Cell Culture Forensics. S. O

1
Cancer Causes and Treatment
Henrietta Lacks
Cell Culture Forensics. S. Obrien PNAS July 3,
2001 vol. 98 no. 14 7656-7658
2
Henrietta Lacks the source of HeLa cells
Cell Culture Forensics. S. Obrien PNAS July 3,
2001 vol. 98 no. 14 7656-7658
3
Henrietta Lacks the source of HeLa cells
During the 1970s and 1980s, 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,
HeLa, established by George Gey at the Johns
Hopkins Medical School in 1951
Cell Culture Forensics. S. Obrien PNAS July 3,
2001 vol. 98 no. 14 7656-7658
4
Henrietta Lacks the source of HeLa cells
An estimated 10 million of research was
discredited.
Cell Culture Forensics. S. Obrien PNAS July 3,
2001 vol. 98 no. 14 7656-7658
5
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.

6
A cell becomes cancerous when there are incorrect
positive AND negative signals.
7
Multiple mutations are required for cancer to
occur
Fig22.17
8
Balance between Longevity and Health
Fig. 3 TRENDS in Ecology and Evolution Vol 21 pg
47
9
How do these mutations arise?
10
Fig 22.18
Chromosome abnormalities in cancer cells
11
Causes of mutations

• Replication errors
• Exacerbated by poor DNA repair
• Genetic predispositions for poor repair or
  already having some mutations
• Limited by telomere length

12
Tbl 22.10
13
Causes of mutations

• Replication errors
• Exacerbated by poor DNA repair
• Limited by telomere length
• Other biological agents
• Viruses
• Transposons

14
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

15
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
16
Chernobyl fireApril 26, 1986
http//video.google.com/videoplay?docid1108163171
078608385
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The Chernobyl accident was by far the largest
unintentional release of radioactive material
into the environment and caused widespread
contamination in Europe.
18
After the accident on April 26, 1986, 116,000
people were evacuated, most from a zone of 30-km
radius. That included about 45,000 people from
the town of Pripyat.
19
The most heavily exposed emergency workers
received doses that were sufficiently high to
kill them in the weeks and months after the
accident.
20
Chernobyl April 26, 1986 Cancer consequences of
the Chernobyl accident 20 years on J.
Radiological Protection 26 (2006)
127140 Elisabeth Cardis et al.
21
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22
The rapidity of increased childhood thyroid
cancer in the heavily contaminated areas of
Belarus, Ukraine and Russia was surprising.
4 years
23
After the accident on April 26, 1986, 116,000
people were evacuated, most from a zone of 30-km
radius. That included about 45,000 people from
the town of Pripyat.
24
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For more pictures http//www.nikongear.com/Chern
obyl/Chernobyl_1.htm
26
US Mortality, 2000
of deaths
of all deaths
Rank
Cause of Death

• 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. Alzheimers disease 49,558 2.1
• Nephritis 37,251 1.5
• 10. Septicemia 31,224 1.3

Source US Mortality Public Use Data Tape 2000,
National Center for Health Statistics, Centers
for Disease Control and Prevention, 2002.
27
Change in the US Death Rates by Cause, 1950
2000
Rate Per 100,000
1950 2000
Cancer
HeartDiseases
Pneumonia/Influenza
CerebrovascularDiseases
Age-adjusted to the 2000 US standard
population. Source US Mortality Volume 1950,
National Vital Statistics Report, 2002, Vol. 50,
No. 15.
28
2003 Estimated US Cancer Cases
Men675,300
Women658,800
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
Prostate 33 Lung bronchus 14 Colon
rectum 11 Urinary bladder 6 Melanoma of
skin 4 Non-Hodgkin
lymphoma 4 Kidney 3 Oral Cavity 3 Leukemia 3
Pancreas 2 All Other Sites 17
Excludes basal and squamous cell skin cancers
and in situ carcinomas except urinary
bladder. Source American Cancer Society, 2003.
29
2003 Estimated US Cancer Deaths
Men285,900
Women270,600
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 bronchus 31 Prostate 10 Colon
rectum 10 Pancreas 5 Non-Hodgkin 4lymphoma
Leukemia 4 Esophagus 4 Liver/intrahepatic 3bi
le duct Urinary bladder 3 Kidney 3 All other
sites 22
ONSOther nervous system. Excludes basal and
squamous cell skin cancers and in situ carcinomas
except urinary bladder. Source American Cancer
Society, 2003.
30
Cancer Death Rates, for Men, US, 1930-1999
Rate Per 100,000
Lung
Stomach
Prostate
Colon and rectum
Pancreas
Liver
Leukemia
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.
31
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.
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37
Treating cancer

