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PubMedDate not supplied

Cyclooxygenase-2 and gastrointestinal cancer.

The cyclooxygenase (COX) enzymes (COX-1 and COX-2) are key enzymes of prostaglandin (PG) biosynthesis. Nonselective non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the enzymatic activity of both COX-1 and COX-2. Selective COX-2 inhibitors have been developed that appear to have 50% less gastrointestinal toxicity than traditional nonselective NSAIDs. Experimental evidence suggests that the COX pathway is involved in tumor promotion. Evidence to support this comes from both clinical and laboratory findings suggesting that chronic NSAID use reduces the relative risk for developing colorectal cancer (CRC). Although the precise mechanism or mechanisms by which these drugs affect tumor progression is not completely understood, it is likely that part of their anti-tumor effect is due to inhibition of the COX- 2 enzyme. COX-2 levels are increased in CRC as well as in several other solid malignancies. COX-2-derived bioactive lipid products promote tumor-associated n eovascularization, inhibit cell death, and stimulate cell proliferation and motility. Additionally, treatment with COX-2-selective inhibitors reduces polyp burden in animal models of intestinal neoplasia and in humans with familial adenomatous polyposis (FAP). Ongoing human clinical trails are under way to test the efficacy of COX-2-selective inhibitors in a number of human cancers.

Animals↗
PubMed2003

Overexpression of cyclooxygenase 2 in hamartomatous polyps of Peutz-Jeghers syndrome.

OBJECTIVE: Peutz-Jeghers syndrome (PJS) is an autosomal-dominant hamartomatous polyposis syndrome. Affected individuals are at risk for intestinal and extraintestinal malignancies. Prostaglandins and polyamines are small molecules believed to be important in tumor formation and growth. Cyclooxygenase (COX) and ornithine decarboxylase (ODC) are key enzymes in the prostaglandin and polyamine biosynthetic pathways, respectively. The aim of this study was to measure and compare COX-1 and COX-2 expression in normal and hamartomatous tissue of PJS patients. METHODS: We measured COX-1 and COX-2 protein expression in normal and hamartomatous GI tissues from affected PJS individuals and compared it with that in normal controls. COX-2 RNA in these tissues was also measured and compared by reverse transcription polymerase chain reaction (PCR). In addition, COX-2 expression was detected in tissue slides by immunostaining. ODC activity was measured between normal and hamartomatous tissues of PJS compared with control tissues. RESULTS: COX-1 expression was similar in normal and control GI tissues. In contrast, COX-2 overexpression was noted in hamartomatous polyp tissue from PJS patients compared with normal control and PJS tissue. COX-2 expression by reverse transcription PCR was 10-fold greater in a hamartoma compared with other tissues. COX-2 expression was noted in the epithelial cells of hamartomatous polyps, and also coursing throughout the stromal tissue of the lamina propria, including muscle cells. ODC activity was similar in the tissues studied. CONCLUSIONS: Selective COX-2 overexpression was noted in hamartomatous polyp tissue from PJS individuals. The results of the study provide an avenue for possible effective chemoprevention of polyp formation and growth in PJS.

Blotting, Western↗
PubMed1987

Colorectal goblet cell mucins in familial adenomatous polyposis.

Ninety two tissue blocks from the left colon and 52 from the right colon were obtained from 112 patients with familial adenomatous polyposis (FAP). Tissues from 137 patients with other conditions served as controls. Within the main study a smaller investigation was performed to compare sections from the left and right colon in the same subject. Several well known histochemical techniques were used to investigate possible changes in sulphation, sialic acid structure (loss of O-acetyl substituents), and changes in the ratio of sialic acid to neutral sugars. In patients with FAP, as in controls, there was increased expression of periodic acid Schiff positive mucin and fucose in the right colon. The only difference between patients with FAP and controls was the indirect demonstration of less neutral mucin in the right colon in FAP, but this did not seem to affect neutral sugars binding to UEA-1, PNL, or HPA. As in the general population, a small proportion of patients with FAP showed a lack of O-acetyl substituted sialic acid. Sialic acid heterogeneity probably has a genetic basis, but this is not associated with the genetic defect underlying FAP.

Adenomatous Polyposis Coli↗
PubMed1995

Human homologue of a candidate for the Mom1 locus, the secretory type II phospholipase A2 (PLA2S-II), maps to 1p35-36.1/D1S199.

Mice heterozygous for the dominant Min mutation in their Apc gene develop multiple intestinal neoplasia. Analogously, family members from familial adenomatous polyposis kindreds inheriting mutations in their human APC homologue develop a similar phenotype. Quantitative trait loci studies have identified the Mom1 locus (for modifier of Min-1), which is responsible for part of the genetic variability in polyp number found among inbred mouse strains. The secretory type II phospholipase [nonpancreatic Pla2s (type II Pla2s or Pla2s-II)] has been demonstrated to be a candidate for Mom1, and a mutation in Pla2s-II in mice carrying the Min mutation has been proposed to account for an increased polyp number compared to mice without the Pla2s-II mutation. In this study, we have mapped the chromosomal position of the human homologue of Pla2s-II. We have identified 3 mega-yeast artificial chromosomes that carry PLA2S-II and localized one of them by fluorescence in situ hybridization to the border between 1p35 and 1p36.1. The presence of the microsatellite marker D1S199 in all three clones integrates PLA2S-II into different genetic maps. This highly polymorphic CA repeat D1S199 has previously been shown by us to identify loss of heterozygosity in 48% of sporadic colorectal tumors, indicating that the human homologue of the Pla2s-II/Mom1 locus might be related to human colorectal cancer.

