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At least 343 records · Page 19Linked to original sources
PubMed1999

Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers.

Peutz-Jeghers syndrome (PJS) is an autosomal-dominant disorder characterized by hamartomatous polyps in the gastrointestinal tract and by pigmented macules of the lips, buccal mucosa, and digits. Less appreciated is the fact that PJS also predisposes patients to an increased risk of gastrointestinal cancer, and pancreatic cancer has been reported in many PJS patients. It was recently shown that germline mutations of the STK11/LKB1 gene are responsible for PJS. We investigated the role of STK11/LKB1 in the development of pancreatic and biliary cancer in patients with and without the PJS. In a PJS patient having a germline splice site mutation in the STK11/LKB1 gene, sequencing analysis of an intestinal polyp and pancreatic cancer from this patient revealed loss of the wild-type allele of the STK11/LKB1 gene in the cancer. Inactivation of STK11/LKB1, by homozygous deletions or somatic sequence mutations coupled with loss of heterozygosity, was also demonstrated in 4-6% of 127 sporadic pancreatic and biliary adenocarcinomas. Our results demonstrate that germline and somatic genetic alterations of the STK11/LKB1 gene may play a causal role in carcinogenesis and that the same gene contributes to the development of both sporadic and familial forms of cancer.

AMP-Activated Protein Kinase Kinases↗
PubMed2002

Sonographic diagnosis of multiple small-bowel intussusceptions in Peutz-Jeghers syndrome: a case report.

Peutz-Jeghers syndrome (PJS) is a rare, though well-described, hereditary polyposis syndrome associated with mucocutaneous pigmentation that typically presents in the second decade of life with complications related to intestinal polyps. We present two cases of teenaged girls presenting with small-bowel intussusceptions within a 3-month period. Sonographic examinations readily revealed small-bowel intussusceptions with secondary small-bowel obstruction. In both the symptoms were less severe than one would expect given the underlying pathology found at subsequent surgery. Sonographic imaging with pathologic correlation is provided.

Child↗
PubMed2005

Impact of physical activity on intestinal cancer development in mice.

Observational epidemiology supports the hypothesis that variation in diet and other lifestyle exposures accounts for a large part of the variation in incidence of colorectal cancer (CRC). Physical inactivity is associated strongly with enhanced CRC risk, but no human intervention studies have shown causality. This paper reviews data from all available studies of the effects of exercise interventions on intestinal neoplasia using rat and mouse models. All 5 published studies of effects of increased physical activity (both forced and voluntary) using carcinogen-treated rat models show strong protection against CRC by greater physical activity. In contrast, there is little convincing evidence of reduced intestinal neoplasia after increased physical activity in the 3 published studies using Apc(Min) mice (which develop multiple intestinal polyps spontaneously) although the nature and amounts of physical activity imposed in rats and mice were similar. Major differences in protocol between the 2 groups of studies are that the rat studies were much longer (at least 20 wk and in most cases 38 wk compared with < or =9 wk for the mouse studies) and the primary endpoint was colorectal carcinoma (rats) rather than small bowel adenomas (mice). The epidemiological evidence for protection against adenoma formation by increased physical activity is weaker than that for carcinoma. The limited evidence available suggests that, compared with rats, mice may show a greater compensation for energy expenditure in exercise through reduction in nonexercise physical activity, thus ameliorating effects. The resulting smaller effects on body weight and body fatness may limit changes in intestinal neoplasia in Apc(Min) mice.

1,2-Dimethylhydrazine↗
PubMed2001

Absence of post-translational aspartyl beta-hydroxylation of epidermal growth factor domains in mice leads to developmental defects and an increased incidence of intestinal neoplasia.

