Cancer

1
Cancer

• Unregulated cell growth
• Family of gt100 related diseases
• Cells multiplying out of control
• Tumor mass of cells from repeated cell division
• A tumor can be benign (not called cancer)
• Grows slowly
• Tissue remains differentiated
• Enclosed in a capsule
• A benign tumor can still be dangerous
• E.g. a brain tumor, slowly crushes brain
• Cells from tumor spread elsewhere metastasis
• Tumor that metastasizes malignant

2
Cancer cells are different

• In culture, are rounded and float rather than
  stick to surfaces.
• Become de-differentiated
• Immortal
• Do not respond to cell signals
• Do not stop growing when crowded or touching
• No contact inhibition
• No dependence on normal growth signals
• Loss of normal number and structure of chromosomes

3
Types of cancer
Cancer is named from the type of tissue in which
it arises. There are various historical
classifications.
Carcinomas from epithelial tissue 90 of all
cancers. Leukemias, lymphomas, and myelomas from
bone marrow and blood cells 8 of all
cancers. Sarcomas solid connective tissue such
as muscle and bone 2 of all cancers. Cells that
multiply often are more likely to form cancers.
http//www.willamette.edu/stas/physiology/labs/la
b1/epithelial2a.jpg
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Cancer and aging
As people age, more mutations accumulate,
increasing the risk of cancer. Also, as cells
age, they too can become cancerous.
http//ovid.iss.it/html/lecture/pc0161/img003.GIF
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Cancer is a genetic disease

• Predisposition to cancer can be inherited
• Breast cancer, retinoblastoma, Li-Fraumeni
• Clonal expansion all cells in a tumor descend
  from the abnormal cell, all inherit bad genes.
• Agents that damage, mutate DNA cause cancer
• Chemicals, UV and ionizing radiation
• Certain genes brought into DNA by viruses cause
  cancer
• Cancer cells show chromosomal loss, damage

6
Review The Cell Cycle

• G1 a time of cell growth and general
  functioning.
• S all the DNA in the cell is doubled to prepare
  for division.
• G2 cell prepares for division.

• M mitosis, actual dividing up of the copied
  chromosomes and distribution to daughter cells.

http//www.med.unibs.it/marchesi/cellcycle.gif
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Review Cell cycle, continued

• G0 cells not dividing may never divide again,
  or may re-enter cycle when needed.

Some cells divide nearly continuously others
enter G0 once mature.
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Cell cycle (continued)

• From cancer research, we have learned that the
  cell cycle is tightly regulated!
• Checkpoints exist at G1/S, at G2/M, and late in
  Mitosis (the M checkpoint)
• At each checkpoint, progress evaluated.
• G1/S checkpoint is DNA in good condition?
• Mutations that allow progression past this
  checkpoint with damaged DNA lead to downward
  spiral of inherited mutations.

9
Molecular regulation

• Two kinds of proteins work together
• cdc kinases and cyclins
• Kinases proteins that phosphorylate other
  proteins
• Adding a PO4 turns molecules on or off
• Kinases always present in the cell
• Cyclins are proteins that change in amounts
  during the cell cycle
• Specific cyclins accumulate at different times.
• Kinase combines with cyclin
• Kinase is activated, given directions
• Kinase phosphorylates proteins controlling cell
  division

10
Kinase/cyclin combination acts during checkpoint
G1/S checkpoint important in cell cycle
regulation. Important tumor suppressor genes
involved in regulation at this step.
Picture based on Hartl Jones, 5th edition.
11
The multi-hit hypothesis

• Cancer results from at least 2 hits, 2
  instances of damage to the DNA.
• Some cancers involve several.
• The gas pedal/ brake analogy
• For the car to move, gas pedal doesnt do much if
  brake is on taking brake off doesnt get car to
  move if gas pedal isnt pressed.
• Cell must get ON signals AND ignore OFF
  signals
• On growth factor stimulation
• Off tumor suppressors

12
New insights into off/on regulation

• Recent research effect of estrogen on entire
  genome of ovarian tissue
• Estrogen is a growth factor, promotes cell
  division
• Genes for promoting cell division AND stopping
  cell division both turned on a balance
• Like riding the brake to keep car under control

13
Genetics of on and off

• On signal mutations are dominant for cancer
• If other mutations present, one mutated copy of
  the gene is enough for cancer.
• Off signal mutations are recessive for cancer.
• But are dominant for a susceptibility to cancer.
• Both copies of tumor suppressor genes must be bad
  for cancer to occur.
• Familial predispositions usually one copy is
  already mutated, much more likely to get a
  mutation in one copy of the gene than both.

