Transcript The Cell Cycle and Cancer

An Introduction to Cancer
US Mortality, 2003
1.
Heart Diseases
No. of % of all
deaths deaths
685,089
28.0
2.
Cancer
556,902
22.7
3.
Cerebrovascular diseases
157,689
6.4
4.
Chronic lower respiratory diseases
126,382
5.2
5.
Accidents (Unintentional injuries)
109,277
4.5
6.
Diabetes mellitus
74,219
3.0
7.
Influenza and pneumonia
65,163
2.7
8.
Alzheimer disease
63,457
2.6
1.
Nephritis
42,453
1.7
10.
Septicemia
34,069
1.4
Rank Cause of Death
2006 Estimated US Cancer Cases*
Men
720,280
Women
679,510
Prostate
33%
31%
Breast
Lung & bronchus
13%
12%
Lung & bronchus
Colon & rectum
10%
11%
Colon & rectum
Urinary bladder
6%
6%
Uterine corpus
Melanoma of skin
5%
Non-Hodgkin
lymphoma
4%
Kidney
3%
3%
Thyroid
Oral cavity
3%
3%
Ovary
Leukemia
3%
2%
Urinary bladder
Pancreas
2%
2%
Pancreas
18%
22%
All Other Sites
All Other Sites
4%
4%
Non-Hodgkin
lymphoma
Melanoma of skin
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
Source: American Cancer Society, 2006.
2006 Estimated US Cancer Deaths*
Men
291,270
Women
273,560 26%
Lung & bronchus
31%
Colon & rectum
10%
15%
Breast
Prostate
9%
10%
Colon & rectum
Pancreas
6%
6%
Pancreas
Leukemia
4%
6%
Ovary
Liver & intrahepatic
bile duct
4%
4%
Leukemia
Esophagus
4%
3% Non-Hodgkin
lymphoma
Non-Hodgkin
lymphoma
3%
3%
Uterine corpus
2%
Multiple myeloma
Urinary bladder
3%
2%
Brain/ONS
Kidney
3%
All other sites
23%
ONS=Other nervous system.
Source: American Cancer Society, 2006.
23%
Lung & bronchus
All other sites
What is cancer?
• Abnormal cell growth (neoplasia)
• Malignant as opposed to benign
– Benign: slow growth, non-invasive, no metastasis
– Malignant: rapid growth, invasive, potential for
metastasis
Phenotype of a cancer cell
• The Six Hallmarks of Cancer
– Self-sufficient growth signals
• Constitutively activated growth factor signalling
– Resistance to anti-growth signals
• Inactivated cell cycle checkpoint
– Immortality
• Inactivated cell death pathway
Phenotype of a cancer cell (cont'd)
• The Six Hallmarks of Cancer
– Resistance to cell death
• Activated anti- cell death signalling
– Sustained angiogenesis
• Activated VEGF signalling
– Invasion and metastasis
• Loss of cell-to-cell interactions, etc.
Is cancer a heritable
disease?
• There are heritable cancer syndromes
• The majority of cancers, however, are not
familial
• Cancer is a genetic disease, but the
majority of mutations that lead to cancer
are somatic
What causes the mutations that
lead to cancer?
• Viruses: HPV --> cervical cancer
• Bacteria: H. pylori --> gastric cancer
• Chemicals --> B[a]P --> lung cancer
– a component of cigarette smoke
benzo[a]pyrene (BaP)
• UV and ionizing radiation --> skin cancer
• What do these agents have in common?
Mutagens
• Viruses: insertional mutagenesis
• Chemicals: DNA adducts
• UV and ionizing radiation: single
and double strand DNA breaks
What types of genes get
mutated in cancer?
• Oncogenes are activated
– Normal function: cell growth, gene transcription
• Tumor suppressor genes are inactivated
– Normal function: DNA repair, cell cycle control,
cell death
Smoking and Cancer
• About one-third of all cancer cases in the
United States are directly attributable to
cigarette smoking.
– Smoke contains many mutagenic chemicals,
and places them in direct contact with lung
tissues.
• damages genes of epithelial cells lining the lungs
Tobacco Reduces Life
Expectancy
Tumor suppressors
• “Guardian(s) of the genome”
• Often involved in maintaining genomic
integrity (DNA repair, chromosome
segregation)
• Mutations in tumor suppressor genes lead
to the “mutator phenotype”—mutation
rates increase
• Often the 1st mutation in a developing
cancer
p53—a classic tumor suppressor
• “The guardian of the genome”
• Senses genomic damage
• Halts the cell cycle and initiates DNA
repair
• If the DNA is irreparable, p53 will initiate
the cell death process
Rb—a classic tumor suppressor
•
•
•
•
Rb binds to a protein called E2F1
E2F1 initiates the G1/S cell cycle transition
When bound to Rb, E2F1 can't function
Thus, Rb is a crucial cell cycle checkpoint
Chromosomal Instability
Tumor-Suppressor Genes
• Tumor suppressor genes encode proteins
that turn off cell division in healthy cells.
