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. Heart Diseases Stroke Pneumonia/ Influenza Cancer Rate Per 100,000

Cancer Death Rates*, for Men, US, *Age-adjusted to the 2000 US standard population. Source: US Mortality Public Use Data Tapes , US Mortality Volumes , National Center for Health Statistics, Centers for Disease Control and Prevention, Lung Colon and rectum Prostate Pancreas Stomach Liver Rate Per 100,000 Leukemia

Cancer Death Rates*, for Women, US, *Age-adjusted to the 2000 US standard population. Source: US Mortality Public Use Data Tapes , US Mortality Volumes , National Center for Health Statistics, Centers for Disease Control and Prevention, Lung Colon and rectum Uterus Stomach Breast Ovary Pancreas Rate Per 100,000

Tobacco Use in the US, *Age-adjusted to 2000 US standard population. Source: Death rates: US Mortality Public Use Tapes, , US Mortality Volumes, , National Center for Health Statistics, Centers for Disease Control and Prevention, Cigarette consumption: Us Department of Agriculture, Per capita cigarette consumption Male lung cancer death rate Female lung cancer death rate

Tobacco Use in the US, *Age-adjusted to 2000 US standard population. Source: Death rates: US Mortality Public Use Tapes, , US Mortality Volumes, , National Center for Health Statistics, Centers for Disease Control and Prevention, Cigarette consumption: Us Department of Agriculture, 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 XX

Normal Multi-Drug Resistance protein MDR toxin/hormone/etc

Some cancers over-express MDR Toxin MDR 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: Mutations continue after cancer develops

O O OOO O O OO OO Cancer 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 Apply chemotherapy X XX XXXX X 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 X XX XXXX X 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 Apply chemotherapy 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 X XX XXXX X XX Kills most cells. Continues to replicate Tumor with cells expressing MDR Evolution: changes in DNA as information transmitted Apply chemotherapy Cancer cell with mutation causing MDR over- production

Some cancers over-express MDR Toxin MDR 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. CB 18.22

How can mutations be minimized?

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.

Human Life Cycle 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 lifestyle and lifespan? Pat Monaghan and Mark F. Haussmann TRENDS in Ecology and Evolution Vol 21 pg 47

Telomere length varies in different parts of adults: telomeres - mitosis stomach & blood cells....short- often

muscle & brain……….long- rare

Telomere length varies in different parts of adults: telomeres - mitosis stomach & blood cells....short- often muscle & brain……….long- rare liver & kidney……..short- rare

Telomere length varies in different parts of adults: telomeres - mitosis stomach & 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 Experiment Approved- start collecting data Approved with changes- after changes, start collecting data Not 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.)