PVS 297 Silbart Causes of Cancer 21105

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PVS 297 SilbartCauses of Cancer2/11/05
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Cancer Trends What single factorhas driven the
dramatic increase in lung cancer rates over the
past 40 years?
(Damjanov, Ivan. Pathobiology for the
Health-Related Professions, 1996, p. 100)
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(Damjanov, Ivan. Pathobiology for the
Health-Related Professions, 1996, p. 100)
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Cancer Incidence - A disease of aging?
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Is cancer a genetic disease
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Stages of Tumor Growth
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The Neoplastic Process
Primary tumors rarely killSecondary tumors
(metastases)are difficult to treat and in
general, cant all be removedby surgery.
(Damjanov, Ivan. Pathobiology for the
Health-Related Professions, 1996, p. 91)
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Cancer can be initiated by1. Physical
agents2. Chemical agents3. Viruses4.
Endogenous damage to DNA (e.g.
oxidation)Smoking increaseslung cancer risk
by22-fold. 400,000 deaths per year
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Structure of some common chemical carcinogens
Do all chemicals cause cancer? No, only about
250/80,000 are thought to cause cancer in humans
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Metabolic Activation of Xenobiotics
Xenobiotic
Metabolite
Elimination
Reactive Intermediate (unstable C or N)
Covalent binding to Macromolecules (e.g.
protein, lipid, DNA or RNA)
Altered Protein (neo-antigen)
DNA Damage (mutation)
Tissue Injury (necrosis)
Cancer
Adapted from (Amdur, Mary O., John Doull,
Curtis D. Klaassen, Toxicology, 1991, p. 125)
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DNA damage induced by UV light and
ionizingradiation. Both single and double
stranded breaks can result. Double strand breaks
are difficult torepair and often lead to cell
death or cancer.
(Damjanov, Ivan. Pathobiology for the
Health-Related Professions, 1996, p. 91)
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Thymine Dimers
UV light also can induce a DNA lesion known as a
thymine dimer. This is an inter-strand covalent
linkagebetween two adjacent thymine residues
(Lehninger, Albert L. Biochemistry, 1975, p. 881)
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DNA damage must berepaired prior to
cellreplication to avoidmutations (and cancer).
(Lehninger, Albert L. Biochemistry, 1975, p. 915)
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Q Why do we care so much about mutations? A An
accumulation of geneticerrors can lead to cell
transformation and altered phenotypic behavior
esp. Angiogenesis and Metastasis !
BLOOD VESSELS change in two useful ways in
response to antiangiogenic therapy. Normal
vessels (a) are well organized and have even
diameters, whereas those from a colon cancer (b)
are dilated and tortuous. Angiogenesis inhibitors
prune excess, inefficient vessels (c)--which
initially "normalizes" the vasculature and helps
chemotherapeutic drugs to reach tumors.
Eventually, though, increasing numbers of
vessels begin to die (d).
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Metastasis
This process refers to the spread of cancer from
its original site to other areas in the body.
Cancer cells have the ability to invade the
blood vessels and find their way into the
bloodstream. Once in the blood, cancer cells can
go to virtually any part of the body and make a
home for themselves. Each cancer has a particular
pattern of spreading (e.g. pancreas and breast
cancer to bone colon cancer to liver).
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Cells dont just divide

• Cell division is a very tightly controlled
  process, involving perhaps as many as 300 genes.
  Specific genes are turned on and off with great
  precision. Proper coordination of these events is
  critical to successful cell division.
• Cells only divide when signaled to do so. These
  signals include hormones, growth factors,
  contacts with neighboring cells, cytokines etc.
  (mitogens).
• Cell sense the signals (in general) via protein
  receptors expressed in the plasma membrane. The
  signal is transduced to reach the nuclease
  through transduction pathways. Inappropriate
  signaling (through mutation) leads to
  inappropriate decisions in the nucleus.

