Cancer Detection and Treatment Henrietta Lacks Cell Culture

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Cancer: Detection and Treatment Henrietta Lacks Cell Culture Forensics. S. O’brien PNAS July 3,

Cancer: Detection and Treatment Henrietta Lacks Cell Culture Forensics. S. O’brien PNAS July 3, 2001 vol. 98 no. 14 7656 -7658

Henrietta Lacks: the source of He. La cells Cell Culture Forensics. S. O’brien PNAS

Henrietta Lacks: the source of He. La cells Cell Culture Forensics. S. O’brien PNAS July 3, 2001 vol. 98 no. 14 7656 -7658

Henrietta Lacks: the source of He. La cells “During the 1970 s and 1980

Henrietta Lacks: the source of He. La cells “During the 1970 s and 1980 s, as many as one in three cell lines deposited in cell culture repositories were imposters, one cell line overtaking or masquerading as another. The most notorious culprit was a cervical carcinoma line, He. La, established by George Gey at the Johns Hopkins Medical School in 1951” Cell Culture Forensics. S. O’brien PNAS July 3, 2001 vol. 98 no. 14 7656 -7658

Henrietta Lacks: the source of He. La cells An estimated $10 million of research

Henrietta Lacks: the source of He. La cells An estimated $10 million of research was discredited. Cell Culture Forensics. S. O’brien PNAS July 3, 2001 vol. 98 no. 14 7656 -7658

Henrietta Lacks: the source of He. La cells DNA fingerprinting has been used to

Henrietta Lacks: the source of He. La cells DNA fingerprinting has been used to differentiate different cell lines. “cell lines from the same person showed 0. 3– 2. 9% fragment differences” Cell Culture Forensics. S. O’brien PNAS July 3, 2001 vol. 98 no. 14 7656 -7658

He. La cell variation J. Cell Biol. Bottomley et al. 41 (3): 806

He. La cell variation J. Cell Biol. Bottomley et al. 41 (3): 806

Balance between Longevity and Health Fig. 3 TRENDS in Ecology and Evolution Vol 21

Balance between Longevity and Health Fig. 3 TRENDS in Ecology and Evolution Vol 21 pg 47

Mutations

Mutations

Cancer: • is the loss of control over cell division. • Tumors are normal

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.

A cell becomes cancerous when there are incorrect positive AND negative signals.

A cell becomes cancerous when there are incorrect positive AND negative signals.

GO! STOP! cancer

GO! STOP! cancer

Multiple mutations are required for cancer to occur Fig 22. 17

Multiple mutations are required for cancer to occur Fig 22. 17

Tbl 22. 10

Tbl 22. 10

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

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

Environment plays a large role in the chance of contracting cancer… The multiethnic cohort

Environment plays a large role in the chance of contracting cancer… The multiethnic cohort study: exploring genes, lifestyle and cancer risk. L Kolonel, D Altshuler, B Henderson (July 2004) Nature Reviews Cancer 4, 519 -527 Fig 1

The rapidity of increased childhood thyroid cancer in the heavily contaminated areas of Belarus,

The rapidity of increased childhood thyroid cancer in the heavily contaminated areas of Belarus, Ukraine and Russia was surprising. 4 years

US Mortality, 2000 Rank Cause of Death # of deaths % of all deaths

US Mortality, 2000 Rank Cause of Death # of deaths % of all deaths 1. Heart Diseases 710, 760 29. 6 2. Cancer 553, 091 23. 0 3. Cerebrovascular diseases 167, 661 7. 0 4. Chronic lower respiratory diseases 122, 009 5. 1 5. Accidents (Unintentional injuries) 97, 900 4. 1 6. Diabetes mellitus 69, 301 2. 9 7. Influenza and Pneumonia 65, 313 2. 7 8. Alzheimer’s disease 49, 558 9. Nephritis 37, 251 1. 5 10. Septicemia 2. 1 31, 224 1. 3 Source: US Mortality Public Use Data Tape 2000, National Center for Health Statistics, Centers for Disease Control and Prevention, 2002.

Change in the US Death Rates* by Cause, 1950 & 2000 Rate Per 100,

Change in the US Death Rates* by Cause, 1950 & 2000 Rate Per 100, 000 1950 2000 Heart Diseases Cerebrovascular Pneumonia/ Influenza Diseases Cancer * Age-adjusted to the 2000 US standard population. Source: US Mortality Volume 1950, National Vital Statistics Report, 2002, Vol. 50, No. 15.

