Colon cancer is the second leading cause of cancer deaths in the U.S. Polyps, the first stage In...
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Actual Cancer Deaths Decrease for Second Year Running Marking what many cancer researchers are calling an important trend, the actual number of cancer deaths in the United States fell by more than 3,000 from 2003 to 2004, the most recent year for which mortality data are available. The steady decline in the rate of cancer deaths also continued.
The downturn from 556,902 deaths in 2003 to 553,888 in 2004 marks the biggest single-year decrease ever and the second consecutive year in which actual deaths - not just the death rate - have dipped. The new mortality numbers were released as part of an annual report released by the American Cancer Society (ACS), Cancer Statistics 2007
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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.
The 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 eventin 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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Crypt
VillusDifferentiated cells
Proliferating cells
A quick look at colon architecture
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Begin with colon cancer cell line
in which the Wnt pathway is ONAdd an inducible dominant negative form of TCF4 that turns the Wnt pathway OFF
Look for genes whose transcription
is regulated by Wnt signaling
Hans Clevers
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Gene turned ON by WntGene turned OFF by Wnt signal
The genes turned ON by Wnt signaling are expressed in crypts
and those that are turned OFF are expressed in villi
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Gene turned ON by WntGene turned OFF by Wnt signal
The genes turned on by Wnt signaling are expressed in crypts
and those that are turned off are expressed in villi
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Wnt signaling turns OFF the transcriptionof an key cell cycle regulator:
the CDK inhibitor p21
mRNA
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The effect on p21 expression is indirectly mediated by the transcription factor c-myc.
Transcription of the myc gene is directly regulatedBy TCF/beta-catenin
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Stromal cells send Wnt signals
Cells that receive them Become stem cells
As cells migrateAway from the crypt, theydifferentiate
Let’s put this together to form a picture of normal colon biologyand how it is perturbed by APC mutations