L312Spring 2007Lecture 25Drummond April 24

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L312/Spring 2007 Lecture 25 Drummond April 24
For today Last of Chapter 21 Cancer p
726-end Last set of study questions
(on final as multiple choice)--post shortly
Exams back by Thursday! All materials
outside my office after that Last time
How tissues are maintained and replaced Mainte
nance signals sent out (secreted) from
neighboring cells specific adhesion
molecules (cadherins) within tissue epigeneti
c modifications preserve tissue memory
(DNA methylation/histone
modifications) Regeneration stem cells
replace all the cell types in a
tissue undifferentiated, self-regenerate
often protected physically from
environmental skin cells generated from
basal level and move up gut cells
generated in crypts and migrate up
differentiation controlled by external
signaling molecules This time the
progression of proliferative cells to cancers
2
Where do new tissue cells come from?
Which cells may become cancerous?
Take home
3
Tissue renewal in the gut--where are new cells
born
4
Which cell-cell events support tissue formation
and why? (what must happen for cells to escape
their normal role?)
(Epigenetic)
Which events prohibit proliferation? How many
changes must occur to become cancerous?
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WHY or HOW? Did these tissue specific events
become lost or overridden? Stop listening to
signals Escape neighbor contacts Forget who
it was Penetrate basal lamina Attach to a new
site Evade the immune system Feed
themselves How many mutations or
epigenetic Changes are essential to become
a Cancer cell or a metastatic cell?
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Three tumor distinctions benign growth
limited to primary locus within
tissue malignant invasive growth exceeds the
limits of the tissue metastatic moves to
other sites within the body (usually by
bloodstream or lymphatic system) how might
treatments differ in each case? what is the role
of the immune system? Distinctions between tumor
genotypes and genomic stability euploid
(correct number of chromosomes) aneuploid
(incorrect chromosome complement usually
higher) Distinctions between genetic
stabilities stable genome (euploid, rare
mutation events 10-6 to 10-7
/gene/division rearrangements (usually
euploid) MIN (microsatellite instability)
usually euploid CIN (chromosomal instability)
usually aneuploid
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More questions about tumorigenesis
Where is the benign/ Malignant crossover?
Where did all the Mutations come from? What do
you need to know?
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Progression to a malignant tumor
What about the Immune system?
Take home Tumor formation requires multiple
mutations (how many?) (is the order
important?) Is a tumor homogeneous? How would
that affect treatment?
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APC an example of a common progression pathway
APC adenomatous polyposis coli
Note extensive crypts generating new epithelial
tissue
10
A possible APC-initiated progression
normal here one bad copy of APC (tumor
syndromes frequently recessive mutations)
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What do ras mutations confer to a cell?
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How does one mutation (ras) confer a new
expression profile?
13
One of many roles of p53, revisited
DNA-PK, ATM (kinase)
Why does p53 loss lead to new tumors (or more
aggressive ones)
What happens if You progress thru The cell
cycle (mitosis) with DSBs?
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A mutation in Rb can render cells insensitive to
external mitogens (and always on for
proliferation)
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Distinguishing between proto-oncogenes and tumor
suppressors
Who is Knudson?
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How can proto-oncogenes be converted into
oncogenes?
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WHY or HOW? Did these tissue specific events
become lost or overridden? Stop listening to
signals Escape neighbor contacts Forget who
it was Penetrate basal lamina Attach to a new
site Evade the immune system Feed
themselves How many mutations or
epigenetic Changes are essential to become
a Cancer cell or a metastatic cell?
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What does a cancer cell have that a normal cell
doesnt?

• They stop listening to their environment (often
  always on or off)
• dont respond to extracellular growth, mitosis,
  apoptosis, or survival
• They dont commit suicide in response to damage
  or abnormalities (e.g. a DSB)
• the apoptotic pathway is often disabled (p53 is a
  key checkpoint effector)
• They dont die of old age
• they maintain their telomeres by re-inducing
  telomerase
• They keep to a path of deviation from the
  original cellular mandate
• Most all tumors are genetically unstable (MIN or
  CIN)
• 1. can have epigenetic basis, e.g., DNA
  methylation normally silences
• They invade their neighbors
• They fail to make cadherins, or express the wrong
  ones, and export proteases
• Which key protein is the likely first target
  of proteases?
• They set up housekeeping in other tissues
• Cells can metastasize to other organs or tissues