Cancer: causes and treatment

Causes of mutations:

• Replication errors– Exacerbated by poor DNA repair

• Other biological agents– Viruses– Transposons

• Environmental factors– Ultraviolet light– Mutagenic chemicals

• smoking, industrial waste, natural toxins

Change in the US Death Rates* by Cause, 1950 & 2000

* Age-adjusted to the 2000 US standard population.Source: US Mortality Volume 1950, National Vital Statistics Report, 2002, Vol. 50, No. 15.

586.8

180.5

48.160.923.7

200.9193.7

258.2

0

100

200

300

400

500

600

HeartDiseases

Stroke Pneumonia/Influenza

Cancer

1950

2000

Rate Per 100,000

Cancer Death Rates*, for Men, US, 1930-1999

*Age-adjusted to the 2000 US standard population.Source: US Mortality Public Use Data Tapes 1960-1999, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2002.

0

20

40

60

80

100

1930 1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995

Lung

Colon and rectum

Prostate

Pancreas

Stomach

Liver

Rate Per 100,000

Leukemia

Cancer Death Rates*, for Women, US, 1930-1999

*Age-adjusted to the 2000 US standard population.Source: US Mortality Public Use Data Tapes 1960-1999, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2002.

0

20

40

60

80

100

1930 1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995

Lung

Colon and rectum

Uterus

Stomach

Breast

Ovary

Pancreas

Rate Per 100,000

Tobacco Use in the US, 1900-1999

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

190019051910191519201925193019351940194519501955196019651970197519801985199019952000Year

Per Capita Cigarette Consumption

0

10

20

30

40

50

60

70

80

90

100

Age-Adjusted Lung Cancer Death

Rates*

*Age-adjusted to 2000 US standard population.

Source: Death rates: US Mortality Public Use Tapes, 1960-1999, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2001. Cigarette consumption: Us Department of Agriculture, 1900-1999.

Per capita cigarette consumption

Male lung cancer death rate

Female lung cancer death rate

Tobacco Use in the US, 1900-1999

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

190019051910191519201925193019351940194519501955196019651970197519801985199019952000Year

Per Capita Cigarette Consumption

0

10

20

30

40

50

60

70

80

90

100

Age-Adjusted Lung Cancer Death

Rates*

*Age-adjusted to 2000 US standard population.

Source: Death rates: US Mortality Public Use Tapes, 1960-1999, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2001. Cigarette consumption: Us Department of Agriculture, 1900-1999.

Per capita cigarette consumption

Male lung cancer death rate

Female lung cancer death rate

Treating cancer:• Avoid it

– Avoid mutagens– DNA repair gets less efficient as we age

T-cells recognize and eliminate abnormal cells; such as cells with many mutations

Our immune system protects us from cancer

Treating cancer:• Avoid it

– Avoid mutagens– DNA repair gets less efficient as we age

• Surgery– Must remove all cancer cells– Non-invasive

Treating cancer:• Avoid it

– Avoid mutagens– DNA repair gets less efficient as we age

• Surgery– Must remove all cancer cells– Non-invasive

• Radiation– Directed at tumor; causes DNA damage

-> cellular self-destruction– Mutagenic, side effects

Treating cancer:• Avoid it

– Avoid mutagens– DNA repair gets less efficient as we age

• Surgery– Must remove all cancer cells– Non-invasive

• Radiation– Directed at tumor – Mutagenic, side effects

• Chemotherapy– Toxins directed at rapidly dividing cells– Mutagenic, many side effects

Chemotherapy

a rapidly dividing cell

Toxin

X X

Normal Multi-Drug Resistance protein

MDR

MD

RMDR

MD

R

toxin/hormone/etc

toxin/hormone/etc

toxin/h

ormon

e/etc

toxin/h

ormon

e/etc

Some cancers over-express MDR

Toxin

MDR

MD

R

MDRMDRMDR

MD

RMDRMDRMDRMDR

MD

RM

DR

toxin toxin

toxin toxin toxin toxin

toxin

toxin

toxin

toxin

toxin toxin

I’m a cancer cell with over-expressing MDR. I laugh at your toxins.

The Epigenetic Progenitor Origin of Human Cancer (2007) A P Feinberg, R Ohlsson, S Henikoff Nature Reviews Genetics 7: 21-31

Mutations continue after cancer develops

O

O

OOO

O

O

OO

OOCancer cell with mutation causing MDR over-production

Evolution: changes in DNA as information transmitted

O

O

OOO

O

O

OO

OO

O

O

OOO

O

O

OO

OO

Applychemotherapy

XXX

XX X XX

XX

Kills most cells. Except if some have mutation that allow them to be resistant.

Evolution: changes in DNA as information transmitted

Cancer cell with mutation causing MDR over-production

O

O

OOO

O

O

OO

OO

O

O

OOO

O

O

OO

OO

O

XXX

XX X XX

XX

Kills most cells. Except if some have mutation that allow them to be resistant.

