Colon cancer is the second leading cause of cancer deaths in the U.S.
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Colon cancer is the second leading cause of cancer deaths
in the U.S.
Polyps, the first stageIn tumor development
http://www.clevelandclinic.org/registries/inherited/fap.htm
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Colorectal cancer150,000 cases diagnosed per year(i.e., your chances are 1/18)> 50,000 deaths (2nd to lung cancer)
Early detection key>90% 5 year survival with early detection60% if it has spread locally<10% if it has metastasized
Data from ACS
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Colorectal cancer treatment1. Surgical removal of tumor
2. This can be followed by either Radiation or chemotherapy (fluorouracil)
3. Chemotherapy also used to slow the progress of metastatic disease
Data from ACS
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HNPCC 3% of all cases. Defects in mismatch repair.
Familial adenomatous polyposis (FAP)1% of all colon cancersCaused by mutation in a single gene = APC
Colon cancer genetics
95% of cases sporadic (no genetic history)
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FamilialAdenomatousPolyposis (FAP)
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300-1000 polyps by age 30100% risk of colon cancer by age 40
Inheriting an APC mutation dramatically increasesYour risk of developing colorectal cancer
www.myriadtests.com
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Treatment with an aspirin-like drugcalled celecoxib (a COX2 inhibitor)led to a 25% reduction in polyp number ,and the remaining polyps shrank.
Hope is this will allow doctors to Delay surgery till later in life
Steinbeck et al. New England Journal of Medicine 342, 1946 (2000).
Until recently the only treatmentWas to surgically remove the colon
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colon polyps
Adenomatous Polyposis Coli (APC)
tumor suppressor
mutated in FAP and in 70% of sporadic cases of colon cancer
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APC mutations arethe earliest event
in the development of the tumor
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APC
To find clues to APC’s function they went fishing for partners
Cell extract
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APCArmadillo
(ß-catenin)
When they went fishing with APC, they pulled out Armadillo
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Eric Wieschaus and Christiane Nüsslein-Volhardused genetics to identify proteins that
set up the embryonic body plan
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The mighty fruit fly
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How is the body plan specified?
Egg ---> animalin 24 hours!
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Wieschaus and Nüsslein-Volhard
removed single genes and looked for effects
on the body plan
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Wingless signaling specifies cell fates in the ventral epidermis
arm mutantwild type
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Wingless signal influences the fatesof neighboring cells
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BePosterior!
Cells instruct one anothervia cell-cell signaling pathways
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BePosterior!
Cell-cell signaling can be influenced by distance between cells
Yes Ma'am!
Pardon me?
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Turn on new genes!
Yes Ma'am!
Cell surface
Nucleus
Signal transduction moves information
from the cell surface to the nucleus and
other cellular targets
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Turn on new genes; pass it on
Yes Ma'am!
Cell surface
Nucleus
Turn on new genes; pass it on Turn on
new genes; pass it on
Turn on new genes; pass it on
Signal transduction occurs through a series of steps
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Artist’s conception of an Armadillo
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Epithelial cells at work
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P la sm a m embrane
α-catenin
ß-catenin
E-cadher in
The mammalian coreadherens junction complex
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Activation of Wingless-responsive genes
CCTTTGATCTTdTCF
Armadillo
Armadillo and dTCF form a bipartite transcription factor
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Elaine Fuch’s Hair Club for Men
Rub ß-catenin here!
Before After
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Level of Wg signal
Wingless signaling modulates the stability of Armadillo protein
Armadillo
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Proliferate!
Yes Ma'am!
Cell surface
Nucleus
Proliferate!
Proliferate!
Proliferate!
Signal transduction can regulate
cell proliferation
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Wild-type APC mutant
In the absence of APC,levels of Armadillo/ß-catenin
rise dramatically
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Our current model for Wnt signaling
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Phosphorylation ofArmadillo/ß-cateninBy GSK3creates a binding site for an E3 ubiquitin ligase
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Arm Repeats
APC is a complex protein
15 AArpts
Arm repeats protein-proteininteraction motif also found in Arm
!5 and 20 amino acids repeatsbind to Arm
SAMP repeats bind Axin
20 AArpts
SAMP rpts
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Arm Repeats
APC is a complex protein
15 AArpts
All tumors carry one allele that makes A truncated APC proteinAnd truncations almost always occur in the “mutation cluster region” (MCR)
20 AArpts
SAMP rpts
Arm Repeats MCR
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Activated Wnt signaling triggers colon cancer
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A branch in the Wnt pathwayallows it to exert more diverse biological and cell biological effects
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Arm Repeats
APC interacts with the cytoskeleton
Microtubule Binding
EB1
directly binds microtubules in vitro
colocalizes with microtubule ends
binds EB1
binds a Kinesin motor and a Rac-GEF
Kinesin andRac-GEF binding
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APC2 actin tubulin merged
APC2 is localized to the cortex, where it could mediate interactions
between mitotic spindles and cortical actin
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wild -type
APC2 ∆S
actin tubulin merged
APC2 mutants have defects in spindle anchoring
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actina-catenin
ArmadilloAPC2
Protein X
microtubules
APC2 helps link spindlesto cortical actin
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APC proteins may play several roles in genomic
instability
APCspindle microtubules
kinetochore
centromere
Clevers, Fodde,Nathke & Sorger labs