tretinoin and Adenomatous-Polyposis-Coli

APC mutations drive human colorectal cancer (CRC) development. A major contributing factor is colonic stem cell (SC) overpopulation. But, the mechanism has not been fully identified. A possible mechanism is the dysregulation of neuroendocrine cell (NEC) maturation by APC mutations because SCs and NECs both reside together in the colonic crypt SC niche where SCs mature into NECs. So, we hypothesized that sequential inactivation of APC alleles in human colonic crypts leads to progressively delayed maturation of SCs into NECs and overpopulation of SCs. Accordingly, we used quantitative immunohistochemical mapping to measure indices and proportions of SCs and NECs in human colon tissues (normal, adenomatous, malignant), which have different APC-zygosity states. In normal crypts, many cells staining for the colonic SC marker ALDH1 co-stained for chromogranin-A (CGA) and other NEC markers. In contrast, in APC-mutant tissues from familial adenomatous polyposis (FAP) patients, the proportion of ALDH+ SCs progressively increased while NECs markedly decreased. To explain how these cell populations change in FAP tissues, we used mathematical modelling to identify kinetic mechanisms. Computational analyses indicated that APC mutations lead to: 1) decreased maturation of ALDH+ SCs into progenitor NECs (not progenitor NECs into mature NECs); 2) diminished feedback signaling by mature NECs. Biological experiments using human CRC cell lines to test model predictions showed that mature GLP-2R+ and SSTR1+ NECs produce, via their signaling peptides, opposing effects on rates of NEC maturation via feedback regulation of progenitor NECs. However, decrease in this feedback signaling wouldn't explain the delayed maturation because both progenitor and mature NECs are depleted in CRCs. So the mechanism for delayed maturation must explain how APC mutation causes the ALDH+ SCs to remain immature. Given that ALDH is a key component of the retinoic acid (RA) signaling pathway, that other components of the RA pathway are selectively expressed in ALDH+ SCs, and that exogenous RA ligands can induce ALDH+ cancer SCs to mature into NECs, RA signaling must be attenuated in ALDH+ SCs in CRC. Thus, attenuation of RA signaling explains why ALDH+ SCs remain immature in APC mutant tissues. Since APC mutation causes increased WNT signaling in FAP and we found that sequential inactivation of APC in FAP patient tissues leads to progressively delayed maturation of colonic ALDH+ SCs, the hypothesis

Topics: Adenomatous Polyposis Coli; Adult Stem Cells; Aldehyde Dehydrogenase 1 Family; Animals; Biomarkers; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Transformation, Neoplastic; Chromogranin A; Colon; Colorectal Neoplasms; Feedback, Physiological; Genes, APC; Glucagon-Like Peptide 2; Glucagon-Like Peptide-2 Receptor; HCT116 Cells; HT29 Cells; Humans; Mice; Models, Genetic; Mutation; Neuroendocrine Cells; Receptors, Somatostatin; Signal Transduction; Somatostatin; Stem Cell Niche; Tretinoin; Wnt Signaling Pathway

Chronic intestinal inflammation accompanies familial adenomatous polyposis (FAP) and is a major risk factor for colorectal cancer in patients with this disease, but the cause of such inflammation is unknown. Because retinoic acid (RA) plays a critical role in maintaining immune homeostasis in the intestine, we hypothesized that altered RA metabolism contributes to inflammation and tumorigenesis in FAP. To assess this hypothesis, we analyzed RA metabolism in the intestines of patients with FAP as well as APC

Topics: Adenoma; Adenomatous Polyposis Coli; Animals; Antineoplastic Agents; Cell Transformation, Neoplastic; Colorectal Neoplasms; Dendritic Cells; Enterocolitis; Genes, APC; Humans; Mice; Phenotype; Th17 Cells; Tretinoin; Tumor Burden; Vitamin A; Vitamin A Deficiency

Although genome-wide hypomethylation is a hallmark of many cancers, roles for active DNA demethylation during tumorigenesis are unknown. Here, loss of the APC tumor suppressor gene causes upregulation of a DNA demethylase system and the concomitant hypomethylation of key intestinal cell fating genes. Notably, this hypomethylation maintained zebrafish intestinal cells in an undifferentiated state that was released upon knockdown of demethylase components. Mechanistically, the demethylase genes are directly activated by Pou5f1 and Cebpβ and are indirectly repressed by retinoic acid, which antagonizes Pou5f1 and Cebpβ. Apc mutants lack retinoic acid as a result of the transcriptional repression of retinol dehydrogenase l1 via a complex that includes Lef1, Groucho2, Ctbp1, Lsd1, and Corest. Our findings imply a model wherein APC controls intestinal cell fating through a switch in DNA methylation dynamics. Wild-type APC and retinoic acid downregulate demethylase components, thereby promoting DNA methylation of key genes and helping progenitors commit to differentiation.

Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Alcohol Oxidoreductases; Animals; Brain; CCAAT-Enhancer-Binding Protein-beta; Cell Line, Tumor; Cell Proliferation; Co-Repressor Proteins; Colonic Neoplasms; DNA Methylation; Humans; Intestinal Mucosa; Intestines; Octamer Transcription Factor-3; Transcription Factors; Transcription, Genetic; Tretinoin; Zebrafish

Mutations in adenomatous polyposis coli (APC) underlie the earliest stages of colorectal carcinogenesis. Consequences of APC mutation include stabilization of beta-catenin, dysregulation of cyclooxygenase-2 (COX-2) expression, and loss of retinoic acid production, events with poorly defined interactions. Here we showed that treatment of zebrafish expressing a truncated form of Apc with either retinoic acid or a selective COX-2 inhibitor decreased beta-catenin protein levels and downstream signaling events. Interestingly, the destruction of beta-catenin in apc mutant embryos following Cox-2 inhibition required the presence of truncated Apc. These findings support roles for retinoic acid and Cox-2 in regulating the stability of beta-catenin following Apc loss. Furthermore, truncated Apc appears to retain the ability to target beta-catenin for destruction, but only in the absence of Cox-2 activity. This novel function of truncated Apc may provide a molecular basis for the efficacy of COX-2 inhibitors in the treatment of colon cancer.

Topics: Adenomatous Polyposis Coli; Animals; beta Catenin; Cyclooxygenase 2; Dinoprostone; Down-Regulation; Gene Expression Regulation; Immunoblotting; In Situ Hybridization; Mutation; RNA; Signal Transduction; Tretinoin; Zebrafish

Mutations in the human adenomatous polyposis coli (APC) gene are thought to initiate colorectal tumorigenesis. The tumor suppressor function of APC is attributed primarily to its ability to regulate the WNT pathway by targeting the destruction of beta-catenin. We report here a novel role for APC in regulating degradation of the transcriptional co-repressor C-terminal-binding protein-1 (CtBP1) through a proteasome-dependent process. Further, CtBP1 suppresses the expression of intestinal retinol dehydrogenases, which are required for retinoic acid production and intestinal differentiation. In support of a role for CtBP1 in initiation of colorectal cancer, adenomas taken from individuals with familial adenomatous polyposis contain high levels of CtBP1 protein in comparison with matched, uninvolved tissue. The relationship between APC and CtBP1 is conserved between humans and zebrafish and provides a mechanistic model explaining APC control of intestinal retinoic acid biosynthesis.

Topics: Adenoma; Adenomatous Polyposis Coli; Alcohol Oxidoreductases; Animals; Base Sequence; beta Catenin; Cell Line, Tumor; Colonic Neoplasms; DNA-Binding Proteins; Genes, APC; Humans; In Vitro Techniques; Intestinal Mucosa; Models, Biological; Mutation; Proteasome Endopeptidase Complex; RNA, Small Interfering; Species Specificity; Tretinoin; Zebrafish

A rare case of Turcot's syndrome is reported in a long-time survivor of glioblastoma multiforme. The patient was treated for his tumor in 1976 with macroscopically complete surgical resection and radiotherapy consisting of 60 Gy to the tumor bed and 40 Gy to the whole brain. Five years later, in 1981, he developed adenocarcinoma of the colon Dukes Stage B which was successfully treated at another hospital by surgery alone. In 1990, he presented with multiple colon polyps and adenocarcinoma Dukes Stage A. For more than 15 years, the patient has been afflicted with cystic and conglobate acne. Possible mechanisms and treatment with 13-cis retinoic acid are discussed.

Topics: Acne Vulgaris; Adenocarcinoma; Adenomatous Polyposis Coli; Adult; Brain Neoplasms; Glioblastoma; Humans; Male; Neoplasms, Multiple Primary; Syndrome; Time Factors; Tretinoin