Transcript Cancer

Chapter 16- Cancer
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Where we’re going
Characteristics of cancer cells
Some names
Convince you that cancer is a result of
multiple genetic defects
Molecular genetics of cancer
We’ll be connecting cancer to growth and
signaling.
A few treatments
Why this is important
• About 1 in 4 of us get cancer, 1 in 5 die of
it- at least.
• It’s very much a disease that can be
understood at the molecular level.
• Our understanding has not resulted in the
cures we’d like
No particular
relevance- painted
by Van Gogh in the
1880’s!
Cancers vary in terms of
getting a type of cancer
and dying from that type
Data 2000-2003
Basic Properties of cancer cells
• Uncontrolled- grow at the usual rate, but
then keep growing when other cells would
normally stop- ignore stopping signals, or
grow w/o added signals.
• Invasive
• Immortal- normal cells undergo
senescence- telomerase is 1 factor.
• Chromosomal abnormalities- aneuploid
Well-behavedstop growing
when they
cover the dish.
Not wellbehavedkeep growing
after they
cover the dish.
Internal
signals allow
serum-free
growth
• Names:
• A. tumor/neoplasm: clone of cells
capable of uncontrolled growth;
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benign: contained
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malignant: spreading
• B. classified by tissue of origin:
• carcinoma-epithelial tissue
• sarcoma- mesodermal origin: muscles,
connective tissue, vascular tissue
• leukemia/lymphoma- blood forming
(hemopoietic) cells
Origins of cancer cells
• Clonal, but highly mutable
• Chronic myelogenous leukemiatranslocation from 22 to 9 (Philadelphia
chromosome)
More than one defect:
• 1016 cell divisions in a lifetime;
• even at a mutation rate of 1/106, we'd have
1010 mutations in every gene! Thus, it
may take 3--7 events, in the same cell, to
make it cancerous. evidence:
• 1. frequency of
cancer, peryear, goes
up with ageaccumulated
mutations. Molecular
evidence agrees with
this.
• http://www.ncbi.nlm.ni
h.gov/books/bv.fcgi?ri
d=mboc4.figgrp.4270
Colon cancer of women
in England & Wales
• 2. tumor progression: e.g., cervical
carcinoma: the cells can be in a
precancerous stage; undifferentiated;
some may be immortal; yet not be
cancerous. Only a fraction of the
precancerous cells become cancerous.
Thus, the changes are typically sequential,
rather than having to be simultaneous.
Very much an evolutionary event!
Normal- small
nuclei
Precancerouscarcinoma in situ
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3. Initiator/promoter studies: Fig. 23-19,
MBOC:
http://www.ncbi.nlm.nih.gov/books/bv.fc
gi?rid=mboc4.figgrp.4300
Many cells revert to a less differentiated
stage- carcinoembryonic antigen is
expressed in embryos, and also in
cancers.
The initiator is
mutagenic, while the
promoter stimulates
growth- the mutant
population increases,
increasing the likelihood
of further mutations
4. Molecular evidence: With the advent of cloned oncogenes,
it's been possible to add such genes to normal cells or animals, and
determine the results.
a. 3T3 cells- already abnormal; single added oncogene makes them
cancerous.
b. normal cells require two oncogenes: myc & ras both result in
transformation. Same results with transgenic mice. 23-30
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.4325
These are mice with
transgenic, overexpressed
oncogenes.
A typical progression of cancer
So what causes all those
mutations?
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Life
Maybe mutagens
Viruses in some cases
Diet can have an effect
However, correlation doesn’t
necessarily mean causation…
How are cancer cells different in
gene expression?
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We can use microarrays to find out!
1000’s of gene-specific sequences.
Isolate mRNA from cell, turn into cDNA
Hybridize to sequences
Can quantify amounts.
ALL- lymphoidlymphocytes
AML: myeloidgranulocytes,
macrophages,
dendritic cells
Sometimes this helps- or not
IV. Molecular genetics of cancer: Two
basic effects that genes can have on cell
growth;
• A. stimulate growth: oncogenes; genes that
are normally turned on as part of growth, now
unusually active. Dominant mutations; also DNA
tumor virus genes.
• B. inhibit excessive growth: some genes seem
to be there to keep oncogenes in line; these
mutations tend to be recessive. Tumor
suppressor genes,
• Cell fusion studies can differentiate between
these- Suppressors are recessive to normal, and
oncogenes are often dominant over normal.
• C. types of stimulatory genes:
• 1. DNA tumor virus genes:
non-permissive infections
result in excessive growth:
human viruses infecting
hamsters. The virus produces
a protein that, in one case
binds and inactivates two of the
major tumor suppressor genesRb and p53, thus allowing
uncontrolled DNA replication.
(Fig 23-35)
• http://www.ncbi.nlm.nih.gov/bo
oks/bv.fcgi?rid=mboc4.figgrp.4
334
2.Oncogenes: most were discovered in RNA
tumor viruses: carried by certain tumor
viruses. We have homologous genes- protooncogenes.
Types- Cell signaling (RAS), cell regulating,
growth factors, GF receptors, transcription
factors, anti-apoptosis proteins.
With more
changes…
Ways to become a bad
oncogene
New copy, overexpressed, comes
in from retrovirus! Retrovirus
activates, by insertion, nearby
proto-oncogene!
These are all
oncogenes
Tumor suppressor genes
• Tend to halt unregulated cell growth-cell
cycle control w/ damage, or inappropriate
signals.
• Need TWO bad copies before problems
occur- recessive.
With further
mutations
Retinoblastoma
gene- hereditary
cancer w/ 90%
penetration- born
w/ 1 bad copy. It
normally is stopping
S phase. E2F is
major TF, turns on
many genes.
P53- the guardian of the genome!!
• Transcription factor
• Made but unstable
• DNA damage (ATM-> CHK2>phosphorylated/stable)
• P21 transcribed- binds CDK/Cyclin, stops
G1-S transition.
• Activates apoptotic genes as well
So, effects
are indirect,
rather than
direct.
Not apoptosis,
necessarily
ATM, Chk2,
??? Which
cancers do
you think
this is
associated
with?
When p53 is deleted,
cancers are less
susceptible to death..
Cancer Therapy
• The problem: they are us! Kill them, kill us!
• Typical chemotherapy or radiation takes
advantage of fairly subtle differences
between them and us in order to kill themmakes us SICK! Plus, many are
carcinogenic-radiation
• Some newer treatments- immunotherapy,
passive and active.
• “Silver bullet” approaches
Passive Immunotherapy
• Antibodies against a protein that is unique
or overexpressed on cancer cells can kill
the cells.
– Herceptin- Ab that’s competitive inhibitor to
growth factor- binds to the receptor, doesn’t
stimulate it, may cause endocytosis.
– Rituxan- Ab against B cell surface protein;
kills certain non-Hodgkin’s lymphoma cells.
Active Immunotherapy
• Coley’s story…Cytokines produced during
a bacterial infection include Tumor
necrosis factor!
• Cancer cells-> cultivate-> use to find
immune cells that react against them->
cultivate-> reintroduce into patient.
• Sometimes works…
Targeting Oncogene activity:
Gleevec
• Inhibits the receptor protein kinase activity
of Abl- one of the receptor oncogenes• The one fused to immunoglobulin in the
Philadelphia chromosome- Chronic
myelogenous Leukemia.
• Revolutionized treatment of this disease.
Things to know
• Characteristics of cancer cells, types of
cancers
• Why we’re convinced that it’s a multi-step
process
• DNA tumor virus genes, oncogenes, tumor
suppressors.
• Ways proto-oncogenes go bad
• Cancer therapy