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At least 1,243 records · Page 69Linked to original sources
PubMed2005

LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes.

Germline mutations of the LKB1 (STK11) tumor suppressor gene lead to Peutz-Jeghers syndrome (PJS) and predisposition to cancer. LKB1 encodes a serine/threonine kinase generally inactivated in PJS patients. We identified the dual phosphatase and tumor suppressor protein PTEN as an LKB1-interacting protein. Several LKB1 point mutations associated with PJS disrupt the interaction with PTEN suggesting that the loss of this interaction might contribute to PJS. Although PTEN and LKB1 are predominantly cytoplasmic and nuclear, respectively, their interaction leads to a cytoplasmic relocalization of LKB1. In addition, we show that PTEN is a substrate of the kinase LKB1 in vitro. As PTEN is a dual phosphatase mutated in autosomal inherited disorders with phenotypes similar to those of PJS (Bannayan-Riley-Ruvalcaba syndrome and Cowden disease), our study suggests a functional link between the proteins involved in different hamartomatous polyposis syndromes and emphasizes the central role played by LKB1 as a tumor suppressor in the small intestine.

AMP-Activated Protein Kinase Kinases↗
PubMed1993

Alteration in intestinal permeability after ileal pouch-anal anastomosis.

PURPOSE: The physiologic changes that occur when the small bowel is used as a reservoir, as in the ileal pouch-anal anastomosis, are poorly understood. Alterations in bowel permeability, which may lead to bacterial translocation that could result in illness or dysfunction of the pouch, may be one such consequence of the pouch procedure. METHODS: Whole-bowel permeability was evaluated in patients with and without the pouch through the use of an orally consumed nonmetabolizable sugar clearance technique. Patients in whom the ileal pouch-anal anastomosis was performed for ulcerative colitis (17 patients) and patients with familial polyposis (7 patients) were compared with normal healthy volunteers (10 patients) and patients with ulcerative colitis with and without curative colectomy and ileostomy (6 and 5 patients, respectively). RESULTS: Measured by this technique, no differences were noted in bowel permeability between the volunteers and patients with ulcerative colitis, even after colectomy and ileostomy (1.7 +/- 0.4 in normal healthy volunteers, 1.8 +/- 0.5 in patients with ulcerative colitis without stoma, and 1.4 +/- 0.2 in patients with ulcerative colitis with ileostomy). The group of patients with an ileal reservoir, however, had a significantly increased index of measured bowel permeability (3.5 +/- 0.5 in patients with ulcerative colitis and 5.1 +/- 0.7 in patients with familial polyposis; P < 0.05 by analysis of variance compared with normal healthy volunteers and patients with ulcerative colitis with or without ileostomy). CONCLUSION: The exact site, cause, and consequence of this possible alteration of bowel permeability are unclear but appear to be related to the presence of the pouch and are not caused by the underlying pathologic diagnosis.

Adenomatous Polyposis Coli↗
PubMed1998

Tales from the human crypt--intestinal stem cell repertoire and the origins of human cancer.

A generally accepted model for the origin of human cancer is that tumours arising from the gut-lining epithelium--the adenomas and carcinomas--are of clonal origin, i.e., they are derived from a single 'abnormal' cell. Recent work has shed considerable light on these matters and suggests that this model may be erroneous and that at least some adenomas are of multiclonal origin. These findings have basic implications for more generalized models of tumourigenesis and for researchers examining the potential clinical value of gene therapy.

Adenoma↗
PubMed2001

Molecular alterations of Barrett's esophagus on microdissected endoscopic biopsies.

Alterations in proto-oncogenes and tumor suppressor genes play a role in the sequence from Barrett's metaplasia to esophageal adenocarcinoma. The present study aims to ascertain whether molecular abnormalities take place in Barrett's metaplasia and low-grade dysplasia and to correlate them with the histological features of the esophageal mucosa. Forty-one formalin-fixed, paraffin-embedded endoscopic esophageal biopsies were classified according to the type of metaplastic changes (noncolumnar fundic and cardial metaplasia; columnar metaplasia, with and without intestinal features). After microdissection samples were examined for loss of heterozygosity (LOH) using polymorphic markers on 5q (D5S82), corresponding to APC (adenomatous polyposis coli) gene, 13q (CA repeat in intron 2 position 14815 to 14998 of the retinoblastoma gene), 17p (D17S513) corresponding to p53 locus, and for p53 mutations. Molecular alterations including LOH, allelic imbalance, and microsatellite instability could be detected in all types of metaplastic changes and sporadically in the squamous epithelium adjacent to the metaplastic tissue. Molecular alterations involving microsatellites D5S82 and the CA repeat inside the retinoblastoma gene were more frequent in nonintestinal metaplasia whereas those involving the p53 locus took place in columnar intestinal metaplasia and in low-grade dysplasia. Clonal changes were demonstrated in different metaplastic areas in three patients. Genetic alterations comprising LOH and microsatellite instability characterize Barrett's mucosa and appear related to the type of metaplastic change. Some of them precede the development of intestinal metaplasia, suggesting that genetic alterations take place earlier than previously thought.