Base Sequence↗
PubMed1996

Action of Min and Mom1 on neoplasia in ectopic intestinal grafts.

Mice heterozygous for Min, a mutant allele of Apc, develop adenomas throughout the intestinal tract. Tumor multiplicity in Min mice is influenced by genetic modifier loci. Previously, we mapped one of these modifier loci, Mom1, to distal mouse chromosome 4. Mom1 is a semidominant modifier of both tumor size and multiplicity in Min mice. Recent evidence suggests that Mom1 may encode a secretory phospholipase, Pla2g2a. Pla2g2a is expressed in a variety of cell types and seems to be involved in inflammatory responses and bacterial defense mechanisms. Here, we determine whether Min and Mom1 act in a tissue-autonomous fashion using ectopic intestinal isografts. Within the small intestinal grafts, both Min and Mom1 act in a tissue-autonomous manner. There is no evidence that either Min or Mom1 has a systemic effect on tumor development. However, within the colonic grafts, the Min phenotype does not appear to be autonomous; the development of colonic tumors in Min mice seems dependent on factors beyond the Min genotype of the colonic epithelium. Micro-environmental factors, such as digestive secretions, dietary components, or intestinal flora, may be critical factors contributing to the development of Min-induced colonic tumors. However, these factors are not required for the action of Min or Mom1 within the small intestine.

Adenomatous Polyposis Coli Protein↗
PubMed1998

[The diagnostic contribution of computed tomography in a case of volvulus of the small intestine after an ileoanal anastomosis].

A case of acquired volvulus as a cause of late small bowel obstruction, in a patient who had undergone a colectomy with ileal pouch-anal anastomosis two years previously, is described. Computed Tomography (CT) accurately demonstrated signs of adhesive strangulating obstruction, detecting also a radial disposition of the loops around the mesenteric root and an abnormal position of the superior mesenteric artery and vein on the right side of the aorta. From a literature survey, there are no previous studies reporting the CT appearance of a small intestine volvulus developed as a complication of an ileal pouch-anal anastomosis.

Adenomatous Polyposis Coli↗
PubMed1975

Peutz-Jeghers syndrome: its natural course and management.

Two hundred and twenty-two patients with Peutz-Jeghers syndrome were ascertained in Japan between 1961 and 1974 through two nationwide surveys, medical literature, and personal examinations. Genetic analysis was made of this group as well as 102 follow-up cases. The average age at diagnosis was 23 in males and 26 in females, with male to female ratio of 1:1.13. Presenting complaints of 170 patients included obstruction (42.8 per cent of patients), abdominal pain (23.4 per cent), rectal bleeding (13.5 per cent), extrusion of polyp (7.2 percent). Diagnosis of 52 patients was based on melanin pigmentation. Intussusception occurred in 46.9 per cent of the patients, most often in the small intestine. Polyps occurred in the stomach in 108 patients (48.6 per cent), small intestine, 142 patients (64 per cent), colon, 118 patients (53.2 per cent) and rectum, 71 patients (32 per cent). Among the 222 patients, cancer was histologically verified in 28. Fifteen early cancers occurred (3 gastric, 8 small intestine, 4 colon), and 11 advanced cancers (3 gastric, 1 small intestine, 6 colon, and 1 both colon and small intestine). Mortality was lower than in patients with familial polyposis coli but higher than in the general population. Conservative surgical management, planned medical follow-up, and the need for a national registration system are stressed.

Adolescent↗
PubMed1998

[COX-2 associated loss of apoptosis activity in intestinal neoplams in Apc gene knock-out mice].

The aim of the study was to characterize both apoptotic and proliferating cells histologically and to analyze localisation and distribution of various apoptosis-associated proteins in tumours of different stages of degeneration in the animal model of Apc-gene defect mice. Such animals show clinical symptoms similar to those of patients suffering from Familial Adenomatous Polyposis (FAP) but develop the neoplasm's mainly in the small intestine. Tumours from all parts of the gut of 90 days old non-treated MIN-mice were classified as adenocarcinomas, histologically. The apoptosis-associated proteins bax, bcl-2, p53 and the COX-2 enzyme were investigated immunohistochemically. Additionally the localisation and distribution of proliferating (BrdU-labeling) and apoptotic (KLENOW, TUNEL) cells were analysed. In the summary we point out: 1. The activity of apoptosis increases in early stage of neoplasm as a defensive mechanism of mucosa. 2. A decrease in apoptosis rate occurs during carcinogenesis. 3. The inversely correlating, clear COX-2 accumulation accompanying carcinoma development supplies evidence for cyclooxygenase-inhibitor treatment is a promising therapeutic attempt in early stage of FAP.

