Reading Assignments for this Material

• Chapter 9-Section 9.3 (pages 183-189).• Chapter 16-section 16.3 (pages 324-328)

• Pages 183-189 will be the material for next Monday’s quiz.

Chapter 16-The Molecular Basis of Cancer

Cancer Risk

• Prevalence-(In Europe and North America-1/5 of us will die from cancer.)

• Risk of cancer increases with age. Why?Declining immune system

Cancer cells exhibit antisocial behavior

• Cancer cells “bully” other cells-push them aside and dominate them

• Cancer cells invade other’s neighborhoods• Cancer cells don’t communicate with other cells

well• Cancer cells don’t respond appropriately to

environmental signals• Cancer cells don’t obey rules of society (like

dying when they should)

What causes cancer?

• Cancer is fundamentally a genetic disease:a) Caused by spontaneous mutations (and failure to repair these mistakes)b)Caused by induced mutations (environmental factors) c)Caused by virus-(HPV for example)

Cancer gene mutations generally fall into a small number of key regulatory pathways.

• Initiation of cell proliferation (division)• Control of cell growth• Response to DNA damage and stress• Glioblastoma (most common brain cancer)

involves mutations in all 3 of these type of pathways.

The process of cancer development

• A normal cell is transformed by mutations and or virus.

• The resulting cancer cells form tumors, masses of abnormal cells within otherwise normal tissue

• If abnormal cells remain at the original site, the lump is called a benign tumor

• Malignant tumors (which cause the disease cancer) invade surrounding tissues and can metastasize, exporting cancer cells to other parts of the body, where they may form secondary tumors

Fig. 12-20

Tumor

A tumor growsfrom a singlecancer cell.

Glandulartissue

Lymphvessel

Bloodvessel

Metastatictumor

Cancercell

Cancer cellsinvade neigh-boring tissue.

Cancer cells spreadto other parts ofthe body.

Cancer cells maysurvive andestablish a newtumor in anotherpart of the body.

1 2 3 4

The eukaryotic cell cycle is regulated by a molecular control system

• The frequency of cell division varies with the type of cell

• These cell cycle differences result from regulation at the molecular level

• Understanding the regulation of the cell cycle at the molecular level helps us to understand how cancer cells escape the usual controls and divide indefinitely

• Cancer Is the price we pay for having tissues that can renew and repair themselves

Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

The Cell Cycle Control System

• The sequential events of the cell cycle are directed by a distinct cell cycle control system, which is similar to a clock

• The clock has specific checkpoints where the cell cycle stops until a go-ahead signal is received

• Checkpoints can be influenced by signals from outside the cell as well as inside the cell.

Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Fig. 12-14

SG1

M checkpoint

G2M

Controlsystem

G1 checkpoint

G2 checkpoint

• For many cells, the G1 checkpoint seems to be the most important one

• If a cell receives a go-ahead signal at the G1 checkpoint, it will usually complete the S, G2, and M phases and divide

• If the cell does not receive the go-ahead signal, it will exit the cycle, switching into a nondividing state called the G0 phase

Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Fig. 12-15

G1

G0

G1 checkpoint

(a) Cell receives a go-ahead signal

G1

(b) Cell does not receive a go-ahead signal

Stop and Go Signs: Internal and External Signals Regulate The Cell Cycle at the Checkpoints

• An example of an internal signal is that kinetochores not attached to spindle microtubules send a molecular signal that delays anaphase-

• Some external signals are growth factors, proteins released by certain cells that stimulate other cells to divide

• For example, platelet-derived growth factor (PDGF) stimulates the division of human fibroblast cells in culture

Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Fig. 12-18

Petriplate

Scalpels

Cultured fibroblasts

Without PDGFcells fail to divide

With PDGFcells prolifer-ate

10 µm

• Another example of external signals is density-dependent inhibition, in which crowded cells stop dividing

• Most animal cells also exhibit anchorage dependence, in which they must be attached to a substratum in order to divide

Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Fig. 12-19

Anchorage dependence

Density-dependent inhibition

Density-dependent inhibition

(a) Normal mammalian cells (b) Cancer cells25 µm25 µm

• Cancer cells exhibit neither density-dependent inhibition nor anchorage dependence

• This is why they can grow out of control to form a mass and invade surrounding tissue

Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Cancer results from genetic changes that affect cell cycle control

• In cancer cells, checkpoints that normally stop cell division no longer function effectively.