14
Genetics visualized
15
What are the on and off signals?

• Off signals tumor suppressor genes
• Genes (and their proteins) which act to prevent
  the cell from proceeding through the cell cycle.
• pRB, p53, BRCA1, BRCA2
• On signals proto-oncogenes
• Genes that stimulate cell division.
• Mutated forms called oncogenes
• Through various malfunctions, stimulate cell
  division when inappropriate.

16
Tumor suppressor genes

• Retinoblastoma
• Cancer of the retina of the eye
• Occurs in about 1 in 15,000, usually ages 1 3.
• 40 inherited susceptibility 60 sporadic
• RB1 gene codes for pRB, a tumor suppressor
• Functions at the G1/S checkpoint
• Protein is active during G0 and G1
• Binds to E2F, a transcription factor
• Prevents E2F from working, prevents transcription
  of genes that aid cell division.

17
RB continued
At G1/S, cyclin complex phosphorylates pRB,
inactivating it and releasing E2F.
E2F is a transcription factor controlling 30
genes needed for progression through cell
cycle. Mutation in both copies of pRB allows
unregulated passage through G1/S checkpoint.
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p53 the Guardian of the Genome

• An important tumor suppressor various signals
  including DNA damage activate p53 which then
• Activates DNA repair
• Blocks cell division
• Prevents replication of damaged DNA
• Triggers apoptosis in damaged cells.
• Cells beyond repair are killed to avoid mutations
• Mutations in p53 account for gt50 of cancers.
• Single mutation is dominant negative because of
  tetrameric structure.

19
Action of p53

• Continually made but continually degraded
• Also Inactive because NOT phosphorylated

DNA damage activates protein kinases Results in
phosphorylation (thus activation) Degradation of
p53 stops. Active p53 accumulates in cell,
carries out its duties
http//www.accelrys.com/webzine/01/q1/appnotes/gen
eatlas_japan/p53.jpg
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BRCA genes

• 10 of breast cancers involve a familial
  susceptibility mutations in BRCA1 or BRCA2.
• Woman with a faulty BRCA1 allele has an 85
  chance of developing mutation in 2nd allele, thus
  getting breast cancer (with risk of ovarian
  cancer)
• Proteins coded for by BRCA1 and 2 in nucleus
• Abundant during S phase
• Work with other proteins in DNA repair, etc.
• Failure of these proteins to repair may result in
  the mutations that lead to cancer.

21
Cancer continued

• Proto-oncogenes to oncogenes
• Proto-oncogenes are normal cell genes that turn
  on cell division.
• A mutated or over-expressed proto-oncogene
  becomes an oncogene gene leading to cancer
• Given other appropriate mutations
• These are dominant mutations for a cancer
  phenotype that is, only one bad copy is enough.
• Two gas pedals one turned on makes it go.

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Control of cell division
Proto-oncogene proteins found in membrane,
cytoplasm, and nucleus.
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Cancer results from too much ON

• Effect of mutations
• Cancer cells produce their own growth factors.
• Increase in growth factor receptors.

• ON signal sent to nucleus no matter what.
• Example ras, described in text.
• Mutation in transcriptional activator wrong
  genes turned on.

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Oncogenes the rude surprise

• Peyton Rous, 1966 Nobel Laureate
• Discovered that viruses could cause cancer in
  chickens (e.g. Rous sarcoma virus)
• Molecular biologists identified genes in the
  viruses that were responsible oncogenes.
• DNA hybridization studies revealed we all have
  comparable genes proto-oncogenes.
• In human cancers, viruses can bring oncogenes
  into our DNA, or changes can occur in our DNA
  without virus involvement.