Barrett Esophagus↗
PubMed1981

Familial polyposis coli associated with bile duct cancer.

The clinical features and surgical management of two patients with primary adenocarcinoma of the bile duct in association with familial polyposis coli are described. The first patient had had subtotal colectomy for familial polyposis coli, and several resections of duodenal tumors. Carcinoma developed in the common bile duct and was treated with intubation and radiation therapy; he is still alive 2 years later. A second patient with cancer at the bifurcation of the bile ducts was treated with intubation and radiotherapy; 1 year later she had intestinal hemorrhage from a sigmoid colon cancer, and multiple colonic polyps were noted. We believe that this is the first report in the English literature of biliary cancer in association with familial polyposis coli or Gardner's syndrome.

Adenocarcinoma↗
PubMed1999

Dysregulation of beta-catenin is common in canine sporadic colorectal tumors.

Human colorectal tumorigenesis is often initiated by APC (adenomatous polyposis coli) or beta-catenin (CTNNB1) mutations, which result in dysregulation of beta-catenin expression, followed by alterations in E-cadherin and/or p53. We examined 32 canine intestinal tumors for expression and intracellular distribution of beta-catenin, E-cadherin, and p53 using immunohistochemistry. beta-Catenin in normal mucosal epithelial cells was restricted to lateral cell membranes, but 13/13 (100%) colorectal adenomas had intense cytoplasmic and/or nuclear reactivity. Three of six (50%) colorectal carcinomas, 2/13 (15%) small intestinal carcinomas, and dysplastic cells in 1/2 focal hyperplastic lesions in the small intestine had a similar pattern of staining; remaining tumors had normal membranous beta-catenin reactivity. There was a correlation (P = 0.007) between abnormal beta-catenin and E-cadherin staining with 11/13 (85%) colorectal adenomas, 3/6 (50%) colorectal carcinomas, and 3/13 (23%) small intestinal carcinomas showing decreased membranous reactivity compared with normal mucosal epithelium. E-cadherin staining was reduced more often in adenomas than in carcinomas (P = 0.04). There were two patterns of nuclear p53 staining: > 60% of nuclei in 2/26 (8%) carcinomas (one colorectal, one small intestinal) were strongly labeled, whereas three colorectal adenomas and one small intestinal carcinoma had fainter staining in 10-20% of cells. Dysregulation of beta-catenin appears to be as important in canine colorectal tumorigenesis as it is in the human disease and could be due to analogous mutations. Malignant progression in canine intestinal tumors does not appear to be dependent on loss of E-cadherin or beta-catenin expression or strongly associated with overexpression of nuclear CMI antibody-reactivity p53.

Adenoma↗
PubMed2003

Adenoma multiplicity in irradiated Apc(Min) mice is modified by chromosome 16 segments from BALB/c.

Ionizing radiation (IR) is a well-characterized carcinogen in humans and mice. The BALB/c mouse strain is unusually sensitive to IR-induced tissue damage and cancer development in a range of organs, suggestive of a partial defect in DNA damage response. This has been confirmed by finding BALB/c-specific functional polymorphism in Prkdc, a gene on mouse chromosome 16 that encodes the catalytic subunit of DNA-dependent protein kinase. Prkdc(BALB) has been associated with increased susceptibility to IR-induced mammary and lymphatic neoplasia. Here, we provide evidence that chromosome 16 segments from BALB/c interact with Apc(Min) (multiple intestinal neoplasia) and specifically enhance IR-induced adenoma development in the upper part of the small intestine.

Adenoma↗
PubMedDate not supplied

Gastro-intestinal tumorigenesis in Smad4 mutant mice.

