MAC2 Cancer

8/4/2019 MAC2 Cancer

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A cancer is an uncontrolled proliferation of cells

Failure in the mechanisms by which the cell cycle isregulated can lead to uncontrolled cell growth and thedevelopment of cancer

In some the rate is fast; in others, slow; but in allcancers the cells never stop dividing.

Cancer cells are usually less differentiated than thenormal cells of the tissue where they arose.
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Cell Cycle

The repeating sequence of growth anddivision through which cells pass eachgeneration

The purpose of the cell cycle is to allowcells to reproduce without alteration ofgenetic material

The stages are well preserved betweenspecies


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Why do cells devide?


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Events of cell cycle

G1 =Growth andpreparation of thechromosomes forreplication

S = Synthesis of DNA

G2 = Preparation formitosis

M = Mitosis

Periode between M and S iscalled G1;

between S and M is G2


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Higly regulated process controlled by a large numberof factors include:

Growth stimulating factors

Growth inhibiting factors

Enzymes that alter functional state of other proteinsby adding (kinases) or removing (phosphatases)phosphate groups

Failure in the mechanisms by which the cell cycle is

regulated can lead to uncontrolled cell growth and thedevelopment of cancer

Cell cycle progression


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There are several factors that regulate thecell cycle and assure a cell divides correctly


Control of Cell Cycle

There are several factors that regulate the cellcycle and assure a cell divides correctly

1. Before a cell divides, theDNA is checked to makesure it has replicated

correctly. (If DNA doesnot copy itself correctly, agene mutation occurs.
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2. Chemical Signals tell acell when to start and

stop dividing
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There are important checkpoints during the cell cycle: At the G1 S transition

At the S G2 transition

At the G2 M transition

Regulation of the cell cycle occurs as a consequenceof cyclin Cdk interaction

Other proteins such as P53, Rb and oncogene play a

role in regulating the cell cycle


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Cyclins and Cyclin Dependent Kinases(Cdk)

Cyclin Cdk Process regulated

Cyclin DCyclin ECyclin ACyclin ACyclin B

Cdk 4,6Cdk 2Cdk 2Cdk 1(Cdc2)Cdk 1

G1 phase progressionG1 to S phaseS phase progressionS through G2M phase


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Waves of Cyclin-Cdk Activity ControlThe Cell Cycle

G1 S G1G2 M

Cyclin D-Cdk 4/6

Cyclin E-Cdk 2CyclinA-Cdk1

Cyclin B-Cdk1

GF

Kin

aseActivit

y

Time


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The cell cycle control system hascheckpoints during G1, G2, S and M

Checkpoint signals report cells status:

Is the cell big enough?

Is environment favorable?

Is DNA replicated?

Are chromosomes attached to oppositepoles?

Checkpoints


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G1 G2S prophase metaphase anaphase Cytokinesis

Mitosis


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Labile Epithelial, Lymphoid,Haemopoietic

Stable Liver, Pancreas, Salivary

gland,Endocrine organs

Permanent Neurons, Skeletal muscle,

Cardiac muscle

Regenerative Capacity


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It was originally assumed that cancerarose from a population of cells thatproliferated more rapidly than normal cells

It is now known that many malignant cellshave longer cell cycle times than theirnormal counterparts

Cell proliferation and cancer


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Malignancies probably arise when there isan imbalance between cell production andcell loss

Cell loss occurred through necrosis,apoptosis and surface shedding

Abnormalities of the cell cycle do not

explain all of the growth of malignanttumors and they are clearly not importantin invasion and metastasis

What happens in malignancy?


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Cell Cycle Is Regulated byOpposing Effects of Positive and NegativeFactors

S

G2 G1

M

Cyclin

Cdk

+

P53

Rb

-


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Cell Cycle Is Regulated ByOpposing Effects of Positive and Negative

Factors

Tumor Suppressor(P53, Rb)

Oncogene(BCl2,BRCA1)

Tumor Suppressor

(P53, Rb)

Oncogene

(BCl2,BRCA1)

Cell proliferation

Cell proliferation

Cell death

Cell death


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APOPTOSIS

For every cell, there is time to live and atime to die

There are two ways in which cells die: They are killed by injuries agents

They are induced to commit suicide (apoptosisor Programmed cell death;PCD)

Two forms of cell death Necrosis

Apoptosis


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Death by Injury

Cells that are damaged by injury, such asby:

Mechanical damage Exposure to toxic chemicals

Undergo a characteristic series of changes:

They are swell

The cell contents leak out, leading to;

Inflammation of surrounding tissues


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Death by Suicide (Apoptosis)

Cells that are induced to commit suicide:

Shrink

Have their mitochondrial break down

Develop bubble-like blebs on their surface

Have the chromatin in their nucleusdegraded and show chromatin

condensation

Break into small, membrane-wrapped,fragment


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Apoptosis Versus Necrosis

Apoptosis

Central part of normal

development Genetically mediated

Involve inorganogenesis, tissuehomeostasis

Necrosis

Results from cell

metabolic collapse Response to injury or

toxic damage


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Apoptosis Versus Necrosis

Apoptosis Shrinkage of cell

Little or no swellingof mitochondria

Intact membrane

Degradation of DNAinto multiple of 180bp

Little or noinflammatoryresponse

Necrosis Swelling of cell

Swelling ofmitochondria

Loss of membraneintegrity

Random degradationof DNA

Intense inflammatoryresponse


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Why Should a Cell CommitSuicide?

There are two different reasons

Apoptosis is needed for proper development The formation of the fingers and the toes of the

fetus requires the removal, by apoptosis of thetissue between them

Apoptosis is needed to destroy cells thatrepresent a thread to integrity of the organism

Cells infected with viruses Cells of the immune system

Cells with DNA damage


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What Makes Cell Decide toCommit Suicide?

The balance between:

The withdrawal of positive signals; that

is, signal needed for continued survival(GF, cytokines, oncogenes)

The receipt of negative signals

(increased levels of oxidant damage ofDNA, tumor suppressor)


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