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How oncogenes are made

• Point mutations
• Ras is a intracellular signal peptide
• Mutation makes it always stimulate cell division
• Translocations
• Burkitts lymphoma t(814) moves myc gene to a
  more active promoter, drives proliferation.
• myc is a gene for a transcription factor.
• Philadelphia chromosome t(922) creates a fusion
  protein (protein kinase) that activates cell
  division.

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How oncogenes are made-2

• Over-expression Gene amplification
• too many copies of receptors, internal signalling
  molecules, transcription factors.
• Example myc. Transcription factor that causes
  transcription of genes involved in cell division.
• Virus insertion may put active promoter next to
  gene.
• Virus may bring in extra copies of gene.
• Cmyc-FISH

www.pathology.unibe.ch/.../ speztech/spez_fish.htm
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Another overview

• Historically, several models of cancer have been
  developed since War on cancer declared by Nixon,
  1970.
• ON/Off switch idea
• Multi-hit hypothesis, textbook colon cancer
• Gatekeeper and Caretaker genes
• Gatekeepers tumor suppressor genes. Prevent
  cells from dividing when theyre not supposed to.
• Caretakers protect the DNA, repair damage.

28
Review of Telomerase

• Because of discontinuous synthesis of linear DNA,
  each round of DNA would shorten the chromosome,
  eventually causing chromosome instability and
  cell death. Telomerase adds protective DNA to
  end, making cell immortal.

29
Cancer and Telomerase

• Stem cells, frequently, rapidly dividing cells,
  maintain telomerase.
• Descendents have a life span.
• Telomerase gene is shut off, enzyme not made.
• Lack of telomerase is a cell clock.
• Chromosome becomes unstable, cell undergoes
  apoptosis and dies replaced by new cells.
• Some cells cheat death.
• Cancer cells turn telomerase back on, become
  immortal. Area of active study.

30
Cancer and the Environment

• Familial predispositions exist, but sporadic
  cancers are more common.
• Environmental factors combine with genetic
  background to produce cancer.
• Microbes, chemicals, radiation all implicated.
• Direct experimentation not possible w/ humans.
• Evidence is correlation, not causation.
• Statistical analysis of epidemiological data
• Not proved that smoking causes cancer
• Need statistical evidence plus plausible mechanism

31
Cancer and microbes

• Retroviruses and other inserting viruses
• RNA to DNA, inserts into chromosome, directs
  synthesis of new RNA. HIV, Rous sarcoma virus.
• DNA viruses that insert Hepatitis B
• Hepatitis B infected 100x more likely to get
  liver cancer
• Epstein Barr Virus, Kaposis sarcoma virus
• EBV associated with Burkitt Lymphoma (and mono)
• Herpes virus KSV causes sarcoma in HIV infection

32
Cancer and microbes-2

• Sex causes cancer Papilloma virus and cancer of
  the cervix.
• Papilloma virus causes warts, including genital
  warts sexually transmitted disease.
• Subtypes, instead of causing warts, inserts into
  DNA, causes increased expression of viral protein
  E7. See next slide.
• Helicobacter pylori
• Bacterium now known to cause ulcers.
• Highly correlated with stomach cancer under
  study.

33
Cancer and microbes-3
pRB is a tumor suppressor protein that prevents
the action of transcription factor E2F by binding
to it. Viral protein E7 bids tightly to pRB,
freeing E2F to transcribe genes promoting cell
division.
http//users.rcn.com/jkimball.ma.ultranet/BiologyP
ages/E/E7_Rb.gif
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Cancer and the environment

• Relatively few cancers are inherited, most
  result from interactions with the environment or
  lifestyles
• Tobacco use
• Benzo-a-pyrene, tar, radioisotopes, formaldehyde
• Diet natural and produced carcinogens
• Aflatoxins, nitrosoamines
• Fiber, antioxidant compounds helpful.
• Radiation UV , ionizing