• Cancer cells in tissue culture can essentially grow forever (immortal). Normal cells only divide 20-50 times in culture before they stop

• HeLa cells (growing continuously in culture since 1951)

An example of changes in the Cell Cycle:

• Assume a skin cell is not dividing (it hasn’t made it past the G-1 checkpoint in the cell cycle). Why?

• The cell is not getting the proper internal/external signals to move past the checkpoint

• Now-suppose the skin is damaged. • Platelets in the blood release PDGF (platelet derived growth

factor). PGDF binds to a receptor on skin cells, this sends a signal to the cell’s DNA to alter the expression of cell cycle regulating proteins and now the cell cycle moves past the G-1 checkpoint allowing cell division to occur. Healing begins.

continued

• Once skin healed, platelets no longer secrete PDGF. Thus skin cell are no longer signaled to express the proteins that move the cell cycle past the G-1 checkpoint. Cell division stops as the cell cycle can no longer move past the G-1 checkpoint.

Normal PGDF signaling

Loss of Cell Cycle Controls in Cancer Cells

• Cancer cells do not respond normally to the body’s control mechanisms

• Cancer cells may not need growth factors to grow and divide. Why?– They may make their own growth factor– They may convey a growth factor’s signal without

the presence of the growth factor– They may have an abnormal cell cycle control system

Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

2 Main classes of genes are critical for cancer- 1)0ncogenes and 2) Tumor Suppressor genes

Oncogenes –a) These are mutants of normal genes (proto-oncogenes) that regulate cell growth b) These genes involve production of hyperactive proteins that stimulate cell divisionc) These are gain of function mutations which have a dominant effect d) The Ras gene regulates normal cell division

Fig. 18-21a

Receptor

Growthfactor

G protein GTP

Ras

GTP

Ras

Protein kinases(phosphorylationcascade)

Transcriptionfactor (activator)

DNA

HyperactiveRas protein(product ofoncogene)issuessignalson its own

MUTATION

NUCLEUS

Gene expression

Protein thatstimulatesthe cell cycle

(a) Cell cycle–stimulating pathway

11

3

4

5

2

Interference with Normal Cell-Signaling Pathways

• Mutations in the ras gene can lead to production of a hyperactive Ras protein and increased cell division

• It’s like a stuck gas pedal in your car. Cell Division keeps going at a faster rate.

How are proto-oncogenes turned into oncogenes?

– Movement of DNA within the genome: if it ends up near an active promoter, transcription may increase

– Amplification of a proto-oncogene: increases the number of copies of the gene

– Point mutations in the proto-oncogene or its control elements: causes an increase in gene expression

Figure 16.16

within a controlelement

Proto-oncogene

Gene amplification:multiple copies ofthe gene

Proto-oncogene Proto-oncogene

Point mutation:

withinthe gene

Translocationor transposition:gene moved tonew locus, undernew controls

Normal growth-stimulating proteinin excess

Newpromoter

OncogeneOncogeneOncogene

Normal growth-stimulating proteinin excess

Normal growth-stimulating protein in excess

Hyperactive ordegradation-resistantprotein

2 Main classes of genes are critical for cancer- 1) 0ncogenes and 2) Tumor Suppressor genes (continued)

Tumor Suppressor Genes:a) Tumor-suppressor genes help prevent uncontrolled cell growth. P53-”guardian angel of the genome”

b)Mutations that decrease protein products of tumor-suppressor genes may contribute to cancer onset

c) Tumor-suppressor proteins (usually activated by damaged DNA)

– Repair damaged DNA

– Inhibit the cell cycle so the cell doesn’t divide until the damaged DNA is repaired