• Avoid it
• Avoid mutagens
• DNA repair gets less efficient as we age

38
Our immune system protects us from cancer
T-cells recognize and eliminate abnormal cells
such as cells with many mutations
39
Fig 22.15
P53 is activated by DNA damage
40
p53 can induce apoptosis via two pathways
Nuclear and/or Mitochondrial
41
Treating cancer

• Avoid it
• Avoid mutagens
• DNA repair gets less efficient as we age
• Surgery
• Must remove all cancer cells
• Non-invasive

42
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
• -gt cellular self-destruction
• Mutagenic, side effects

43
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

44
Chemotherapy
Toxin
X
X
a rapidly dividing cell
45
Normal Multi-Drug Resistance protein
toxin/hormone/etc
MDR
toxin/hormone/etc
toxin/hormone/etc
MDR
MDR
MDR
toxin/hormone/etc
46
Some cancers over-express MDR
toxin
toxin
toxin
toxin
Toxin
MDR
MDR
MDR
MDR
Im a cancer cell with over-expressing MDR. I
laugh at your toxins.
toxin
MDR
toxin
MDR
toxin
toxin
MDR
MDR
MDR
MDR
MDR
MDR
toxin
toxin
toxin
toxin
47
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
48
Evolution changes in DNA as information
transmitted
O
O
O
Cancer cell with mutation causing MDR
over-production
O
O
O
O
O
O
O
O
49
Evolution changes in DNA as information
transmitted
O
O
O
Cancer cell with mutation causing MDR
over-production
O
O
O
O
O
O
O
O
Apply chemo-therapy
X
X
X
O
O
O
X
X
X
O
O
O
O
X
X
X
X
O
O
O
O
Kills most cells. Except if some have mutation
that allow them to be resistant.
50
Evolution changes in DNA as information
transmitted
O
O
O
Cancer cell with mutation causing MDR
over-production
O
O
O
O
O
O
O
O
Apply chemo-therapy
Continues to replicate
O
X
X
X
O
O
O
X
X
X
O
O
O
O
X
X
X
X
O
O
O
O
Kills most cells. Except if some have mutation
that allow them to be resistant.
51
Evolution changes in DNA as information
transmitted
O
O
O
Cancer cell with mutation causing MDR
over-production
O
O
O
O
O
O
O
O
Apply chemo-therapy
Continues to replicate
O
X
X
X
O
O
O
X
X
X
O
O
O
O
O
O
O
O
O
O
O
X
X
X
X
O
O
O
O
Kills most cells. Except if some have mutation
that allow them to be resistant.
O
O
O
O
Tumor with cells expressing MDR
52
Some cancers over-express MDR
toxin
toxin
toxin
toxin
Toxin
MDR
MDR
MDR
MDR
Im a cancer cell with over-expressing MDR. I
laugh at your toxins.
toxin
MDR
toxin
MDR
toxin
toxin
MDR
MDR
MDR
MDR
MDR
MDR
toxin
toxin
toxin
toxin
53
Effect of active smoking on the human bronchial
epithelium transcriptome (2007)R Chari, K M
Lonergan, R T Ng, C MacAulay, W L Lam, and S
LamBMC Genomics, 8297
54
Table 1 Subject Demographics
CScurrent smoker, FSformer smoker, NSnever
smoked
Effect of active smoking on the human bronchial
epithelium transcriptome (2007) R Chari et el.
BMC Genomics, 8297
55
Overlapping and unique genes expression
Effect of active smoking on the human bronchial
epithelium transcriptome (2007) R Chari et el.
BMC Genomics, 8297
Fig 1B
56
Some changes in gene expression induced by
smoking are reversible
CABYR
ENTPD8
TFF3
Fig 4A
Effect of active smoking on the human bronchial
epithelium transcriptome (2007) R Chari et el.
BMC Genomics, 8297
57
Smoking can induce irreversible changes in gene
expression
MUC5AC
GSK3B
Fig 4B
Effect of active smoking on the human bronchial
epithelium transcriptome (2007) R Chari et el.
BMC Genomics, 8297
58
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

59
Cancer Causes and Treatment
Henrietta Lacks
Cell Culture Forensics. S. Obrien PNAS July 3,
2001 vol. 98 no. 14 7656-7658