Normal Cell

Growth



Proto-oncogenes Oncogenes

Gain ofFunction

Mutations

Overactive proto-oncogene ONCOGENE



Receptor

DNA

TOO MUCH

Cell

Cell nucleus


Signalingenzymes

Too ManyGrowth factors

“Go ahead, go

ahead…”

Oncogenes and Tumor Growth: Example

TUMOR



Tumor Suppressor Genes

Tumor suppressor

genes – geneswhose products

(proteins) inhibit

cell division

Tumor Suppressor GeneProteins

DNA

Signalingenzymes

Growth factor

Receptor


Regulated CellProliferation



Mutation of Tumor Suppressor Genes

Loss of

FunctionMutation



Tumor Suppressor Genes


DNA

Signalingenzymes

Growth factor

Receptor



TOO MUCH

Cell TUMOR



p53

p53 – tumor suppressor that is mutated in more

than 55% of human cancers

Survival of cells with damaged DNA



Rb Protein

Rb – tumor suppressor protein, interprets growth signals

and nutrient availability – what happens if mutated?



What Causes DNA Mutations?

Cancer (unregulated cell division) is caused by

mutations in genes carrying instructions for the

synthesis of cell cycle control system proteins

What causes these mutations?

Genetics (inheritance)

Mutagens

Viruses

Lifestyle



Can Cancer be Inherited?

Most mutations that lead to cancer arise in the

organ where the cancer starts (ex. lung, colon)

These mutations do not affect germ cells (cells that

generate gametes) – therefore not passed to offspring

Some mutations do occur in germ cells and are

passed from generation to generation

Single mutation – increases cancer risk (but need to

acquire additional mutations)

Example: BRCA1, BRCA2 and RB genes



Mutagens

Mutagens – physical or chemical (carcinogens) agents

that cause mutations

Examples - high energy radiation (X-rays, UV light, radongas), chemical compounds/pollutants (asbestos, uranium,

vinyl chloride, benzene, some insecticides, some herbicides,

etc.)



Viruses

Viruses linked to cancer:

Hepatitis B and C – liver cancer

Epstein-Barr virus – Burkitt’s Lymphoma

Human papillomavirus (HPV) – cervical cancer

Kaposi’s Sarcoma Associated Herpes virus – Kaposi’s

Sarcoma

Human T-cell Lymphotropic Virus – T-cell leukemia

P l ti B d St di



Population-Based Studies

CANADA:Leukemia

Regions of Highest Incidence

BRAZIL:Cervicalcancer

U.S.:Coloncancer

AUSTRALIA:Skin

cancer

CHINA:Liver

cancer

U.K.:Lung

cancer

JAPAN:Stomachcancer

H dit ? B h i ? Oth F t ?



Heredity? Behaviors? Other Factors?

100

50

50

Stomach Cancer(Number of new cases per 100,000 people)

U.S.Japan Japanesefamiliesin U.S.

100

70

7

0

Colon Cancer(Number of new cases per 100,000 people)

U.S.Japan Japanesefamiliesin U.S.

Diet: Limit Fats and Calories



Diet: Limit Fats and Calories

0

Number of Cases(per 100,000

people)

Grams (per person per day)

Correlation Between Meat Consumption and ColonCancer Rates in Different Countries

40

30

20

10

30020010080

Low Strength Radiation



Low-Strength Radiation

Annual Sunshine(UV radiation)

SkinCancer

Incidence

Most

Dallas

Pittsburgh

High

Detroit

LowLeast

Avoid Tobacco



Avoid Tobacco

15x

10x

5x

Non-smoker

Cigarettes Smoked per Day

Lung Cancer Risk Increases withCigarette Consumption

LungCancer

Risk

0 15 30



Lung Cancer Statistics

Lung cancer deaths attributed to smoking:

90% (men)

80% (women)

Cigarette smoking is the leading preventable cause

of death in the United States (438,000 deaths/year;

170,000 from lung cancer)

Toxins in cigarette smoke increase number of DNA

mutations



What Causes Cancer?

Cancer (unregulated cell division) is caused by

mutations in genes carrying instructions for the

synthesis of cell cycle control system proteins



Multiple Hit Theory

Multiple Hit Theory:

multiple mutations

(4+) are required to

develop cancer

it generally takes

many years to

accumulate these

mutations



Cancer Risk and Aging

400

300

200

100

Cancer Risk and Aging

Number of

Cancer

Cases

(per 100,000

people)

Age of Person (in years)

Colon

Breast

0 20 40 60 80



Cancer is NOT a Single Disease

There are numerous mutations that can lead

to uncontrolled cell division

Makes treating cancer VERY challenging!



Cancer Treatments - Current

Surgery - localized

Radiation - localized

Chemotherapy – systemic; many side

effects



Cancer Treatments - Future

Earlier detection (physical and genetic )

Better diagnosis (ID specific mutation)

More specific treatments

“Knowing the molecular profile of a patient’s tumor should permit

a doctor to focus of inhibiting the mechanisms driving that

particular tumor, one day choosing from an arsenal of drugs a set

that will interfere with the specific molecules involved in the

initiation, growth and spread of the cancer.”



The Cancer Genome Atlas (TCGA)

http://cancergenome.nih.gov/about/index.asp

The Cancer Genome Atlas - coordinated effort

to accelerate understanding of the molecular

basis of cancer

National Cancer Institute (NCI) National Human Genome Research Institute (NHGRI)

Cancer Treatments - Future



Documents

17 Cell Cycle, Mitosis, And Cancer Pt 2