•Homework #3 is due 11/15•Bonus #2 is posted•No class on 11/20
Mitosis is tightly regulated: checkpoints
A cell becomes cancerous when there are incorrect positive AND negative
signals.
GO! STOP!
cancer
similar to Fig 15.36
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
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
X X
Normal Multi-Drug Resistance protein
MDR
MD
RMDR
MD
Rtoxin/hormone/etc
toxin/hormone/etc
toxin/h
ormon
e/etctoxi
n/h
orm
one/
etc
Some cancers over-express MDR
Toxin
MDR
MD
R
MDRMDRMDR
MD
RMDRMDRMDRMDR
MD
RM
DR
toxin toxin
toxin toxin toxin toxin
toxintoxinto
xin
toxi
n
toxin toxin
I’m a cancer cell with over-expressing MDR. I laugh at your toxins.
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The Epigenetic Progenitor Origin of Human Cancer (2007) A P Feinberg, R Ohlsson, S Henikoff Nature Reviews Genetics 7: 21-31
Mutations continue after cancer develops
O
O
OOO
O
O
OO
OOCancer 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
Applychemo-therapy
XXX
XX X XXXX
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
XXX
XX X XXXX
Kills most cells.Except if some have mutation that allow them to be resistant.
Continues to replicate
Evolution: changes in DNA as information transmitted
Applychemo-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
XXX
XX X XXXX
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
Applychemo-therapy
Cancer cell with mutation causing MDR over-production
Some cancers over-express MDR
Toxin
MDR
MD
R
MDRMDRMDR
MD
RMDRMDRMDRMDR
MD
RM
DR
toxin toxin
toxin toxin toxin toxin
toxintoxinto
xin
toxi
n
toxin toxin
I’m a cancer cell with over-expressing MDR. I laugh at your toxins.
Cells need the proximity of blood vessels to survive
One of the latest chemotherapy treatments involves cutting off the blood supply to the tumor.(anti-angiogenesis)
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
Fig 13.18-19
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
Patients cancer free for 5+ years
Patients cancer spread in 5 years
Use of microarray to estimate genes likely present in malignant cancers
similar to Fig 13.18-19
different genes
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 LamBMC Genomics, 8:297
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Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8:297
CS=current smoker, FS=former smoker, NS=never smoked
Table 1: Subject Demographics
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Overlapping and unique genes expression
Fig 1B
Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8:297
Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8:297
Table 3: Reversible gene expression upon smoking cessation related to mucus secretion (genes in bold have not been previously associated with smoking)
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CABYR ENTPD8 TFF3
Fig 4AEffect 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
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MUC5AC GSK3B
Fig 4BEffect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8:297
Smoking can induce irreversible changes in gene expression
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
•Homework #3 is due 11/15•Bonus #2 is posted•No class on 11/20