The BAH genomic locus encodes three distinct proteins: junctin, humbug, and BAH. All three proteins share common exons, but differ significantly based upon the use of alternative terminal exons. The biological roles of BAH and humbug and their functional relationship to junctin remain unclear. To evaluate the role of BAH in vivo, the catalytic domain of BAH was specifically targeted such that the coding regions of junctin and humbug remained undisturbed. BAH null mice lack measurable BAH protein in several tissues, lack aspartyl beta-hydroxylase activity in liver preparations, and exhibit no hydroxylation of the epidermal growth factor (EGF) domain of clotting Factor X. In addition to reduced fertility in females, BAH null mice display several developmental defects including syndactyly, facial dysmorphology, and a mild defect in hard palate formation. The developmental defects present in BAH null mice are similar to defects observed in knock-outs and hypomorphs of the Notch ligand Serrate-2. In this work, beta-hydroxylation of Asp residues in EGF domains is demonstrated for a soluble form of a Notch ligand, human Jagged-1. These results along with recent reports that another post-translational modification of EGF domains in Notch gene family members (glycosylation by Fringe) alters Notch pathway signaling, lends credence to the suggestion that aspartyl beta-hydroxylation may represent another post-translational modification of EGF domains that can modulate Notch pathway signaling. Previous work has demonstrated increased levels of BAH in certain tumor tissues and a role for BAH in tumorigenesis has been proposed. The role of hydroxylase in tumor formation was tested directly by crossing BAH KO mice with an intestinal tumor model, APCmin mice. Surprisingly, BAH null/APCmin mice show a statistically significant increase in both intestinal polyp size and number when compared with BAH wild-type/APCmin controls. These results suggest that, in contrast to expectations, loss of BAH catalytic activity may promote tumor formation.

Amino Acid Sequence↗
PubMed1996

Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2).

Two cyclooxygenase isozymes catalyze conversion of arachidonic acid to prostaglandin H2: constitutive COX-1 and inducible COX-2. To assess the role of COX-2 in colorectal tumorigenisis, we determined the effects of COX-2 gene (Ptgs2) knockouts and a novel COX-2 inhibitor on Apc delta716 knockout mice, a model of human familial adenomatous polyposis. A Ptgs2 null mutation reduced the number and size of the intestinal polyps dramatically. Furthermore, treating Apc delta716 mice with a novel COX-2 inhibitor reduced the polyp number more significantly than with sulindac, which inhibits both isoenzymes. These results provide direct genetic evidence that COX-2 plays a key role in tumorigenesis and indicate that COX-2-selective inhibitors can be a novel class of therapeutic agents for colorectal polyposis and cancer.

Adenomatous Polyposis Coli↗
PubMed2004

Downregulation of prostaglandin E receptor subtype EP3 during colon cancer development.

BACKGROUND AND AIMS: Involvement of prostaglandin E(2) (PGE(2)) receptors EP(1), EP(2), and EP(4) in the formation of aberrant crypt foci (ACF) and/or intestinal polyps has been suggested. In contrast, EP(3) appears to have no influence on the early stages of colon carcinogenesis. In the present study, we examined expression of PGE(2) receptor subtypes EP(1), EP(2), EP(3), and EP(4) in normal colon mucosa and colon cancers, and assessed the contribution of EP(3) to colon cancer development. METHODS: mRNA expression of PGE(2) receptor subtypes EP(1), EP(2), EP(3), and EP(4) in normal colon mucosa and colon cancers in azoxymethane (AOM) treated mice and rats, and in humans, were examined by reverse transcription-polymerase chain reaction (RT-PCR), quantitative real time RT-PCR, and immunohistochemical analyses. Evaluation of the role of EP(3) was performed by intraperitoneal injection of AOM, using EP(3) receptor knockout mice. Effects of EP(3) receptor activation on cell growth of human colon cancer cell lines were examined using ONO-AE-248, an EP(3) selective agonist. Moreover, EP(3) expression in colon cancer cell lines was analysed with or without 5-aza-2'-deoxycytidine (5-aza-dC) treatment. RESULTS: Expression levels of EP(1) and EP(2) mRNA were increased in cancer tissues. EP(4) mRNA was constantly expressed in normal mucosa and cancers. In contrast, expression of EP(3) mRNA was markedly decreased in colon cancer tissues, being 5% in mice, 9% in rats, and 28% in humans compared with normal colon mucosa, analysed by quantitative real time RT-PCR. Immunohistochemical staining demonstrated the rat EP(3) receptor protein to be expressed in epithelial cells of normal mucosa and some parts of small carcinomas but hardly detectable in large carcinomas of the colon. Colon cancer development induced by AOM in EP(3) receptor knockout mice was enhanced compared with wild-type mice, with a higher incidence of colon tumours (78% v 57%) and mean number of tumours per mouse (2.17 (0.51) v 0.75 (0.15); p<0.05). Expression of EP(3) mRNA was detected in only one of 11 human colon cancer cell lines tested. Treatment with 5 microM of an EP(3) selective agonist, ONO-AE-248, resulted in a 30% decrease in viable cell numbers in the HCA-7 human colon cancer cell line in which EP(3) was expressed. Treatment with 5-aza-dC restored EP(3) expression in CACO-2, CW-2, and DLD-1 cells but not in WiDr cells, suggesting involvement of hypermethylation in the downregulation of EP(3) to some extent. CONCLUSION: The PGE(2) receptor subtype EP(3) plays an important role in suppression of cell growth and its downregulation enhances colon carcinogenesis at a later stage. Hypermethylation of the EP(3) receptor gene could occur and may contribute towards downregulating EP(3) expression to some extent in colon cancers.