– Activates “suicide genes” when DNA damage is irreparable and causes programmed cell death (apoptosis)

d) Estimated that 50% of all cancers involve a mutation in the P53 gene

Importance of Tumor Suppressor genes for normal cell function:

• Suppression of the cell cycle can be important in the case of damage to a cell’s DNA; p53 prevents a cell from passing on mutations due to DNA damage

• Mutations in the p53 gene prevent suppression of the cell cycle (knocks out the brakes that stop down cell division)

Figure 16.18

Protein kinases

NUCLEUS

DNA damagein genome

Defectiveor missingtranscriptionfactor

MUTATIONUVlight

1

2

3

Inhibitoryproteinabsent

DNA damagein genome

UVlight

Active formof p53

Protein thatinhibits thecell cycle

Summary-Mutation in key genes (like Ras and P-53)can cause two problematic molecular events:

• Inactivation of tumor suppressor genes like P53 (defective brakes-you can’t stop cell division in damaged/mutated cells)

• Interference with normal signaling pathways that control cell division like Ras (stuck gas pedal-allows cell cycle to move past checkpoints when it shouldn’t ).

• Mutations in the ras proto-oncogene and p53 tumor-suppressor gene are common in human cancers

Fig. 18-21

Receptor

Growthfactor

G protein

GTP

Ras

GTP

Ras

Protein kinases(phosphorylationcascade)

Transcriptionfactor (activator)

DNA

HyperactiveRas protein(product ofoncogene)issuessignalson its own

MUTATION

NUCLEUS

Gene expression

Protein thatstimulatesthe cell cycle

(a) Cell cycle–stimulating pathway

MUTATIONProtein kinases

DNA

DNA damagein genome

Defective ormissingtranscriptionfactor, suchas p53, cannotactivatetranscription

Protein thatinhibitsthe cell cycle

Activeformof p53

UVlight

(b) Cell cycle–inhibiting pathway

(c) Effects of mutations

EFFECTS OF MUTATIONS

Cell cycle notinhibited

Protein absent

Increased celldivision

Proteinoverexpressed

Cell cycleoverstimulated

1

2

3

4

5

2

1

3

The Multistep Model of Cancer Development

• Multiple somatic mutations are generally needed for full-fledged cancer; thus the incidence increases with age

• The multistep path to cancer is well supported by studies of human colorectal cancer, one of the best-understood types of cancer

• The first sign of colorectal cancer is often a polyp, a small benign growth in the colon lining

• About half a dozen changes must occur at the DNA level for a cell to become fully cancerous

• These changes generally include at least one active oncogene and the mutation or loss of several tumor-suppressor genes

• Most tumor suppressor alleles are recessive so you would have to have mutations in both allelic pairs to lose this function.

Figure 16.19

Colon

Loss of tumor-suppressor geneAPC (or other)

Loss oftumor-suppressor gene p53

Activation ofras oncogene

Colon wallNormal colonepithelial cells

Small benigngrowth(polyp)

Loss of tumor-suppressor gene DCC

Malignanttumor(carcinoma)

Larger benigngrowth(adenoma)

Additionalmutations

1 2

3

4

5

Inherited Predisposition and Other Factors Contributing to Cancer

• Individuals can inherit oncogenes or mutant alleles of tumor-suppressor genes (some cancers run in families)

• Inherited mutations in the tumor-suppressor gene adenomatous polyposis coli (APC)are common in individuals with colorectal cancer

• Mutations in the BRCA1 or BRCA2 gene are found in at least half of inherited breast cancers and test can detect these mutations

• A woman who inherits one mutant BRCA1 allele has a 60% chance of breast cancer before the age 50 versus a 2% chance if you don’t have the mutant allele

• DNA breakage can contribute to cancer, thus the risk of cancer can be lowered by minimizing exposure to agents that damage DNA, such as ultraviolet radiation and chemicals found in cigarette smoke (stopping the use of tobacco could prevent as much as 30% of cancer deaths.)

• Also, viruses play a role in about 15% of human cancers by donating an oncogene to a cell, disrupting a tumor-suppressor gene, or converting a proto-oncogene into an oncogene