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PubMed1999

Alkaline sphingomyelinases and ceramidases of the gastrointestinal tract.

In addition to the acid and neutral sphingomyelinases (SMase) that occur in most tissues, distinct alkaline sphingomyelinases occur in the mucosa of the gastrointestinal tract and human bile. These enzymes exhibit characteristic properties with regard to bile-salt dependence, protease resistance, and longitudinal distribution in the gut. Alkaline SMase has now been partially purified from human bile and from rat small intestine. It is thought to have a role in sphingomyelin (SM) digestion but may also be important for the generation of antiproliferative sphingolipid messengers in the gut. It occurs throughout the whole length of the intestine and also in the colon. It is decreased in colon cancer tissue compared to surrounding mucosa and is extremely low in colon mucosa from patients with familial adenomatous polyposis (FAP). This chapter reviews the properties and potential physiological and pathophysiological significance of alkaline SMase. It also briefly summarizes the knowledge about sphingolipid digestion and about the ceramidases of the gut.

Amidohydrolases↗
PubMed1998

Apc1638N: a mouse model for familial adenomatous polyposis-associated desmoid tumors and cutaneous cysts.

BACKGROUND & AIMS: Germline mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominant predisposition to the formation of multiple colorectal adenomas. Moreover, patients with FAP are at high risk of developing several extracolonic manifestations, including desmoids, cutaneous cysts, and tumors of the upper gastrointestinal tract. Although by definition desmoids are nonmalignant, because of their aggressive invasion of local structures, they represent one of the major causes of morbidity and mortality among patients with FAP. METHODS: This study describes the histopathologic and molecular characterization of Apc1638N, a mouse model for the broad spectrum of extracolonic manifestations characteristic of FAP. RESULTS: Heterozygous Apc+/Apc1638N animals develop fully penetrant and multifocal cutaneous follicular cysts and desmoid tumors in addition to attenuated polyposis of the upper gastrointestinal tract. Moreover, breeding of Apc+/Apc1638N mice in a p53-deficient background results in a dramatic seven-fold increase of the desmoid multiplicity. CONCLUSIONS: Because of the attenuated nature of their intestinal phenotype, these mice survive longer than other murine models for Apc-driven tumorigenesis. Therefore, Apc1638N represents an ideal laboratory tool to test various therapeutic intervention strategies for the management of intestinal as well as extraintestinal tumors.

Adenomatous Polyposis Coli↗
PubMed1987

Large bowel cancer in the young.

Eighty-five patients aged 40 or less who presented with colorectal carcinoma over a 32-year period were reviewed. The incidence was 2.5 per cent of all patients with large bowel cancer (n = 3426). Predisposing causes included familial polyposis (eight patients), panprotocolitis (ulcerative, one, Crohn's, one) and irradiation (one), four patients were pregnant, one-third of the patients presented as emergencies, and 43 per cent of these had intestinal obstruction. Five-year survival rates were 41 per cent overall and 59 per cent after "curative" resection. Survival was equivalent both for elective and emergency admission and for mucinous carcinomas (n = 16) and those non-mucinous carcinomas of moderate histological differentiation. Five-year survival rates were poorer when the history was less than three months in duration (20 per cent vs 45 per cent: P = 0.02) and for rectal and rectosigmoid tumours than colonic tumours (31 per cent vs 50 per cent: P = 0.05). Radical resection is indicated when feasible: four of five patients with involvement of adjacent viscera and four of six patients with resectable recurrence survived beyond 10 years. The outcome is similar to that at all ages, any unfavourable pathological features being balanced by improved survival following emergency operations.

Adenocarcinoma↗