The SMAD4 gene plays a key role in the TGF-beta signaling pathway. We inactivated its mouse homolog Smad4. The homozygous mutants were embryonically lethal, whereas the heterozygotes were viable and fertile. Although young heterozygotes appeared normal, old mice developed gastric and duodenal polyps similar to human juvenile polyps characterized by abundant stroma and eosinophilic infiltrations. These data are consistent with the reports that a subset of human juvenile polyposis kindreds carry germline mutations in the SMAD4 gene. We then introduced the Smad4 mutation into the Apc(Delta716) knockout mice, a model for human familial adenomatous polyposis. Because both Apc and Smad4 are located on mouse chromosome 18, we constructed by meiotic recombination compound heterozygotes carrying both mutations on the same chromosome. In such mice, intestinal polyps developed into more malignant tumors than those in the simple Apc(Delta716) heterozygotes, showing an extensive stromal cell proliferation and strong submucosal invasion. These results indicate that mutations in SMAD4 play a significant role in the malignant progression of colorectal tumors.

Adenomatous Polyposis Coli Protein↗
PubMed1999

Differential expression of matrilysin and cyclooxygenase-2 in intestinal and colorectal neoplasms.

Both the matrix metalloproteinase matrilysin and the prostaglandin H synthase cyclooxygenase-2 (Cox-2), are thought to play key roles in colorectal carcinogenesis. These enzymes are overexpressed in 85-90% of human colorectal cancers. Furthermore, mice carrying an adenomatous polyposis coli germline mutation that are also nullizygous for either matrilysin or Cox-2 display a significant reduction in tumor multiplicity. To determine if there is a direct link between matrilysin and Cox-2, their expression was characterized in two mouse models of intestinal carcinogenesis and in human colorectal tumor samples. Both matrilysin and Cox-2 expression was increased in the mouse models and in the human colorectal cancers; however, immunohistochemistry and in situ hybridization indicated that their localization within the tumors was different. In the mouse models, Cox-2 was expressed in the superficial stroma, whereas matrilysin expression was localized exclusively to the neoplastic epithelium. In contrast, in human colorectal cancers, both Cox-2 and matrilysin were expressed in the neoplastic epithelium. Although over 80% of the specimens expressed both matrilysin and Cox-2, the levels and localization of matrilysin and Cox-2 expression were distinct. Cox-2 expression was strongest in well-differentiated areas, and matrilysin immunostaining was strongest in the more dysplastic and invasive regions of the tumor. These results indicate that these two important modulators of colorectal tumorigenesis are differentially expressed and imply that the therapeutic benefit may be improved by combination therapy utilizing selective Cox-2 and matrilysin inhibitors.

Animals↗
PubMed1995

The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia.

Mutations in the APC gene are responsible for various familial and sporadic colorectal cancers. Min mice carry a dominant mutation in the homolog of the Apc gene and develop multiple adenomas throughout their small and large intestine. Quantitative trait loci studies have identified a locus, Mom1, which maps to the distal region of chromosome 4, that dramatically modifies Min-induced tumor number. We report here the identification of a candidate gene for Mom1. The gene for secretory type II phospholipase A2 (Pla2s) maps to the same region that contains Mom1 and displays 100% concordance between allele type and tumor susceptibility. Expression and sequence analysis revealed that Mom1 susceptible strains are most likely null for Pla2s activity. Our results indicate that Pla2s acts as a novel gene that modifies polyp number by altering the cellular microenvironment within the intestinal crypt.

Adenomatous Polyposis Coli↗
PubMed1975

The occult osteomatous changes in the mandible in patients with familial polyposis coli.

Characteristic radio-opaque lesions were detected in the manibular bone, most clearly on the panoramic X-ray, in 27 or 93-2 per cent out of 29 cases in 15 families with familial polyposis coli, including 21 cases without Gardner's stigmata, 7 cases with the incomplete syndrome and 1 with the complete syndrome. Only 3 out of 19 members of these families who were free from polposis had radio-opaque jaw lesions. The cases with polyposis of other types also showed a negative result. The radiological diagnosis suggested that the lesions were of the character of endosteoma. Our observation is considered to be significant evidence in the understanding of the pathogenesis of Gardner's syndrome as well as a useful method of the early detection of carriers in the polyposis family.

Adolescent↗
PubMed1996

Salvage surgery for ileal pouch outlet obstruction.

