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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) > 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 Colorectal cancer treatment 1. 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 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 Familial Adenomatous Polyposis (FAP) Inheriting FAP-related mutations dramatically increases your risk of developing colorectal cancer. 93% colorectal cancers by age 50 100% colorectal cancers lifetime risk 0.2% colorectal cancers by age 50 6% colorectal cancers lifetime risk 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 40% reduction in advanced adenomas. Problem--increased cardiovascular risk. The hope is this will allow doctors to Delay surgery till later in life New England Journal of Medicine 342, 1946 (2000) And NCI Cancer Bulletin, April 16, 2008. So what causes Familial Adenomatous Polyposis (FAP) Figure 7.23 The Biology of Cancer (© Garland Science 2007) Adenomatous Polyposis Coli (APC) tumor suppressor mutated in FAP and in 70% of sporadic cases of colon cancer colon polyps APC mutations are the earliest event in the development of the tumor To find clues to APC’s function they went fishing for partners APC Cell extract Fishing with APC Colon cancer WT cell line ? first, immunoprecipitation APC Fishing with APC Colon cancer WT cell line co-immunoprecipitation p95= -catenin When they went fishing with APC, they pulled out Armadillo Armadillo (ß-catenin) APC Eric Wieschaus and Christiane Nüsslein-Volhard used genetics to identify proteins that set up the embryonic body plan The mighty fruit fly How is the body plan specified? Egg ---> animal in 24 hours! Wieschaus and Nüsslein-Volhard removed single genes and looked for effects on the body plan 2 young scientists 1 microscope 1 year 26,978 flies 139 new genes Five Signal Transduction Pathways Shape virtually all cell fates choices RTK Wnt TGF-β Hedgehog Notch Five Signal Transduction Pathways Shape virtually all cell fates choices All also play key roles in many cancers RTK Wnt TGF-β Hedgehog Notch Wingless signaling specifies cell fates in the ventral epidermis wild type arm mutant Wingless signal influences the fates of neighboring cells Cells instruct one another via cell-cell signaling pathways Be Posterior! Cell-cell signaling can be influenced by distance between cells Pardon me? Yes Ma'am! Be Posterior! Turn on new genes! Cell surface Signal transduction moves information from the cell surface to the nucleus and other cellular targets Yes Ma'am! Nucleus Turn on new genes; pass it on Turn on new genes; pass it on Turn on new genes; pass it on Cell surface Signal transduction occurs through a series of steps Turn on new genes; pass it on Yes Ma'am! Nucleus Artist’s conception of an Armadillo Epithelial cells at work The mammalian core adherens junction complex E- cadher in P la sm a m emb ran e -catenin ß-c at enin Armadillo and dTCF form a bipartite transcription factor Armadillo dTCF CCTTTGATCTT Activation of Wingless-responsive genes Armadillo and TCF activate Wingless target genes Without Wingless signal Groucho Repression of Wingless-responsive genes TCF CCTTTGATCTT With Wingless signal Armadillo TCF CCTTTGATCTT Activation of Wingless-responsive genes Elaine Fuch’s Hair Club for Men Rub ß-catenin here! Before After Wingless signaling modulates the stability of Armadillo protein Level of Wg signal Armadillo Proliferate! Proliferate! Cell surface Proliferate! Proliferate! Signal transduction can regulate cell proliferation Yes Ma'am! Nucleus In the absence of APC, levels of Armadillo/ß-catenin rise dramatically Wild-type APC mutant Our current model for Wnt signaling Phosphorylation of Armadillo/ß-catenin By GSK3 creates a binding site for an E3 ubiquitin ligase APC is a complex protein Arm Repeats 15 AA rpts 20 AA rpts 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 APC is a complex protein Arm Repeats 15 AA rpts 20 AA rpts SAMP rpts Arm Repeats MCR All tumors carry one allele that makes A truncated APC protein And truncations almost always occur in the “mutation cluster region” (MCR) Activated Wnt signaling triggers colon cancer A quick look at colon architecture Differentiated cells Proliferating cells Villus Crypt 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 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 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 Wnt signaling turns OFF the transcription of 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 regulated By TCF/beta-catenin The data The model 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