– Cancer may be initiated by the inappropriate
activation of proteins that regulate the cell
cycle, or by the inactivation of proteins that
normally suppress cell division.
Cancer and the Cell Cycle
• Cells control proliferation at several
checkpoints.
– All these controls must be inactivated for cancer to
be initiated.
• Induction of most cancers involves mutations of several
genes.
– explains why most cancers occur in people over 40
» more time for individual cells to accumulate multiple
mutations
The Cell Cycle and Cancer
Cancer
• Cancer is a growth disorder of cells.
– uncontrolled and invasive growth
• results in tumor
– may metastasize
– can be caused by mutagenic chemicals or
possibly viruses
• cell division never stops in a cancerous line, and
are thus essentially immortal
Causes of Cancer
• Sarcomas - arise in connective tissue or
muscle
• Carcinomas - arise in epithelial tissue
– Carcinogens are agents thought to cause
cancer.
• Ames test
– Carcinogenic chemicals are all mutagenic.
The Stages of the Cell Cycle
1. Click on picture for cell cycle animation –
will go to www.cancerquest.org)
2. Use alt-tab keys to go between website
and power point presentation.
3. Click on blank space to proceed to next slide.)
Cancer and the Cell Cycle
• Oncogenes - genes that when introduced into
normal cells cause them to become cancerous
– Originally discovered by transfection - nuclear
DNA from tumor cells is isolated and cleaved into
random fragments, and tested for ability to induce
cancer
Cancer and the Cell Cycle
• Proto-oncogenes are genes encoding proteins
that stimulate cell division.
– Mutated proto-oncogenes become cancer-causing
genes (oncogenes).
• Mutated alleles of many oncogenes are genetically
dominant.
There are several factors that regulate the
cell cycle and assure a cell divides correctly.
1.Before a cell divides,
the DNA is checked
to make sure it has
replicated correctly. (If
DNA does not copy
itself correctly, a gene
mutation occurs.
DNA replication animation:click
on DNA picture
2. Chemical Signals tell a cell when to start
and stop dividing.
(Target cells animation: click on go
sign)
Neighboring cells communicate with dividing
cells to regulate their growth also.
(Normal contact inhibition animation: click on petri dish)
Cancer is a disease of the cell cycle. Some
of the body’s cells divide uncontrollably and
tumors form.
Tumor in Colon
Tumors in Liver
DNA mutations disrupt the cell cycle.
Mutations may be
caused by:
1. radiation
2. smoking
3. Pollutants
4. chemicals
5. viruses
While normal cells will stop dividing if there is a mutation in
the DNA, cancer cells will continue to divide with mutation.
Due to DNA mutations, cancer cells ignore
the chemical signals that start and stop the
cell cycle.
2 animations of cancer cells dividing: click on picture
Due to DNA mutations, cancer cells cannot
communicate with neighboring cells. Cells
continue to grow and form tumors.
Skin cancer
(cancer cells dividing: click on
picture.)
SUMMARY
Normal Cell Division
1. DNA is replicated
properly.
2. Chemical signals start
and stop the cell cycle.
3. Cells communicate with
each other so they
don’t become
overcrowded.
Cancer Cells
1. Mutations occur in the
DNA when it is
replicated.
2. Chemical signals that
start and stop the cell
cycle are ignored.
3. Cells do not communicate
with each other and
tumors form.
What can cancer therapies
target?
• Classic cancer therapies target rapidly
dividing cells
• Target the DNA
– Ionizing radiation
– Chemotherapy
• Many side effects
– Hair loss
– Weakened immune system
– Problems with GI tract
What can cancer therapies target?
Cancer treatments include drugs that can stop
cancer cells from dividing.
What can cancer therapies
target?
• A person's immune system will not
target tumor cells because they appear
to be “self”
• Some new therapies focus on
activating one's immune system
against a cancer
What can cancer therapies
target?
• Modern, targeted therapies attack
specific proteins that are abnormally
expressed in a tumor
• May block over-expressed growth
factor receptors --> Herceptin
• Generally, there are few side effects
since these therapies are specifically
targeted to cancer cells
Curing Cancer
• Preventing start of cancer
– receiving signal to divide
• mutations that increase number of receptors on
cell surface amplify the division signal
– relay switch
• passage of signal into the cell’s interior
– relay switch stuck in “ON” position
Curing Cancer
– amplifying the signal
• amplification of signal within cytoplasm
– releasing the brake
• used to restrain cell division
– checking readiness
• ensures DNA is undamaged and ready to divide
– stepping on the gas
• restore telomerase inhibitor
Potential Cancer Therapy
Targets
Curing Cancer
• Preventing the spread of cancer
– tumor growth
• angiogenesis inhibitors
– metastasis
• cells break off and migrate