Sixteen patients with ileal pouch outlet mechanical obstruction had major abdominal revision of the ileoanal anastomosis. Before operation all had severe difficulty in evacuation which required catheterization in 11. Eleven patients had a long efferent limb and/or long anorectal cuff, and five had a persistent stricture at the ileoanal anastomosis. None had pouchitis. The pouch was fully mobilized abdominally and the obstructing lesion resected. A new handsewn ileoanal anastomosis was formed. In two cases pouch volume was increased by incorporating an additional loop of ileum. All anastomoses but one were covered by a loop ileostomy. There were no deaths. Major complications occurred in two patients. Function was assessed in 15 patients; in one the ileostomy had not been closed. Median (interquartile range) frequency of defaecation per 24 h fell from 15 (7.3-19.5) to 6 (4.5-6.0) (P = 0.0033). Of the 11 patients who required a catheter before operation six evacuated spontaneously, three were improved but intubated on some occasions and two were unchanged after revisional surgery. Of the ten incontinent patients, five became continent, four were improved and one remained unchanged. There was a new continence disturbance in four (minor nocturnal in three) of the remaining five patients. One patient underwent further abdominal salvage surgery and another required establishment of an ileostomy because of poor function. Combined abdominoanal salvage surgery for outlet mechanical obstruction was successful in averting an ileostomy in 13 of 16 patients, and significantly improved pouch function in 12 of 15.

Adenomatous Polyposis Coli↗
PubMed1993

Colectomy with ileorectal anastomosis lowers rectal mucosal cell proliferation in familial adenomatous polyposis.

Rectal polyp regression has been observed in familial adenomatous polyposis (FAP) after colectomy and ileorectal anastomosis (IRA). In view of the association between risk of neoplasia and epithelial cell turnover rates, a study was conducted to determine the effect of colectomy and IRA on rectal mucosal proliferation in FAP. Endoscopic biopsies of flat rectal mucosa were taken from 12 FAP patients with an established IRA and 10 FAP patients prior to colectomy. Mucosal proliferation was assessed by flash-labeling S-phase cells with bromodeoxyuridine. Labeled cells were visualized on paraffin sections with an immunohistochemical stain using a monoclonal antibody to bromodeoxyuridine. Twenty crypt columns were analyzed. The mean labeling index (percent labeled cells/crypt) of the FAP patients with established IRAs (7.0 +/- 1.4 percent) was significantly less than that of the precolectomy patients (12.8 +/- 3.0 percent) (Mann-Whitney U test, P = 0.0004). Comparison of labeled distribution curves shows a contraction of the crypt proliferative zone in the IRA group. Colectomy with IRA in FAP is associated with a significant reduction in rectal mucosal cell proliferation. These findings support the claim of reduced risk of rectal cancer following this procedure in FAP and are of relevance to the study of environmental vs. genetic control of cell proliferation.

Adenomatous Polyposis Coli↗
PubMed2003

Familial adenomatous polyposis and duodenal lymphoma: report of a case.

The occurrence of duodenal polyposis is well recognized in familial adenomatous polyposis. Lymphoid hyperplasia in association with familial adenomatous polyposis usually occurs in the terminal ileum, but it can occur in the duodenum and may be endoscopically difficult to distinguish from an adenoma. A case report is presented in which a 54-year-old male with familial adenomatous polyposis, who 20 years earlier had a subtotal colectomy and ileorectal anastomosis, presented with a large rectal villous tumor and was found to have a duodenal extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The role of lymphoid hyperplasia in the development of mucosa-associated lymphoid tissue lymphoma is discussed, as well as the issue of mucosa-associated lymphoid tissue lymphoma in familial adenomatous polyposis. In cases in which biopsies of polypoid lesions in patients with familial adenomatous polyposis show dense lymphoid aggregates, flow cytometry may assist in the diagnosis.

Adenomatous Polyposis Coli↗
PubMed2001

Laparascope-assisted versus conventional restorative proctocolectomy with rectal mucosectomy.

To assess the advantages of a laparoscope-assisted proctocolectomy with ileal J-pouch anal anastomosis compared with conventional procedures, we retrospectively analyzed the results of the two procedures as follows: Eleven patients including five patients with familial adenomatous polyposis (FAP) and six with ulcerative colitis (UC) underwent a laparoscope-assisted proctocolectomy and hand-sewn ileal J-pouch anal anastomosis at our department from June 1997 to November 1999. This laparoscope-assisted colectomy (LAC) group was then compared with a group of 13 patients who had undergone conventional ileal pouch anal anastomosis using a standard laparotomy from 1986 to 1997. The median operative time of the LAC group was 8h 23min, which was 81 min longer than that of the standard colectomy (SC) group. The number of days during which eating was prohibited were similar in the two groups but the median postoperative hospital stay was significantly shorter in the LAC group (24.1 days). In the LAC group, the small incisions showed better cosmetic results and there was also a remarkable reduction in the degree of postoperative pain. In conclusion, a laparoscope-assisted proctocolectomy with ileal J-pouch anal anastomosis can be employed widely in patients with FAP and also in selected patients with UC.

Adenomatous Polyposis Coli↗