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

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.

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

colon polyps

Adenomatous Polyposis Coli (APC)

tumor suppressor

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

APC mutations arethe earliest eventin 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

Crypt

VillusDifferentiated cells

Proliferating cells

A quick look at colon architecture

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

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

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

Wnt signaling turns OFF the transcriptionof an key cell cycle regulator:

the CDK inhibitor p21

mRNA

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

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