Announcements

1
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).

2
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
• Brownback opposes
• Giuliani wont say
• Romney supported as governor of MA now opposes
• McCain supports
• Democrats
• Clinton, Obama, Edwards support

3
Day 43 Outline/Objectives

• Cell biology of cancer
• 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.

4
Cancer cells defined by

• Ability to proliferate uncontrollably
• Causes tumor formation
• Angiogenesis feeds the tumor
• Cancer cells increase secretion of angiogenesis
  activators and decrease angiogenesis inhibitors
• Ability to spread through the body.
• Invasion cancer cells migrate into surrounding
  tissues, blood vessels
• Metastasis cancer cells spread through
  circulatory system to establish secondary tumors.

5
Normal versus tumor growth in skin

• Cancer cells dont 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.

6
Normal and transformed cell properties

• Normal cells
• Regulated growth
• Dependent on GFs
• Subject to cycle cycle control
• Anchorage-dependent
• Contact inhibited (density-dependent)
• Subject to apoptosis
• Flattened cells, normal nuclei, normal chromosome
  number

• Transformed (cancer) cells
• Uncontrolled growth
• Independent of GFs
• Dont obey checkpoints
• Anchorage-independent
• Loss of contact inhibition gt pile up in culture
• Escape apoptosis pathways
• Rounded cells, large nuclei, abnormal chromosome
  number

7
Stages in Process of Metastasis

• ? 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
• origin and blood flow pattarns
• Most organs gt lungs
• Stomach, colon gt liver
• Molecular interactions
• E.g. prostate cancer cells respond to growth
  factors secreted by bone cells

8
Tumor ProgressionEvolution 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.
9
Causes of Cancer

• Inherited or spontaneous gene mutations
• Chemicals (carcinogens) ? mutations in DNA
• Either directly or after activation in liver
• E.g. chemicals in tobacco smoke
• 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
• Viruses and other infectious agents ? tissue
  damage or introduction of cancer-causing genes
  (oncogenes)
• Less common
• Epstein-Barr virus gt Burkitts lymphoma
• Hepatitis B and C viruses gt liver cancer
• Human papillomavirus gt cervical cancer

10
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.

11
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13
Discovery of oncogenesTransforming 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 TRVs, most
  oncogenes not caused by TRVs.
• Varmus and Bishop studied Rous Sarcoma Virus
  (RSV) in chickens, which carried gene called src

14
Southern Blots Probed with viral src Gene
Revealed Cellular Origin of Oncogenes
Infected chicken 1 Infected chicken
2 Uninfected chicken DNA DNA DNA
(Negative Control)
v-src
c-src Proto-oncogene SURPRISE!
15
Origin of Transforming Retroviruses
Capsid protein Reverse Transcriptase Envelope
Protein
Mutation creates oncogene
16
Cancers Usually Result from a Series of Mutations
in a Single Cell

• Development of colon cancer

oncogene
Tumor suppressors
oncogene
17
SOS II InstructionsBIO 324, ID hertz1pl, CRN
22008085,

• Please use only a pencil and erase thoroughly if
  you change a response.
• The Course Designator Number for this class is
  BIO 324.
• The CMU Faculty ID for this class is hertz1pl.
  Please enter this alpha/numeric code in the
  section titled CMU Faculty User ID.
• The Course Reference Number for this class is
  22008085. Enter this 5-digit number in the
  section titled Course Reference Number.
• 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.
• 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.
• 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.