Animals↗
PubMed1979

Desmoid tumors and mesenteric fibromatosis in Gardner's syndrome: report of kindred 109.

Kindred 109, from which Gardner's syndrome was first described, now has 224 members, 28 of whom have inherited the syndrome. Among the group of 28, desmoid tumors or mesenteric fibromatosis or both have developed in eight (29%). In four patients, the fibrous dysplasia appeared to originate in postsurgical abdominal incisional scars; in two of these cases, the mesenteric involvement resulted in death. In one patient, the process was present in the mesentery at the original operation. In three patients, the fibrous dysplastic lesions were extraincisional, with no known trauma associated with their occurrence.

Abdominal Muscles↗
PubMed1977

Diet and metabolism: large-bowel cancer.

Epidemiological data demonstrate that colon cancer incidence is associated mainly with high dietary fat consumption. Studies in metabolic epidemiology indicate that high fat intake influences both the amount and type of bile acids and neutral sterols and intestinal microflora acting on these compounds which may contain tumorigenic activity for the colon. This is compatible with the results of studies comparing populations with high or low risk for the colon cancer and patients with colon cancer.

Bacteria↗
PubMed1975

Epidermoid cysts, polyposis coli and Gardner's syndrome.

One hundred and ninety-six members of 15 families with Gardner's syndrome were investigated to determine the type of skin cyst that is part of this syndrome. These were shown to be epidermoid cysts and not pilar cysts or steatocystoma multiplex. They were solitary or multiple and seldom large and disfiguring. The skin cysts often occurred before the intestinal polyps were detectable. The presence of epidermoid cysts in children should be an indication for sigmoidoscopy when the child reaches the age of 14 years, and at 3-yearly intervals thereafter up to the age of 30 years, whether or not there is a family history of polyposis coli. At present it is not possible to say if Gardner's syndrome is the same as, or different from, familial polyposis. Until all patients with colonic polyps have a full clinical examination, looking for skin cysts and osteomas, X-rays of the skull and long bones to detect osteomas and dental X-rays for abnormalities of the teeth this question will remain unanswered.

Adolescent↗
PubMed1976

Efforts in cancer diagnosis: national task forces--large bowel cancer.

Current information from the National Large Bowel Cancer Project and other sources is given concerning new leads and avenues of research that may be used in early diagnosis or possibly in monitoring therapy. The search for biological markers has developed in two general directions: (1) to identify by genetic studies patients with a high probability of developing cancer who will provide insight into biochemical changes as premalignant lesions develop into frankly developed cancer, and (2) to fine differences between tissue and body fluid constituents in normal subjects and patients with cancer. Screening for colon cancer is discussed with a selective diagnostic approach and with emphasis on this approach in early diagnosis of asymptomatic high risk patients.

Adult↗