Transcript Cancer Doesn’t Happen Overnight

Cancer Doesn’t
Happen Overnight
The Multi-Step Origin of Cancer
Cancer Occurrence With Age
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The curve is an exponential
rather than additive curve
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Multiple events must occur
before the threshold is met.
Once a critical number of
events have occurred the
likelihood of cancer
increases rapidly
There is no “upper”
boundary on the curve
Most Carcinogens are
Mutagens
The Ames test for mutagenicity. The test uses a strain of Salmonella bacteria
that require histidine in the medium because of a defect in a gene necessary
for histidine synthesis. Mutagens can cause a further change in this gene that
reverses the defect, creating revertant bacteria that do not require histidine.
To increase the sensitivity of the test, the bacteria also have a defect in their
DNA repair machinery that makes them especially susceptible to agents that
damage DNA. A majority of compounds that are mutagenic in tests such as
this are also carcinogenic and vice versa
Carcinogens Listed in the Eleventh ReportNIH Toxicology Program
Part A. Known to be Human Carcinogens. (abbreviated list)
Name or synonym Page No.
Aflatoxins 8
Alcoholic Beverage Consumption 10
Analgesic Mixtures Containing Phenacetin 212
Arsenic Compounds, Inorganic 18
Asbestos 21
Benzene 26
Coal Tars (See Coal Tars and Coal Tar Pitches) 68
Coke Oven Emissions 71
Diethylstilbestrol 98
Dyes Metabolized to Benzidine (See Benzidine and Dyes Metabolized to Benzidine) 29
Environmental Tobacco Smoke (See Tobacco Related Exposures) 251
Estrogens, Steroidal 115
Ethylene Oxide 118
Hepatitis B Virus 131
Hepatitis C Virus 133
Human Papillomas Viruses: Some Genital-Mucosal Types 142
Radon (See Ionizing Radiation) 152
Smokeless Tobacco (See Tobacco Related Exposures) 253
Solar Radiation (See Ultraviolet Radiation Related Exposures) 266
Sunlamps or Sunbeds, Exposure to (See Ultraviolet Radiation Related Exposures) 266
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD); “Dioxin” 241
Tobacco Smoking (See Tobacco Related Exposures) 255
Vinyl Chloride 272
Ultraviolet Radiation, Broad Spectrum UV Radiation (See Ultraviolet Radiation Related Exposures) 266
X-Radiation and Gamma Radiation (See Ionizing Radiation) 147
Bold entries indicate new or changed listing in The Report on Carcinogens, Eleventh Edition.
Red entries- exposure is common and preventable
Carcinogenesis is Accelerated by Tumor
Promoters*
*Carcinogens are mutagens; promoters are mitogenic
(stimulate cell division).
Steps Toward Cancer
Exposure to carcinogens (mutagens)
 Appearance of cells with mutant proto-oncogenes
or tumor suppressor genes
. These steps are common to the appearance of
most cancers. However in some cases exposure
to carcinogens is not necessary
 Exposure to tumor promoters (mitogens) alone
can stimulate cell division and result in higher
incidence of replication errors that uncover preexisting tumor suppressor mutatons
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Estrogen as a Tumor Promoter
Breast
~ number of menstrual cycles
without pregnancy
Tumor Suppressors Like p53
guard the genome
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Normal cells have very little
p53
Mice can survive with no
p53 gene at all
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These mice usually die of
cancer at about 3 months.
DNA damage stabilizes p53
P53 induces p21
P21 halts the cell cycle
If DNA is not repaired
during pause p53 causes
apoptosis
Aquired mutations in these tumor
suppressor genes can result in sporadic
cancer
Inherited cancer
Abnormal gene
Other non-inherited cancers seen with this
gene
Retinoblastoma
RBI
Many different cancers
Li-Fraumeni Syndrome (sarcomas, brain
tumors, leukemia)
P53
Many different cancers
Melanoma
INK4a
Many different cancers
Colorectal cancer (due to familial
polyposis)
APC
Most colorectal cancers
Colorectal cancer (without polyposis)
MLH1, MSH2, or
MSH6
Colorectal, gastric, endometrial cancers
Breast and/or ovarian
BRCA1, BRCA2
Only rare ovarian cancers
Wilms Tumor
WTI
Wilms tumors
Nerve tumors, including brain
NF1, NF2
Small numbers of colon cancers,
melanomas, neuroblastoma
Kidney cancer
VHL
Certain types of kidney cancers
Proposed steps toward colon
cancer
Ademotous polyps
Colon cancer
APC = Tumor suppressor gene often inherited as recessive mutation
p53 = Tumor suppressor – prevents replication of damaged DNA
K- Ras = Oncogene acts in growth signaling pathway
Smad 4 = tumor suppressor slows growth & promotes differentiation
Loss of Checkpoint Control
Results in Genetic Instability
(A) The karyotype of a typical cancer shows many gross abnormalities
in chromosome number and structure. Considerable variation can also
exist from cell to cell. (B) The karyotype of a tumor that has a stable
chromosome complement with few chromosomal anomalies. Its defects
are mostly invisible, having been created by defects in DNA mismatch
repair.
Consequences of Genetic
Instability
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Most cells lose critical genes and die.
Some cells proliferate but are not fit enough
to form tumors and eventually die.
Some cells have just the right set of genes to
out compete normal cells and other unstable
cells and become the progenitors of a
carcinoma.