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

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

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

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)

FamilialAdenomatousPolyposis (FAP)

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

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

colon polyps

Adenomatous Polyposis Coli (APC)

tumor suppressor

mutated in FAP and in 70% of sporadic cases of colon cancer

APC mutations arethe earliest event

in the development of the tumor

APC

To find clues to APC’s function they went fishing for partners

Cell extract

APCArmadillo

(ß-catenin)

When they went fishing with APC, they pulled out Armadillo

Eric Wieschaus and Christiane Nüsslein-Volhardused genetics to identify proteins that

set up the embryonic body plan

The mighty fruit fly

How is the body plan specified?

Egg ---> animalin 24 hours!

Wieschaus and Nüsslein-Volhard

removed single genes and looked for effects

on the body plan

Wingless signaling specifies cell fates in the ventral epidermis

arm mutantwild type

Wingless signal influences the fatesof neighboring cells

BePosterior!

Cells instruct one anothervia cell-cell signaling pathways

BePosterior!

Cell-cell signaling can be influenced by distance between cells

Yes Ma'am!

Pardon me?

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

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

Artist’s conception of an Armadillo

Epithelial cells at work

P la sm a m embrane

α-catenin

ß-catenin

E-cadher in

The mammalian coreadherens junction complex

Activation of Wingless-responsive genes

CCTTTGATCTTdTCF

Armadillo

Armadillo and dTCF form a bipartite transcription factor

Elaine Fuch’s Hair Club for Men

Rub ß-catenin here!

Before After

Level of Wg signal

Wingless signaling modulates the stability of Armadillo protein

Armadillo

Proliferate!

Yes Ma'am!

Cell surface

Nucleus

Proliferate!

Proliferate!

Proliferate!

Signal transduction can regulate

cell proliferation

Wild-type APC mutant

In the absence of APC,levels of Armadillo/ß-catenin

rise dramatically

Our current model for Wnt signaling

Phosphorylation ofArmadillo/ß-cateninBy GSK3creates a binding site for an E3 ubiquitin ligase

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

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

Activated Wnt signaling triggers colon cancer

A branch in the Wnt pathwayallows it to exert more diverse biological and cell biological effects

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

APC2 actin tubulin merged

APC2 is localized to the cortex, where it could mediate interactions

between mitotic spindles and cortical actin

wild -type

APC2 ∆S

actin tubulin merged

APC2 mutants have defects in spindle anchoring

actina-catenin

ArmadilloAPC2

Protein X

microtubules

APC2 helps link spindlesto cortical actin

APC proteins may play several roles in genomic

instability

APCspindle microtubules

kinetochore

centromere

Clevers, Fodde,Nathke & Sorger labs