Adenocarcinoma↗
PubMed1991

Epithelial and neuroendocrine tumors of the duodenum.

This review considers the pathologic features of epithelial tumors and tumor-like lesions of the duodenum and highlights potential pitfalls in their histological diagnosis. The tumor-like lesions include Brunner's gland hamartoma, myoepithelial hamartoma, and the mucosal polyps of the Peutz-Jeghers and juvenile polyposis syndromes. The true neoplasms are of two broad groups. The first includes duodenal adenomas and carcinomas, whose microscopic features, histogenetic relationships, and clinical significance closely mimic their commoner counterparts in the large intestine and which, when multiple, are closely associated with familial adenomatous polyposis coli. The second includes a number of uncommon endocrine cell tumors showing a great diversity of histological pattern, and which may be single or multiple. Among these are typical argyrophil carcinoids, which may secrete gastrin to give rise to the Zollinger-Ellison syndrome, and which may occur as part of the inherited multiple endocrine neoplasia syndrome type 1 (MEN-1); glandular somatostatin-rich, apparently nonargyrophil, carcinoids containing psammoma bodies that can be easily confused histologically with adenocarcinomas, and which are linked to type 1 neurofibromatosis (von Recklinghausen's disease) and phaeochromocytoma; and the gangliocytic paraganglioma, a rare tumor composed of neural elements, ganglion cells, and endocrine cells. Accurate histologic diagnosis of mucosal tumors and tumor-like lesions of the duodenum is important not only for immediate patient management, but also because it may provide the first clue to the existence of an inherited tumor syndrome, with its broader implications for the patient's family and potentially important consequences for genetic counseling.

Adenocarcinoma↗
PubMed2003

Adenocarcinoma and multiple adenomas of the large intestine, associated with Cronkhite-Canada syndrome.

The Cronkhite-Canada syndrome is a rare non-hereditary disorder with generalised gastrointestinal polyposis, associated with ectodermal changes. We report here a case of adenocarcinoma and multiple adenomas of the large intestine associated with Cronkhite-Canada syndrome in a 61-year-old Japanese man. Histologically, the rectal tumour was composed of well-differentiated tubular adenocarcinoma, admixed with foci of adenomatous components, and associated with hyperplastic mucosa of Cronkhite-Canada syndrome. Multiple polyps, >20 polyps < or = 2.0 cm in diameter, were found near the carcinoma of the resected rectum. Histologically, superficial parts of the polyps were composed of tubular adenomas, and basal parts of the polyps were hyperplastic dilated glands. It was speculated that, in the present case, the rectal adenocarcinoma arose from mucosal hyperplasia (Cronkhite-Canada polyp)-adenoma-carcinoma pathway. This suggested that Cronkhite-Canada syndrome has definite malignant potential, although the frequency of malignant transformation is thought to be low in Cronkhite-Canada syndrome.

Adenocarcinoma↗
PubMed2002

The food mutagen 2-amino-9H-pyrido[2,3-b]indole (AalphaC) but not its methylated form (MeAalphaC) increases intestinal tumorigenesis in neonatally exposed multiple intestinal neoplasia mice.

The heterocyclic amines 2-amino-9H-pyrido[2,3-b]indole (AalphaC) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAalphaC) are carcinogenic in several organs in rodents, but not in the intestinal tract. However, AalphaC induces DNA adducts, mutations and preneoplastic aberrant crypt foci (ACF) in rodent colons. The purpose of this study was to examine whether AalphaC and MeAalphaC could affect intestinal tumorigenesis in C57BL/6J-Min/+ (multiple intestinal neoplasia) mice. These mice are heterozygous for a germline nonsense mutation in codon 850 of the tumor suppressor gene adenomatous polyposis coli (Apc), producing a truncated non-functional Apc protein. They develop multiple intestinal adenomas, and are particularly susceptible to intestinal carcinogens that affect the Apc gene, especially when exposed neonatally. Whole litters consisting of Min/+ and +/+ (wild-type) mice of both sexes were given a single s.c. injection of 0.22 mmol/kg AalphaC (40.3 mg/kg) or MeAalphaC (43.4 mg/kg) or the vehicle 1:1 dimethylsulfoxide:0.9% NaCl on days 3-6 after birth, and were terminated at 11 weeks. AalphaC increased the number and diameter of small intestinal tumors, but not the number of colonic tumors or dysplastic ACF, in female and male Min/+ mice separately. In pooled data from females and males, colonic tumors and ACF found after AalphaC exposure appeared to be smaller than the spontaneous lesions, indicating later induction, slower growth or both. In contrast to AalphaC, MeAalphaC did not affect intestinal tumorigenesis in Min/+ mice. No effects were found by any of the amino-alpha-carbolines in the +/+ mice. AalphaC was less potent than the heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.

Animals↗