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At least 811 records · Page 45Linked to original sources
PubMed2000

Antagonism of arachidonic acid is linked to the antitumorigenic effect of dietary eicosapentaenoic acid in Apc(Min/+) mice.

The multiple intestinal neoplasia (Apc(Min/+)) mouse possesses a germline mutation at codon 850 of the adenomatous polyposis coli (Apc) gene resulting in the formation of a nonfunctional truncated gene product. Following a somatic mutation of the remaining wild-type allele, mice spontaneously develop approximately 40-50 tumors throughout the intestinal tract. This mouse model has been used to study intestinal tumorigenesis because this mutation is analogous to the inherited APC mutation in humans with familial adenomatous polyposis (FAP). These individuals characteristically develop numerous adenomas throughout their intestinal tracts. Only a few studies have evaluated the effects of dietary fatty acids on tumorigenesis in this animal model with varying results, and none have linked these effects to alterations in arachidonic acid (AA) metabolism. This study was designed to evaluate the antitumorigenic effect of dietary (n-3) polyunsaturated fatty acids (PUFA) in the Apc(Min/+) mouse model and to determine whether these effects are related to inhibition of AA metabolism. Male Apc(Min/+)mice were fed diets supplemented with eicosapentaenoic acid (EPA), AA or a combination of AA + EPA. Mean tumor number in the EPA group was 68% lower (P<0.05) compared with the control group, whereas AA supplementation did not significantly alter tumor load. The reduction in tumor load coincided with significant reductions in intestinal AA content and levels of prostaglandins. However, supplementing AA to the EPA diet (AA + EPA) abolished the antitumorigenic effect of EPA, increased tissue AA content fourfold and prostaglandin production two- to fourfold. These results indicate that AA is involved in tumorigenesis and suggest that EPA's ability to reduce tumor load in Apc(Min/+) mice is related to reductions in tissue AA content or its metabolism.

Analysis of Variance↗
PubMed2006

Identification of the IFITM family as a new molecular marker in human colorectal tumors.

We analyzed the expression profiles of intestinal adenomas from a new murine familial adenomatous polyposis model (Apc(delta14/+)) using suppression subtractive hybridization to identify novel diagnostic markers of colorectal carcinogenesis. We identified 18 candidate genes having increased expression levels in the adenoma. Subsequent Northern blotting, real-time reverse transcription-PCR, and in situ hybridization analysis confirmed their induction in beta-catenin-activated epithelial cells of murine adenomas. We showed that most of the genes also have altered expression levels in human colonic adenomas and carcinomas. We focused on the IFITM genes that encode IFN-inducible transmembrane proteins. Serial analyses of gene expression levels revealed high levels of expression in early and late intestinal neoplasm in both mice and humans. Using a conditional mouse model of Apc inactivation and a human colon carcinoma cell line, we showed that IFITM gene expression is rapidly induced after activation of the beta-catenin signaling. Using a large-scale analysis of human tumors, we showed that IFITM gene expression is significantly up-regulated specifically in colorectal tumors and thus may be a useful diagnostic tool in these tumors.

Adenocarcinoma↗
PubMed1989

[Extensive resection of the colon in children].

On the basis of the analysis of 98 major colonic resections in children with Hirschsprung's disease, anorectal developmental defects, diffuse colonic polyposis, the problems of mobilization of bringing down the different portions of the intestine are considered.

Adenomatous Polyposis Coli↗
PubMed1998

Aspirin prevents tumors in a murine model of familial adenomatous polyposis.

BACKGROUND: Both human and murine studies suggest that anti-inflammatory drugs prevent intestinal neoplasia. The purpose of this study was to investigate the role of aspirin as a chemopreventive agent for colorectal cancer. METHODS: We administered aspirin to the Min/+ mouse, an animal with a germline mutation in Apc, a gene that is essential for normal epithelial cell growth and differentiation. Apc mutation increases cytoplasmic beta-catenin, a regulatory protein associated with the cytoskeleton. Min/+ mice develop multiple intestinal adenomas and exhibit altered cell growth in the preneoplastic intestinal epithelium. RESULTS: Aspirin decreased the rate of tumor formation in Min/+ mice by 44%. Aspirin also normalized enterocyte growth by increasing apoptosis and proliferation in the preneoplastic intestinal mucosa. Finally, aspirin produced a decrease in intracellular beta-catenin levels, suggesting that modulation of this protein is associated with tumor prevention. CONCLUSIONS: These data confirm a role for aspirin in suppression of Apc-associated intestinal carcinogenesis.

Adenomatous Polyposis Coli↗
PubMed1988

[Familial gastro-intestinal adenomatosis].

Twenty-seven cases of familial gastro-intestinal adenomatosis are reported. There was no difference in pathology between 11 cases with familial involvement and 16 cases without. Juvenile, lymphoid as well as hyperplastic polyps coexisting with adenomas were found in a few cases. The risk of developing cancer in adenomas of 0.5 cm, 0.5-0.9 cm, 1.0-1.9 cm and 2.0 cm were 0%, 1.1%, 9% and 75%, respectively. Size seems to be the most critical and reliable indicator of malignant transformation. Proctectomy and colectomy of distal colon combined with removal of the adenomas equal to or larger than 1.0 cm through endoscope might be the better surgical intervention to avoid carcinomatous change. The term "familial polyposis coli" is suggested to be designated as "familial gastro-intestinal adenomatosis".

Adenomatous Polyposis Coli↗
PubMed2001

Small intestinal neoplasms.

