•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