Transcript Transformed (cancer) cells

Announcements
• Correction: same assay for pluripotency can be
used for adult stem cells as for ES cells.
• Wednesday, April 25: cell biology of cancer, pp.
762-770, 775-789
• Friday, April 27, 9 AM: optional review session
• Monday, April 30, 8 AM: final exam
– 139 points; 90 points from days 34-43; 49 points
cumulative (days 1-43).
Positions of Presidential
contenders on ES cell research
• From Nature, 19 April, 2007
• New policy could easily be put into law by
executive order.
• Republicans:
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Brownback: opposes
Giuliani: won’t say
Romney: supported as governor of MA; now opposes
McCain: supports
• Democrats:
– Clinton, Obama, Edwards support
Day 43 Outline/Objectives
A.
Cell biology of cancer
1.
2.
3.
B.
Features of cancer cells
Stages of tumor progression
Oncogenes and tumor
suppressor genes
SOS
After reading the text, attending
lecture, and reviewing lecture
notes, you should be able to:
• Discuss the two features of
cancer cells: (1) unregulated
cell proliferation and (2) ability
to spread.
• Compare an contrast the
properties of transformed
versus non-transformed cells.
• Compare and contrast the
properties of oncogenes and
tumor suppressor genes,
giving examples of each.
Cancer cells defined by
1. Ability to proliferate uncontrollably
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•
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Causes tumor formation
Angiogenesis feeds the tumor
Cancer cells increase secretion of angiogenesis
activators and decrease angiogenesis inhibitors
2. Ability to spread through the body.
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Invasion: cancer cells migrate into surrounding
tissues, blood vessels
Metastasis: cancer cells spread through circulatory
system to establish secondary tumors.
Normal versus tumor growth in skin
• Cancer cells don’t
necessarily divide
faster than normal
cells.
• Normal: Rates of
cell division and
differentiation
balanced.
• Tumor: Balance of
cell division and
cell differentiation
favors cell division.
Normal and transformed cell
properties
Normal cells
• Regulated growth
– Dependent on GF’s
– Subject to cycle cycle
control
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•
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Transformed (cancer) cells
• Uncontrolled growth
– Independent of GF’s
– Don’t obey checkpoints
• Anchorage-independent
• Loss of contact inhibition >
Anchorage-dependent
Contact inhibited (density- pile up in culture
• Escape apoptosis
dependent)
pathways
Subject to apoptosis
• Rounded cells, large
Flattened cells, normal
nuclei, abnormal
nuclei, normal
chromosome number
chromosome number
Stages in Process of
Metastasis
1.
2.
3.
↓ E-cadherin, ↑ motility, ↑
proteases, which digest
basal lamina.
In blood most cancer cells
die but some that survive and
reproduce well are selected.
Metastases form at
preferential sites, based on
a.
origin and blood flow
pattarns
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•
b.
Most organs > lungs
Stomach, colon > liver
Molecular interactions
•
E.g. prostate cancer cells
respond to growth factors
secreted by bone cells
Tumor Progression:
Evolution at the Cellular Level
Benign tumor (polyp in
epithelial cells) is confined
by basal lamina; then
additional mutation occurs.
Malignant tumor (carcinoma
in epithelial cells) grows
very fast, becomes invasive,
and metastasizes.
Causes of Cancer
1. Inherited or spontaneous gene mutations
2. Chemicals (carcinogens) → mutations in DNA
– Either directly or after activation in liver
– E.g. chemicals in tobacco smoke
3. Ionizing and ultraviolet radiation → mutations in DNA
– Ionizing radiation removes electrons, generating reactive ions
that cause DNA damage
– UV radiation causes pyrimidine dimer formation in DNA
4. Viruses and other infectious agents → tissue damage or
introduction of cancer-causing genes (oncogenes)
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–
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Less common
Epstein-Barr virus > Burkitt’s lymphoma
Hepatitis B and C viruses > liver cancer
Human papillomavirus > cervical cancer
Oncogenes and Tumor
Suppressors
Proto-oncogene
• Normal gene (c-onc)
involved in cell
proliferation.
• Gain-of-function,
dominant mutation
creates an oncogene
(onc), which causes
cancer.
• 1 mutant copy
(heterozygous condition)
is sufficient to cause
cancer.
Tumor Suppressor
• Gene which normally acts
to suppress cell
proliferation.
• Loss-of-function,
recessive mutation in
tumor suppressor gene
causes cancer.
• 2 mutant copies are
necessary to cause
cancer.
Discovery of oncogenes:
Transforming retroviruses and src
• Discovered by Harold Varmus and M. Bishop,
1975-76 (Nobel Prize, 1989).
• A transforming retrovirus:
– cancer-causing single-stranded RNA virus
– Uses reverse transcriptase enzyme to make ssDNA,
then dsDNA, which integrates into host DNA.
– Note: not all retroviruses are TRV’s, most
oncogenes not caused by TRV’s.
• Varmus and Bishop studied Rous Sarcoma
Virus (RSV) in chickens, which carried gene
called src:
Southern Blots Probed with viral src Gene
Revealed Cellular Origin of Oncogenes
Infected chicken #1
DNA
Infected chicken #2 Uninfected chicken
DNA
DNA (Negative Control)
v-src
c-src
Proto-oncogene
SURPRISE!
Origin of Transforming
Retroviruses
Capsid protein Reverse Transcriptase Envelope Protein
Mutation creates oncogene
Cancers Usually Result from a Series
of Mutations in a Single Cell
• Development of colon cancer:
oncogene
oncogene Tumor suppressors
SOS II Instructions
BIO 324, ID hertz1pl, CRN 22008085,
A. Please use only a pencil and erase thoroughly if you change a
response.
B. The Course Designator Number for this class is BIO 324.
C. The CMU Faculty ID for this class is hertz1pl. Please enter this
alpha/numeric code in the section titled “CMU Faculty User ID.”
D. The Course Reference Number for this class is 22008085. Enter this
5-digit number in the section titled “Course Reference Number.”
E. Please mark the appropriate response to the remaining questions. If
you do not have an opinion with regard to any question, please leave
the response to the question blank. When finished, return the
completed survey to the front of the class.
F. You may express your personal reactions to this class on the
accompanying “Individual Opinions” sheet that is provided for this
purpose. Please include the section number in the space provided.
G. Please answer the following additional questions:
9. The instructor has stimulated my thinking.
10. I have needed to work hard to achieve success in this course.