What is Cancer? Large number of complex diseases Behave differently depending upon cell type from which originate –Age on onset, invasiveness, response.

What is Cancer?

• Large number of complex diseases• Behave differently depending upon cell

type from which originate– Age on onset, invasiveness, response to

treatment

• Common general properties– Abnormal cell growth/division (cell

proliferation)– Spread to other regions of body (metastasis)

• Malignant tumors

Genetics of Cancer

Cancer       * mean "crab"        * genetic disease * great variety of malignant tumor -uncontrolled cell growth

Properties of Cancer Cells

• Genetic instability– Mutator phenotype– Duplicating, losing and translocating

chromosomes or portions of them common

• Chronic myelogenous leukemia (CML)– Chromosome 9/chromosome 22

translocation– BCR gene fused to ABL (protein kinase)– Mutant signal transduction protein

stimulates cells constantly to proliferate

Normal and Cancer Karyotypes

• Chromosome painting• (a) is a normal cell, (b) is a “very messed up”

cancer cell

• Tumor arises from a single cell – clonality arise from a single aberrant cell that then prolifera

te• Cancer requires mutation of multiple genes• Cancers often develop in progressive steps

– From mildly aberrant cells to malignant– Process called tumorigenesis

Transformation is a multistep

process

Tumorigenesis of Cervical Cancer

Three types of changes from normal cell to cancer cell

density-dependent inhibition

autocrine growth inhibition

contact inhibition

Cancer cell 의 특징

• Invasion--collegnase secretion• Angiogenesis--cancer cells secrete growth factors that promoter formation of new blood vessels• Defective differentiation--fail to differentiate normally (leukemia) • Apoptosis failure (damaged DNA death) • Metastasis

Immortalization and transformation

telomerase activity * essential for tumor formations, * critical parameter for

immortalization is reactivation of telomerase

Two kinds of Cancer genes

1) oncogene ( 종양유발유전자 ) induce cell transformation (cancer cells) 2) tumor suppressor genes ( 종양억제유전자 )) inhibit cell proliferation, negative regulatory inhibit cell proliferation, negative regulatory proteinprotein

*. *. Types of genes which may mutate toTypes of genes which may mutate to cause cancercause cancer• DNA repair genes• telomerase

Oncogenes

• oncogene is mutated form of normal genes called proto-oncogene • proto-oncogene; control of cell proliferation and differentiation • oncogenic virus oncogenic DNA virus oncogenic RNA virus (retrovial oncogene) src

proto-oncogen activation

normal cell genes from which oncogene originated, encoding proteins that function in

  1) signal transduction pathway 2) controlling normal cell proliferation       

Proto-oncogene activation

Functions of oncogene products

1) uncotrolled proliferation of cancer cell

2) defective differentiation

3) failure to programmed cell death

ras Proto-oncogenes

• Involved in signal transduction pathway– As are many proto-oncogene products

• ras family genes mutated in 40% of all cancers

• Involved in signal transduction pathway from growth factor receptor to nucleus– G protein– Mutant form lacks GTPase activity and rem

ains active

Tumour suppressor genes

• The gene’s normal function is to regulate cell division. Both alleles need to be mutated or

removed in order to lose the gene activity.• The first mutation may be inherited or somatic.• The second mutation will often be a gross event leading to loss of heterozygosity in the surrounding area.

Tumor suppressor genes

block abnormal growth and malignant transformation

• proto-oncogene; dominant in action • tumor-suppressor gene ; recessive ( Rb, p53, INK4, APC, DCC)

Functions of tumor suppressor gene products

tumor development by eliminating negative regulatory proteins

ex) WT1, Rb and INK4, p53 gene product, APC and DCC

p53

• suppresses progression through the cell cycle in response to DNA damage

• initiates apoptosis if the damage to the cell is severe

• acts as a tumour suppressor• is a transcription factor and once activated, it rep

resses transcription of one set of genes (several of which are involved in stimulating cell growth) while stimulating expression of other genes involved in cell cycle control

p53 Tumor Suppressor Gene

• Mutated (inactivated) in more than 50% of all cancers

• p53 regulates (activates or represses) transcription of more than 50 different genes

• p53 regulated by Mdm2 (prevents the phosphorylations and acetylations that activate inactive p53)

• Activated p53 levels rise rapidly if DNA is damaged or repair intermediates accumulate

p53 Function

• Activated p53 acts as transcription factor to turn on genes that– arrest the cell cycle so DNA can be repaired

• Initiates synthesis of p21, which inhibits CDK4/cyuclinD1 complex, blocking entry into S phase

• Genes expressed which retard rate of DNA replication

• Other products block G2/M progression– Initiate apoptosis if DNA cannot be readily repaired

• Turns on Bax gene, represses Bcl2 gene• Bax homodimers activate process of cell destruction• Cancer cells lacking p53 do not initiate pathway even

if DNA/cellular damage is great

pRB Function

• Tumor suppressor protein that controls the G1/S checkpoint

• Found in nucleus and activity regulated by level of phosphorylation (by CDK4/cyclinD1 complex)– Nonphosphorylated version binds to TFs such as E2

F, inactivating them– Free E2F and the other regulators turn on >30 gene

s required for transition to S phase

RB1 Tumor Suppressor Gene

• Retinoblastoma 1 gene• Involved in breast, bone, lung, bladder and

retinal cancers (among others)• Inheriting one mutated (inactivated) copy of

gene increases chances of retinoblastoma formation from 1/14,000-20,000 to 85% (plus increases other cancer rates)– Loss of second copy in a cell eliminates

function– Normal cells unlikely to lose both good

copies

Third category of cancer-causing genes.

