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Colon cancer: the second
leading cause of cancer deaths
in the U.S.
Polyps, the first stage
In tumor development
http://www.clevelandclinic.org/registries/inherited/fap.htm
Familial adenomatous polyposis (FAP) =
inherited predisposition to colon cancer
Cancer cells proliferate
without differentiating,
a property of our body’s
normal stem cells
Normal cells are “contact-inhibited” and
stop growing when they reach confluence
Tumor cells are no longer
“contact inhibited”
Cancer cells have alterations in
cell adhesion and the cytoskeleton
Normal
“Transformed”
Cancer develops through gradual changes
in cell morphology and properties
Normal
Carcinoma in situ
Dysplasia
Malignant carcinoma
Metastasis: the movement of tumor cells
to new sites via the blood vessels
or lymphatic system
Benign tumor
Break through
basal lamina
Adhere to
capillary wall
Escape
capillary
Invade
capillary
Form
metastasis
Some normal cells
like those of
the neural crest
have similar properties
but end by
differentiating
at their new sites
The forces of Natural Selection
drive the multistep process
ECB Fig. 21-44
A single mutation is NOT enough!
Cancer cells
accumulate
chromosomal
abnormalities
What types of genes are mutated in cancers?
Two broad categories
Oncogenes
Mutational activation of proteins
that normally
Promote cell proliferation
What types of genes are mutated in cancers?
Two broad categories
Oncogenes
Mutational activation of proteins
that normally
Promote cell proliferation
Tumor suppressor genes
Mutational inactivation
of proteins that normally
inhibit cell proliferation
Cells instruct one another
via cell-cell signals
Be
Posterior!
Signal transduction moves information
from the cell surface to the nucleus
& other cellular targets
Turn on
new genes!
Cell surface
Yes
Ma'am!
Nucleus
Signal transduction
occurs in a
series of steps
Turn on
new genes;
pass it on
Turn on
new genes;
pass it on Turn on
new genes;
pass it on
Cell surface
Turn on
new genes;
pass it on
Yes
Ma'am!
Nucleus
Cell-cell signals
can regulate
cell proliferation
Proliferate!
Proliferate!
Cell surface
Proliferate!
Proliferate!
Yes
Ma'am!
Nucleus
Cancer often results from alterations in
proteins in signal transduction pathways
Cancer often results from alterations in
proteins in signal transduction pathways
Src in its normal context
Normal skin cell tightly adherent to ECM
Wounding->platelet recruitment->
cell migration and proliferation
Many viral oncogenes are kinases
including receptor tyrosine kinases
Activating mutations in RTKs take
several forms but all lead to
ligand-independent dimerization
and thus activation
Gene amplification is also
a common mechanism
of inappropriate gene activation
in human tumors
Double minute chromosomes
Tandem duplications
RTK signaling ultimately leads to
activation of a transcription factor
Gilbert Fig. 6.15
Elements of the ras
signal transduction pathway
are often activated in cancers
Remember this?
The vul mutations helped define
the RTK-Ras pathway
We are making progress: The modern drug
Gleevec stops certain cancers by blocking the
kinase activity of protein tyrosine kinases
Gleevec works for chronic myeloid
leukemia
Gleevec also works for
the cancers caused by
activation of
White-spotting=(c-kit)
Steel
Outside
the cell
White-spotting
(aka c-kit)
Lipid
bilayer
Inside
the cell
Tyrosine kinase domain
P
In response to binding of Steel factor,
kinase is activated and target proteins
are phosphorylated
What types of genes are mutated in cancers?
Two broad categories
Oncogenes
Mutational activation of proteins
that normally
Promote cell proliferation
Tumor suppressor genes
Mutational inactivation
of proteins that normally
inhibit cell proliferation
Rb puts the brakes on
cell proliferation
Rb
E2F DP
DO NOT
transcribe gene
required for DNA
replication
Rb phosphorylation
frees E2F/DP to
turn on genes
required for proliferation
P
P
DP
E2F
Transcribe gene
required for DNA
replication
Retinal tumor in patient that
inherited a mutant copy of Rb
Even though its caused by
a loss-of-function mutation
Retinoblastoma is inherited in
a dominant fashion
What’s up with that?
Normal individual w ith
tw o functional copies of Rb gene
Rb
Rb
Rb
Rb
Rb
Rb
Rb
Rb
Rb
In rare cell one copy mutated,
but second copy remains
In person w ith hereditary
Retinoblastoma, all cells start
w ith one mutant copy
Rb
Rb
Rb
Rb
If somatic mutation occurs, cell
has no functional Rb
and tumor develops
Mechanisms to inactivate
the second Rb allele
One strategy for
isolating oncogenes