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Colon cancer is the second leading cause of cancer deaths in the U.S.

Colon cancer is 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). Adenomatous Polyposis Coli (APC). tumor suppressor.

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Colon cancer is the second leading cause of cancer deaths in the U.S.

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  1. Colon cancer is 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

  2. Familial Adenomatous Polyposis (FAP)

  3. Adenomatous Polyposis Coli (APC) tumor suppressor mutated in inherited and many sporadic cases of colon cancer colon polyps

  4. APC mutations are the earliest event in the development of the tumor

  5. Inheriting an APC mutation dramatically increases your risk of developing colorectal cancer 300-1000 polyps by age 30 100% risk of colon cancer by age 40 www.myriadtests.com

  6. Wingless and Hedgehog signaling specify cell fates in the ventral epidermis wild type arm mutant

  7. Wingless signal influences the fates of neighboring cells

  8. Artist’s conception of an Armadillo

  9. Wingless signaling modulates the stability of Armadillo protein Level of Wg signal Armadillo

  10. In the absence of APC, levels of Armadillo/ß-catenin rise dramatically APC mutant Wild-type

  11. A slightly less simplified view of our current model for Wnt signaling:

  12. Activated Wnt signaling triggers colon cancer

  13. A quick look at colon architecture Villus Differentiated cells Proliferating cells Crypt

  14. Begin with colon cancer cell line in which the Wnt pathway is ON Add an inducible dominant negative form of TCF4 that turns the Wnt pathway off Anti-TCF4 antibody

  15. Make mRNA from cells with the pathway OFF or ON Carry out a microarray screen 120 genes UP 115 genes DOWN

  16. 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 Wnt Gene turned OFF by Wnt signal

  17. Wnt signaling is normally required to turn on genes expressed in crypts Tcf4 +/- Tcf4 -/- CD44 c-myc

  18. Wnt signaling represses genes expressed in the villi Tcf4 +/- Tcf4 -/- p21 FABP-L

  19. Wnt signaling turns off the expression of a key cell cycle regulator: the CDK inhibitor p21 mRNA

  20. The data The model

  21. The effect on p21 expression is mediated by the transcription factor c-myc which is a direct Wnt target gene

  22. Let’s put this together to form a picture of normal colon biology and how it is perturbed by APC mutations As cells migrate away from the crypt, they differentiate Cells that receive them become stem cells Stromal cells send Wnt signals

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