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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 HeLa cells
Cell Culture Forensics. S. O’brien PNAS July 3, 2001 vol. 98 no. 14 7656-7658
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. O’brien PNAS July 3, 2001 vol. 98 no. 14 7656-7658
Henrietta Lacks: the
source of HeLa 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 HeLa 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
HeLa 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 pg 47
Mutations
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.
GO!
STOP!
cancer
Multiple mutations are
required for cancer to occur
Fig
22.17
Tbl 22.10
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 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, Ukraine and Russia was surprising.
4 years
US Mortality, 2000
1.
Heart Diseases
# of
deaths
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
Rank Cause of Death
10. Septicemia
% of all
deaths
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 100,000
600
586.8
1950
500
2000
400
300
258.2
200
100
0
193.7 200.9
180.5
60.9
Heart
Diseases
48.1
23.7
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
14%
12%
Lung & bronchus
Colon & rectum
11%
11%
Colon & rectum
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
20%
All Other Sites
Prostate
33%
Lung & bronchus
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.
2003 Estimated US Cancer Deaths*
Lung & bronchus 31%
Men
285,900
Women
270,600
25% Lung & bronchus
Prostate
10%
15% Breast
Colon & rectum
10%
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.
100
Cancer Death Rates*, for Men, US,
1930-1999
Rate Per 100,000
Lung
80
60
Stomach
Prostate
40
Colon and rectum
20
Pancreas
0
1930
Liver
Leukemia
1935
1940
1945
1950
1955
1960
1965
1970
1975
1980
1985
1990
*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.
1995
Cancer Death Rates*, for Women, US,
1930-1999
100
Rate Per 100,000
80
60
Lung
Uterus
40
Breast
Colon and rectum
Stomach
20
Ovary
Pancreas
0
1930
1935
1940
1945
1950
1955
1960
1965
1970
1975
1980
1985
1990
*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.
1995
Tobacco Use in the US, 1900-1999
4000
Per capita cigarette
consumption
90
80
3500
70
3000
60
2500
50
2000
40
1500
30
1000
20
500
Female lung
10
cancer death rate
0
0
19
0
19 0
0
19 5
1
19 0
1
19 5
20
19
2
19 5
3
19 0
3
19 5
4
19 0
4
19 5
5
19 0
5
19 5
6
19 0
6
19 5
7
19 0
7
19 5
8
19 0
85
19
9
19 0
9
20 5
00
Per Capita Cigarette Consumption
4500
100
Year
*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.
Age-Adjusted Lung Cancer Death
Rates*
Male lung cancer
death rate
5000
Tobacco Use in the US, 1900-1999
4000
Per capita cigarette
consumption
90
80
3500
70
3000
60
2500
50
2000
40
1500
30
1000
20
500
Female lung
10
cancer death rate
0
0
19
0
19 0
0
19 5
1
19 0
1
19 5
20
19
2
19 5
3
19 0
3
19 5
4
19 0
4
19 5
5
19 0
5
19 5
6
19 0
6
19 5
7
19 0
7
19 5
8
19 0
85
19
9
19 0
9
20 5
00
Per Capita Cigarette Consumption
4500
100
Year
*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.
Age-Adjusted Lung Cancer Death
Rates*
Male lung cancer
death rate
5000
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 as cells with many mutations
Fig 22.15
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
X
X
a rapidly dividing cell
Normal Multi-Drug Resistance protein
toxin/hormone/etc
MDR
MDR
toxin/hormone/etc
toxin/hormone/etc
MDR
toxin/hormone/etc
MDR
toxin
toxin
toxin
MDR
MDR
MDR
MDR
MDR
MDR
MDR
MDR
MDR
MDR
toxin
toxin
toxin
toxin
toxin
toxin
I’m a cancer cell with
over-expressing MDR.
I laugh at your toxins.
MDR
toxin
toxin
MDR
toxin
Some cancers over-express MDR
Mutations continue after cancer develops
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
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
O
O
O
O
O
O
O
O
Cancer cell with
mutation causing
MDR over-production
Evolution: changes in DNA as information transmitted
O
O
O
O
O
O
O
O
O
O
O
Apply
chemotherapy
X
O
O
O
X
X
O
X
X
X
O
O
X
X
O
X
X
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
O
O
O
O
O
O
O
O
Apply
chemotherapy
O
X
O
O
O
X
X
O
X
X
X
O
O
X
X
O
X
O
O
O
O
Kills most cells.
Except if some have mutation
that allow them to be resistant.
X
Cancer cell with
mutation causing
MDR over-production
Continues to
replicate
Evolution: changes in DNA as information transmitted
O
O
O
O
O
O
O
O
O
O
O
Cancer cell with
mutation causing
MDR over-production
Apply
chemotherapy
O
X
O
O
X
O
O
O
O
Kills most cells.
Except if some have mutation
that allow them to be resistant.
X
O
O
X
X
O
X
X
X
O
O
X
X
O
Continues to
replicate
O
O
O
O
O
O
O
O
O
O
Tumor with cells expressing MDR
toxin
toxin
toxin
MDR
MDR
MDR
MDR
MDR
MDR
MDR
MDR
MDR
MDR
toxin
toxin
toxin
toxin
toxin
toxin
I’m a cancer cell with
over-expressing MDR.
I laugh at your toxins.
MDR
toxin
toxin
MDR
toxin
Some cancers over-express MDR
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
(angiogenesis)
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 to die is directed
to newly growing blood
vessels by interacting
with Integrins.
Integrins are present on newly
growing blood vessels, but
not on established blood
vessels.
Detecting
Cancer or
Types of
Cancer
Normal Cells
Cancer Cells
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
Making cDNA
from RNA
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
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
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 M Lonergan, R T Ng, C
MacAulay, W L Lam, and S Lam
BMC Genomics, 8:297
Table 1: Subject Demographics
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
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
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Effect of active smoking on the human
bronchial epithelium transcriptome (2007)
R Chari et el. BMC Genomics, 8:297
Fig 1B
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
ENTPD8
TFF3
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8:297
Fig 4A
Smoking can induce irreversible changes in
gene expression
MUC5AC
GSK3B
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8:297
Fig 4B
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, 2001 vol. 98 no. 14 7656-7658