2003 Estimated US Cancer Cases* Men 675, 300 Women 658, 800 32% Breast Prostate

2003 Estimated US Cancer Cases* Men 675, 300 Women 658, 800 32% Breast Prostate 33% Lung & bronchus 14% Colon & rectum 11% Urinary bladder 6% 6% Uterine corpus Melanoma of skin 4% 4% Ovary 4% Non-Hodgkin lymphoma 3% Melanoma of skin 3% Thyroid 2% Pancreas 2% Urinary bladder Non-Hodgkin lymphoma 4% Kidney 3% Oral Cavity 3% Leukemia 3% Pancreas 2% All Other Sites 17% 12% Lung & bronchus 11% Colon & rectum 20% All Other Sites *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2003.

2003 Estimated US Cancer Deaths* Lung & bronchus 31% Prostate 10% Colon & rectum

2003 Estimated US Cancer Deaths* Lung & bronchus 31% Prostate 10% Colon & rectum 10% Men 285, 900 Women 270, 600 25% Lung & bronchus 15% Breast 11% Colon & rectum Pancreas 5% 6% Pancreas Non-Hodgkin lymphoma 4% 5% Ovary Leukemia 4% 4% Non-Hodgkin lymphoma Esophagus 4% 4% Leukemia Liver/intrahepatic bile duct 3% 3% Uterine corpus Urinary bladder 3% 2% Brain/ONS Kidney 3% 2% Multiple myeloma All other sites 22% 23% All other sites ONS=Other nervous system. *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2003.

Cancer Death Rates*, for Men, US, 19301999 Rate Per 100, 000 Lung Stomach Prostate

Cancer Death Rates*, for Men, US, 19301999 Rate Per 100, 000 Lung Stomach Prostate Colon and rectum Pancreas Leukemia Liver *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.

Cancer Death Rates*, for Women, US, 1930 -1999 Rate Per 100, 000 Lung Uterus

Cancer Death Rates*, for Women, US, 1930 -1999 Rate Per 100, 000 Lung Uterus Breast Colon and rectum Stomach Ovary Pancreas *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.

Tobacco Use in the US, 1900 -1999 Male lung cancer death rate Per capita

Tobacco Use in the US, 1900 -1999 Male lung cancer death rate Per capita cigarette consumption Female lung cancer death rate *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.

Tobacco Use in the US, 1900 -1999 Male lung cancer death rate Per capita

Tobacco Use in the US, 1900 -1999 Male lung cancer death rate Per capita cigarette consumption Female lung cancer death rate *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.

Treating cancer: • Avoid it – Avoid mutagens – DNA repair gets less efficient

Treating cancer: • Avoid it – Avoid mutagens – DNA repair gets less efficient as we age

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

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

Fig 22. 15 P 53 is activated by DNA damage

Fig 22. 15 P 53 is activated by DNA damage

p 53 can induce apoptosis via two pathways: Nuclear and/or Mitochondrial

p 53 can induce apoptosis via two pathways: Nuclear and/or Mitochondrial

Treating cancer: • Avoid it – Avoid mutagens – DNA repair gets less efficient

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

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

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 n xi To X X a rapidly dividing cell

Chemotherapy n xi To X X a rapidly dividing cell

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

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

Some cancers over-express MDR toxin MDR MDR xi To toxin MDR MDR MDR toxin

Some cancers over-express MDR toxin MDR MDR xi To toxin MDR MDR MDR toxin toxin MDR n I’m a cancer cell with over-expressing MDR. I laugh at your toxins.

Mutations continue after cancer develops The Epigenetic Progenitor Origin of Human Cancer (2007) A

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

Evolution: changes in DNA as information transmitted O O O Cancer cell with mutation

Evolution: changes in DNA as information transmitted O O O Cancer cell with mutation causing MDR over-production

Evolution: changes in DNA as information transmitted O O O Apply chemotherapy O O

Evolution: changes in DNA as information transmitted O O O Apply chemotherapy O O X X X X X O O O O O Kills most cells. Except if some have mutation that allow them to be resistant. Cancer cell with mutation causing MDR over-production

Evolution: changes in DNA as information transmitted O O O Apply chemotherapy O O

Evolution: changes in DNA as information transmitted O O O Apply chemotherapy O O O X X X X X O O Cancer cell with mutation causing MDR over-production O O O Kills most cells. Except if some have mutation that allow them to be resistant. Continues to replicate

Evolution: changes in DNA as information transmitted O O O Cancer cell with mutation

Evolution: changes in DNA as information transmitted O O O Cancer cell with mutation causing MDR over-production Apply chemotherapy O O O X X X X X O O O Continues to replicate O O O O Kills most cells. Except if some have mutation that allow them to be resistant. O O O O O Tumor with cells expressing MDR

Some cancers over-express MDR toxin MDR MDR xi To toxin MDR MDR MDR toxin

Some cancers over-express MDR toxin MDR MDR xi To toxin MDR MDR MDR toxin toxin MDR n I’m a cancer cell with over-expressing MDR. I laugh at your toxins.