- excision, mismatch repair

- cancer effects are indirect

Defective DNA repair = increase rate of failure to repair mutations

- mutations accumulate in the genome

Significance - have an increased chance of mutation in a proto-oncogene and/or tumor suppressing

gene

DNA repair genes (Mutator genes)

cancer is a disease of the cell cyclecancer is a disease of the cell cycle

The Main Jobs of the Cell Cycle:

1. To accurately transmit the genetic information!

2. To maintain normal ploidy; i.e. diploidy!

Euploidy: additions of whole chromosome setse.g. n, 2n, 3n, 4n = haploid, diploid, triploid, tetraploid

Aneuploidy: additions or subtractions of one or more single chromosomes

e.g. 2n + 1, 2n -1, 2n + 2, etc.

• The cell cycle consists of two major phases:– Interphase, where chromosomes duplicate

and cell parts are made

– The mitotic phase, when cell division occurs

The cell cycle multiplies cells

Figure 8.5

Defects in Cell Cycle Regulation

• Cell cycle - G1, S, G2, M phases• Progression through cycle is regulated and

specific blocks or checkpoints exist• Nondividing cell (quiescent) is in an extend

ed G1 phase called G0– Cancer cells never enter G0

Cell Cycle Checkpoints

• G1/S– Monitors cell size and for DNA

damage• G2/M

– Replication complete, DNA damage?• M

– Spindle fibers connected, etc.?• G0

– Does body require more of my type of cell?

Cell Cycle

Regulators of Cell Cycle

• Cyclins and cyclin-dependent kinases (CDKs)

• Cyclins synthesized and destroyed in a precise pattern– A cyclin bind to a specific CDKs, activating it

• Other proteins phosphorylated/activated• CDK4/cyclinD activate transcription factors for genes

such as DNA polymerase delta and DNA ligase• CDK1/cyclinB trigger events of early mitosis (chromo

some condensation, nuclear membrane breakdown, etc.)

Two Types of Cell Cycle Control

1. A Cascade of Protein Phosphorylations Phosphorylation = phosphate groups (PO4) are added onto substrates by enzymes called kinases

That guy Kinase asked me out and then told me he wanted give me a phosphate group to turn me on…ugh..

men!

Oh no he

didn’t.

RbP

= Hypo-phosphorylated (Under-phosphorylated)

Retinoblastoma Protein (Rb) = an important cell cycle regulator and tumor suppressor that is controlled by how much it is phosphorylated. It is a SUBSTRATE for the enzyme cyclin-dependent KINASE (cdk).

RbP

P P

PP

= Hyper-phosphorylated (Over-phosphorylated)

E2F • Transcription Factor: a protein that helps TRANSCRIBE

genes (DNA RNA)

• E2F is a transcription factor that is responsible for helping transcription of genes that help cells enter S phase

E2FS-phase Gene

Pretend this is a gene (piece of DNA) that needs to be transcribed to help push cells into S phase; without the transcription factor, E2F, it is NOT transcribed (no mRNA is made).

S-phase Gene

When E2F is allowed to “sit” on the gene, it helps the gene to undergo transcription. Copies of mRNA are made

Copies of mRNA

Transcription

E2F

Rb and cdk’s

RbP

RbP

P P

PP

Cyclin cdk

No Transcription;No S-phase genes;No continuation through the cell cycle

E2F

S-phase Gene

Transcription

S-phase Gene

S-phase genes transcribed!Let’s go start S-phase!

Cdk inhibitors

E2FRb

P

RbP

P P

PPCyclin cdk

E2F

S-phase Gene

p16p21

p21 and p16 are proteins that inhibit the function of cdk’s. If you inhibit cdk function, Rb DOES NOT get hyperphosphorylated and E2F is NOT able to transcribe genes; when cdk inhibitors are around, the cell cycle is stopped!

Two Types of Cell Cycle Control2. Checkpoint Control

Checkpoints are places in the cell cycle where a cell will be stopped so that it can be checked for mistakes.

Hey buddy, I don’t care whatcha say! I am not letting you through unless your DNA is

correct!

Cell Cycle Checkpoints

M

G1G2

S

= DNA Damage Checkpoints

= Spindle Checkpoints

= G1 Checkpoint

= G2 Checkpoint

Balance

E2F

Cyclin

cdk

p16

p21

RbP

RbP

P P

PP

CheckpointProteins

CANCER

STOP GO

Cancer Cells Evade Two “Safety” Mechanisms Built into the Cell Cycle

1. Once p53 is inactivated, cells with DNA damage don’t arrest from G1 and don’t undergo apoptosis.

2. Telomerase enzyme is activated, avoiding the limit to

cell divisions imposed by telomere shortening.

The Hallmarks of Cancer

Summary of Cancer

• It is a group of diseases caused by loss of cell cycle control.

• Cancer is associated with abnormal

uncontrolled cell growth.

• Carcinogens are substances which cause cancer by mutating DNA.

• There are many genes that can mutate to cause loss of control of the cell cycle or genomic stability (DNA repair).