An Introduction to Cancer

US Mortality, 2003
No. of % of all
Rank Cause of Death deaths deaths
1. Heart Diseases 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

 2006 Estimated US Cancer Cases*
Men Women
720,280 679,510
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% 4% Non-Hodgkin
lymphoma
Non-Hodgkin 4%
lymphoma 4% Melanoma of skin
Kidney 3% 3% Thyroid
Oral cavity 3% 3% Ovary
Leukemia 3% 2% Urinary bladder
Pancreas 2% 2% Pancreas
All Other Sites18% 22% All Other Sites

*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 Women
Lung & bronchus 31% 291,270 273,560 26% Lung & bronchus
Colon & rectum 10% 15% Breast
Prostate 9% 10% Colon & rectum
Pancreas 6% 6% Pancreas
Leukemia 4% 6% Ovary
Liver & intrahepatic 4% 4% Leukemia
bile duct
3% Non-Hodgkin
Esophagus 4% lymphoma
Non-Hodgkin 3% 3% Uterine corpus
lymphoma
2% Multiple myeloma
Urinary bladder 3%
2% Brain/ONS
Kidney 3%
23% All other sites
All other sites 23%

ONS=Other nervous system.

Source: American Cancer Society, 2006.
 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
Cancer
CellCells
Division

1. Mutations
DNA is replicated
occur in properly.
the DNA when it is replicated.
2. Chemical signals that
startstart
and stop
and stop
the cell
the cycle.
cell cycle are
ignored.
3. Cells communicate with each other so they don’t
3. Cells
become
do not
overcrowded.
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