One of the latest chemotherapy treatments involves cutting off the blood supply to the

One of the latest chemotherapy treatments involves cutting off the blood supply to the tumor. (anti-angiogenesis) Cells need the proximity of blood vessels to survive

Tumors must have sufficient blood flow to continue cell division induce blood vessel growth

Tumors must have sufficient blood flow to continue cell division induce blood vessel growth (angiogenesis)

Tumors Evolve: Only tumor cells near blood vessels or that can attract blood vessels

Tumors Evolve: Only tumor cells near blood vessels or that can attract blood vessels survive.

Targeting toxins to cancer cells… A vesicle with mutant genes that cause blood vessels

Targeting toxins to cancer cells… A vesicle with mutant genes that cause blood vessels to die is directed to newly growing blood vessels by interacting with Integrins are present on newly growing blood vessels, but not on established blood vessels.

Detecting Cancer or Types of Cancer

Detecting Cancer or Types of Cancer

Normal Cells Cancer Cells

Normal Cells Cancer Cells

A Microarray is a chip with DNA sequences (genes) bound to the surface at

A Microarray is a chip with DNA sequences (genes) bound to the surface at known locations. It can be used to track or monitor expression of many genes.

Tracking changes in gene expression using a Microarray

Tracking changes in gene expression using a Microarray

Making c. DNA from RNA

Making c. DNA from RNA

Tracking changes in gene expression using a Microarray

Tracking changes in gene expression using a Microarray

Tracking changes in gene expression using a Microarray

Tracking changes in gene expression using a Microarray

Use of microarray to estimate genes likely present in malignant cancers

Use of microarray to estimate genes likely present in malignant cancers

Use of microarray to estimate genes likely different genes present in malignant cancers Patients

Use of microarray to estimate genes likely different genes present in malignant cancers Patients cancer free for 5+ years Patients cancer spread in 5 years similar to Fig 22. 19

Fig 22. 19 Microarrays can be used to get information about types of cancers

Fig 22. 19 Microarrays can be used to get information about types of cancers

Young (>55) Breast cancer patients More accurate profiling of tumors results in more accurate

Young (>55) Breast cancer patients More accurate profiling of tumors results in more accurate choices of treatments. Patients with benign tumors can avoid chemotherapy (adjuvant).

Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari, K

Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari, K M Lonergan, R T Ng, C Mac. Aulay, W L Lam, and S Lam BMC Genomics, 8: 297

Table 1: Subject Demographics CS=current smoker, FS=former smoker, NS=never smoked Effect of active smoking

Table 1: Subject Demographics CS=current smoker, FS=former smoker, NS=never smoked Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8: 297

Overlapping and unique genes expression Effect of active smoking on the human bronchial epithelium

Overlapping and unique genes expression Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8: 297 Fig 1 B

Table 3: Reversible gene expression upon smoking cessation related to mucus secretion (genes in

Table 3: Reversible gene expression upon smoking cessation related to mucus secretion (genes in bold have not been previously associated with smoking) Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8: 297

Some changes in gene expression induced by smoking are reversible CABYR ENTPD 8 Effect

Some changes in gene expression induced by smoking are reversible CABYR ENTPD 8 Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8: 297 TFF 3 Fig 4 A

Smoking can induce irreversible changes in gene expression MUC 5 AC GSK 3 B

Smoking can induce irreversible changes in gene expression MUC 5 AC GSK 3 B Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8: 297 Fig 4 B

Treating cancer: • Avoid it – Avoid mutagens – DNA repair gets less efficient

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

Cancer: Detection and Treatment Henrietta Lacks Cell Culture Forensics. S. O’brien PNAS July 3,

Cancer: Detection and Treatment Henrietta Lacks Cell Culture Forensics. S. O’brien PNAS July 3, 2001 vol. 98 no. 14 7656 -7658