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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. Colorectal cancer. 150,000 cases diagnosed per year (i.e., your chances are 1/18)

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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. Colorectal cancer 150,000 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 detection 60% if it has spread locally <10% if it has metastasized Data from ACS

  3. Colorectal cancer treatment 1. Surgical removal of tumor This can be followed by either Radiation or chemotherapy (fluorouracil) 3. Chemotherapy also used to slow the progress of metastatic disease Data from ACS

  4. Colon cancer genetics 95% of cases sporadic (no genetic history) HNPCC 3% of all cases. Defects in mismatch repair. Familial adenomatous polyposis (FAP) 1% of all colon cancers Caused by mutation in a single gene = APC

  5. Familial Adenomatous Polyposis (FAP)

  6. 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

  7. Until recently the only treatment Was to surgically remove the colon Treatment with an aspirin-like drug called 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).

  8. Adenomatous Polyposis Coli (APC) tumor suppressor mutated in FAP and in 70% of sporadic cases of colon cancer colon polyps

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

  10. To find clues to APC’s function they went fishing for partners APC Cell extract

  11. When they went fishing with APC, they pulled out Armadillo Armadillo APC (ß-catenin)

  12. Eric Wieschaus and Christiane Nüsslein-Volhard used genetics to identify proteins that set up the embryonic body plan

  13. The mighty fruit fly

  14. How is the body plan specified? Egg ---> animal in 24 hours!

  15. Wieschaus and Nüsslein-Volhard removed single genes and looked for effects on the body plan

  16. Wingless signaling specifies cell fates in the ventral epidermis wild type arm mutant

  17. Wingless signal influences the fates of neighboring cells

  18. Artist’s conception of an Armadillo

  19. Epithelial cells at work

  20. Elaine Fuch’s Hair Club for Men Rub ß-catenin here! Before After

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

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

  23. Our current model for Wnt signaling

  24. Phosphorylation of Armadillo/ß-catenin By GSK3 creates a binding site for an E3 ubiquitin ligase

  25. APC is a complex protein 15 AA rpts 20 AA rpts Arm Repeats SAMP rpts Arm repeats protein-protein interaction motif also found in Arm !5 and 20 amino acids repeats bind to Arm SAMP repeats bind Axin

  26. Arm Repeats APC is a complex protein 15 AA rpts 20 AA rpts Arm Repeats SAMP rpts MCR All tumors carry one allele that makes A truncated APC protein And truncations almost always occur in the “mutation cluster region” (MCR)

  27. Activated Wnt signaling triggers colon cancer

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

  29. 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 Look for genes whose transcription is regulated by Wnt signaling Hans Clevers

  30. 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

  31. 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

  32. Wnt signaling turns OFF the transcription of an key cell cycle regulator: the CDK inhibitor p21 mRNA

  33. The effect on p21 expression is indirectly mediated by the transcription factor c-myc. Transcription of the myc gene is directly regulated By TCF/beta-catenin

  34. 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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