Continues to replicate

Evolution: changes in DNA as information transmitted

Applychemotherapy

Cancer cell with mutation causing MDR over-production

O

O

OOO

O

O

OO

OO

O

O

OOO

O

O

OO

OO

O

O

OOO

O

O

OO

OO

O

XXX

XX X XX

XX

Kills most cells.

Continues to replicate

Tumor with cells expressing MDR

Evolution: changes in DNA as information transmitted

Applychemotherapy

Cancer cell with mutation causing MDR over-production

Some cancers over-express MDR

Toxin

MDR

MD

R

MDRMDRMDR

MD

RMDRMDRMDRMDR

MD

RM

DR

toxin toxin

toxin toxin toxin toxin

toxin

toxin

toxin

toxin

toxin toxin

I’m a cancer cell with over-expressing MDR. I laugh at your toxins.

Treating cancer:• Avoid it

– Avoid mutagens– DNA repair gets less efficient as we age

• Surgery– Must remove all cancer cells– Non-invasive

• Radiation– Directed at tumor – Mutagenic, side effects

• Chemotherapy– Toxins directed at rapidly dividing cells– Mutagenic, many side effects

Multiple mutations are required for a single cell to become cancerous.

CB18.22

How can mutations be minimized?

Telomeres are non-gene DNA at the ends of DNA strands.

Telomeres are non-gene DNA at the ends of DNA strands.

Telomeres are shortened during DNA replication.

Telomeres are non-gene DNA at the ends of DNA strands.

Telomeres are shortened during DNA replication, and also by DNA damage.

Telomeres are non-gene DNA at the ends of DNA strands.

Short telomeres will cause cells to stop replicating or cell death.

The critical size is unknown.

HumanLifeCycle

high levels of telomerase

very little telomerase

Why not produce telomerase all of the time?

high levels of telomerase

very little telomerase

Telomeres are non-gene DNA at the ends of DNA strands.

Telomeres are shortened during DNA replication, and by DNA damage.

Short telomeres will cause cell senescence or cell death.Telomere size is an indirect measure of mutations.

Fig. 3 TRENDS in Ecology and Evolution Vol 21 pg 47

Balance between Longevity and Health

Do telomere dynamics link lifestyleand lifespan?

Pat Monaghan and Mark F. HaussmannTRENDS in Ecology and Evolution

Vol 21 pg 47

Telomere length varies in different parts of adults:

telomeres - mitosisstomach &blood cells....short - often

Telomere length varies in different parts of adults:

telomeres - mitosisstomach &blood cells....short - often

muscle &brain……….long - rare

Telomere length varies in different parts of adults:

telomeres - mitosisstomach &blood cells....short - often

muscle &brain……….long - rare

liver &kidney……..short - rare

Telomere length varies in different parts of adults:

telomeres - mitosisstomach &blood cells....short - often

muscle &brain……….long - rare

liver &kidney……..short - rare

gametes……long

Zebra finch

Telomere length in red blood cells of different birds

Fig. 1 TRENDS in Ecology and Evolution Vol 21 pg 47

Age (years)

common tern

Telomere length in red blood cells of different birds

Fig. 1 TRENDS in Ecology and Evolution Vol 21 pg 47

Age (years)

albatross

TRENDS in Ecology and Evolution Vol 21 pg 47

Telomere length in red blood cells of different birds

Leach’s storm petrel

Telomere length in red blood cells of different birds

Fig. 1 TRENDS in Ecology and Evolution Vol 21 pg 47

Zebra finch

Leach’s storm petrel

common tern

albatross

Telomere length in red blood cells of different birds, different species have different patterns of telomere length and age

Fig. 1 TRENDS in Ecology and Evolution Vol 21 pg 47

Fig. 2 TRENDS in Ecology and Evolution Vol 21 pg 47

Telomere length in white blood cells of different aged people. Telomere length

generally declines, but there is wide variability

Telomeres are non-gene DNA at the ends of DNA strands.

Telomeres are more sensitive to DNA damage, and may act as a sensor for overall DNA damage levels in a cell.

Does telomere length indicate longevity?

THE LANCET • Vol 361 • pg 393

Telomere length and mortality in people over 60 years old

upper 50% of telomere length

lower 50% of telomere length

proportion surviving %

years after initial assessment

Telomere length may indicate biological age.

Early stress may cause premature telomere degradation.

Fig. 3 TRENDS in Ecology and Evolution Vol 21 pg 47

Balance between Longevity and Health

Exam 1 score (100pts) = take-home + in-class

Proposal = 5 points of 20 point ExperimentApproved- start collecting dataApproved with changes- after changes, start collecting dataNot approved- Need to resubmit new proposal. Do not collect data until new proposal is approved.Original proposal will be turned in with report (Do not lose it.)