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Once a cell receives a signal to divide, it
enters the cell cycle 18-24 hours later you
have two cells!
Hartwell, Hunt and Nurse sharedthe 2001 Nobel
Prize (physiologyand medicine) for
discoveringkey regulators of this cycle
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http//www.people.virginia.edu/rjh9u/celcycreg.ht
ml
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Once signals are receivedat the membrane
receptor,the cell passes thebaton from
proteinto protein, ultimatelyaltering gene
expressionwithin the nucleus.
Over-expression or activating mutationscan
leave the cell in analways onconfiguration.
Genome Informatics 13 361-2 (2002)
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Definition of Proto-oncogenes and oncogenes

• Proto-oncogenes - segments of DNA, that are
  responsible for cell growth and proliferation.
  They normally remain dormant until activated
  during cell repliction.
• Over 50 such segments currently identified.
• Cellular oncogenes, "c-onc" have 3 letter code.
• Chromosomal location known for many human
  oncogenes.
• Often produce a protein product - enzyme with
  regulatory activity.

Oncogenes - Oncogenes are mutated forms of genes
that are normally present in a cells chromosomal
DNA. These are genes whose action positively
promotes cell proliferation. The normal
non-mutant versions are properly called
proto-oncogenes. The mutated versions are either
over-expressed, or fold into a permanently
activated configuration.
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Proto-oncogenes regulate the cell cycle
Inappropriate expression (either by timing or
amount) can result in disordered growth
characteristics, generally manifest by early
entry into the cell cycle, or the loss of
important checkpoint controls. Additionally,
mutations altering the function (activity) of
these genes can cause dis-regulated growth
characteristics.
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(Damjonov, Ivan. Pathobiology for the
Health-Related Professions, 1996, p. 94.)
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Oncogene Activation via Chromosomal Translocation
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Gene A
Gene B
e.g. promoter
Gene B
Gene B
Gene A
Gene A
Gene B
Fusion Protein
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But inhibitory pathways are also critically
important!
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Terminal Differentiation

• Actively dividing cells can also receive signals
  to stop dividing. This is termed terminal
  differentiation, and marks the end of the
  maturation process. These cells generally will
  perform a given function for the rest of their
  lives, without further cell division. Example
  TGF-beta, retinoic acid, vitamin D etc.
• Disruption of such signals also favors tumor
  progression.

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Cell Cycle Checkpoints G1/S G2/M
G1/S Repair error before replicating
DNA G2/MCorrect problems with mitotic
spindles and chromosome alignment
before mitosis.
Molecular Pathology Volume 51(6) December 1998
pp 310-316
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Sensing DNA Damage is Critical

• Cells with extensive damage to DNA activate death
  pathways an irreversible sequence of events
  leading to DNA destruction and a non-inflammatory
  degradation (blebbing of cells etc.).
• Genomic instability occurs when cells lose the
  ability to sense damage, pause, repair, and
  proceed forward in the cell cycle. Genetic errors
  then begin accumulating at an accelerated rate.
• When this occurs, they also lose some of their
  ability to enter death pathways.
• Taken together, significant changes in the tumors
  rate of evolution occur, leading to rapid
  phenotypic changes in behavior due to altered
  gene expression.

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The Cell Cycle and its Regulation
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Definition of Tumor Suppressor Genes
Tumor suppressor genes - Tumor suppressor gene
products inhibit cell proliferation. Mutated
versions of these genes are often found in cancer
cells, and have lost their function. The most
important tumor suppressor genes are responsible
for cell cycle check-point control. This allows
the cell to repair errors before proceeding
through the cell cycle.
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Oncoproteins
(Hartwell, Leland H. and Michael B. Kastan. "Cell
Cycle Control and Cancer", Science, December 16,
1994, Vol. 266, p. 1823.)
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http//www-ermm.cbcu.cam.ac.uk/02004416h.htm
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So . . . Mutations in genessuch as cyclin D1,
cdk4 or E2F are gain of functionmutations
oncogenes Mutations in pRB or p16INK4a are
loss of function mutations in tumor
suppressor genes.
Pressing the acceleratorreleasing the brakes
Toward Mechanism-Based Cancer Care (JAMA.
2001285588-593)
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Tumor Suppressor Genes
(Damjanov, Ivan. Pathobiology for the
Health-Related Professions, 1996, p. 95)
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This single gene defectcan result in a heritable
susceptibility to retinaltumor (retinoblastoma)
http//www.akronchildrens.org/neuropathology/fig7-
2.html
http//e42.um.edu.mx/ministeriomedico/ Archivos/15
.jpg
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There are master switches that control the
function of many genes!