Homework #3 is due 11/19 Bonus #2 is posted

Cancer: is the loss of control over cell division. Tumors are normal cells that are dividing inappropriately. –They stop performing their “normal” function, and are dividing repeatedly.

Multiple mutations are required for cancer to occur

How do these mutations arise?

Causes of mutations: Replication errors –Exacerbated by poor DNA repair –Limited by telomere length

Causes of mutations: Replication errors –Exacerbated by poor DNA repair –Limited by telomere length Other biological agents –Viruses –Transposons

Causes of mutations: Replication errors –Exacerbated by poor DNA repair –Limited by telomere length Other biological agents –Viruses –Transposons Environmental factors –Ultraviolet light –Mutagenic chemicals smoking, industrial waste, natural toxins

Source: US Mortality Public Use Data Tape 2000, National Center for Health Statistics, Centers for Disease Control and Prevention, Heart Diseases710, Cancer553, Cerebrovascular diseases167, Chronic lower respiratory diseases122, Accidents (Unintentional injuries) 97, Diabetes mellitus 69, Influenza and Pneumonia 65, Alzheimer’s disease 49, Nephritis 37, Septicemia 31, RankCause of Death # of deaths % of all deaths US Mortality, 2000

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 Cerebrovascular Diseases Pneumonia/ Influenza Cancer Rate Per 100,000

2003 Estimated US Cancer Cases* *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, Men 675,300 Women 658,800 32%Breast 12%Lung & bronchus 11%Colon & rectum 6%Uterine corpus 4%Ovary 4%Non-Hodgkin lymphoma 3%Melanoma of skin 3%Thyroid 2%Pancreas 2%Urinary bladder 20%All Other Sites Prostate33% Lung & bronchus14% Colon & rectum11% Urinary bladder6% Melanoma of skin4% Non-Hodgkin lymphoma4% Kidney3% Oral Cavity3% Leukemia3% Pancreas2% All Other Sites17%

2003 Estimated US Cancer Deaths* ONS=Other nervous system. *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, Men 285,900 Women 270,600 25%Lung & bronchus 15%Breast 11%Colon & rectum 6%Pancreas 5%Ovary 4%Non-Hodgkin lymphoma 4%Leukemia 3%Uterine corpus 2%Brain/ONS 2%Multiple myeloma 23%All other sites Lung & bronchus31% Prostate 10% Colon & rectum 10% Pancreas5% Non-Hodgkin4% lymphoma Leukemia4% Esophagus4% Liver/intrahepatic3% bile duct Urinary bladder3% Kidney3% All other sites22%

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

Environment plays a large role in the chance of contracting cancer.

T-cells recognize and eliminate abnormal cells; such as cells with many mutations Our immune system protects us from cancer

P53 is activated by DNA damage

p53 can induce apoptosis via two pathways: Nuclear and/or Mitochondrial

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 chemo- therapy 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 chemo- therapy 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. Except if some have mutation that allow them to be resistant. Continues to replicate Tumor with cells expressing MDR Evolution: changes in DNA as information transmitted Apply chemo- therapy 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.