Small intestinal neoplasms are uncommonly encountered in clinical practice. They may occur sporadically, in association with genetic diseases (e.g., familial adenomatous polyposis coli or Peutz-Jeghers syndrome), or in association with chronic intestinal inflammatory disorders (e.g., Crohn's disease or celiac sprue). Benign small intestinal tumors (e.g., leiomyoma, lipoma, hamartoma, or desmoid tumor) usually are asymptomatic but may present with intussusception. Primary malignancies of the small intestine-including adenocarcinoma, leiomyosarcoma, carcinoid, and lymphoma-may present with intestinal obstruction, jaundice, bleeding, or pain. Extraintestinal neoplasms may involve the intestine via contiguous spread or peritoneal metastasis. Hematogenous metastases to the intestine from an extraintestinal primary are unusual and are most typical of melanoma. Because the small intestine is relatively inaccessible to routine endoscopy, diagnosis of small intestinal neoplasms is often delayed for months after onset of symptoms. When the diagnosis is suspected, enteroclysis is the most useful imaging study. Small bowel endoscopy (enteroscopy) is increasingly widely available and may permit earlier, nonoperative diagnosis.

Biopsy, Needle↗
PubMedDate not supplied

Approach to angiogenesis inhibition based on cyclooxygenase-2.

Two cyclooxygenase (COX) isoforms have been identified: COX-1 and COX-2. COX-1 is the constitutively expressed form of the enzyme and is ubiquitous in its distribution. COX-2 is inducible and is present in inflammatory foci, tumors, and neovasculature. Expression of COX-2 appears to be important in tumor promotion, growth, and metastasis. It is up-regulated in a variety of premalignant disorders and malignancies. COX inhibitors have a major role in the treatment of inflammation and pain. Epidemiologic evidence in patients who take nonsteroidal anti-inflammatory drugs links COX inhibition with decreases in malignant esophageal, stomach, colon, lung, and breast tumors. Nonselective COX inhibitors have demonstrated efficacy in control of familial adenomatous polyposis, a disorder associated with the development of thousands of benign intestinal polyps. The selective COX-2 inhibitor celecoxib (Celebrex, Pharmacia) has been shown to reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis as an adjunct to usual care. Celecoxib has recently been approved for this indication and offers the potential for equivalent or greater efficacy than that seen with nonselective COX inhibitors but without the gastrointestinal mucosal toxicity and the inhibition of platelet function associated with those agents. Angiogenesis is a feature of both benign and malignant disease. Because COX-2 is up-regulated in the neovasculature of the rheumatoid pannus and in malignant tumors and their surrounding stroma, selective COX-2 inhibitors may be able to modify the progression of these disorders through the control of angiogenesis.

Angiogenesis Inhibitors↗
PubMed2004

Prevention of colorectal cancer through the use of COX-2 selective inhibitors.

Colorectal cancer is a major cause of morbidity and mortality accounting for an estimated 550,000 deaths annually worldwide. Colonic neoplasia develops in a stepwise fashion progressing from normal mucosa to adenomatous polyps to carcinoma, a process that takes years, thereby providing a prime opportunity for intervention. Although early detection by fecal occult blood testing and sigmoidoscopy can decrease the risk of cancer-related death by 20-30%, most persons never undergo appropriate screening. Population-based studies have previously determined that long-term ingestion of aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs) leads to a 40-50% reduction in mortality. from colorectal cancer. These observational studies fueled subsequent mechanistic investigations that led to the identification of a molecular target, cyclooxygenase-2 (COX-2). COX-2 has tumor-promoting properties. Expression of COX-2 is virtually undetectable in normal intestinal mucosa, but is increased in approximately 50% of colonic adenomas and in 90% of colorectal carcinomas. Experimental studies in mice have revealed that genetic ablation or pharmacologic inhibition of COX-2 attenuates the number and size of intestinal polyps that develop in animals harboring a mutation in Apc, which confers an increased risk for intestinal neoplasia. Recent clinical studies using specific COX-2 inhibitors have shown that these compounds can: (1) reduce intestinal polyp burden in patients with familial adenomatous polyposis; (2) prevent the occurrence and/ or recurrence of colorectal adenomas and cancers; and (3) negatively regulate angiogenesis in colorectal cancer liver metastases. Compared to nonselective NSAIDs, COX-2 specific inhibitors cause substantially fewer gastrointestinal side effects. These findings indicate that a widely used and relatively safe class of drugs may represent a viable and effective anticancer strategy for a disease that causes over a half-million deaths per year.

Animals↗
PubMedDate not supplied

Bannayan-Riley-Ruvalcaba syndrome: spectrum of intestinal pathology including juvenile polyps.

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a disorder that includes juvenile polyposis as part of its pathologic spectrum, and it recently has been shown to share phenotypic and genotypic features with Cowden's disease. In existing literature, descriptions of intestinal pathology in patients with BRRS are relatively sparse and occasionally erroneous. We describe the intestinal pathology in multiple specimens from three children with BRRS. Examination of gastrointestinal biopsies from these children revealed predominantly colonic and rectal polyps with the histology of juvenile polyps. Additionally, two cases with clusters of ectopic ganglion cells within the lamina propria, one in a colonic polyp and one in a duodenal biopsy, and an atypical polyp were observed. Bannayan-Riley-Ruvalcaba syndrome should be included in the list of differential diagnostic considerations when a child or young adult presents with a juvenile polyp, particularly if unusual histologic features such as atypical polyps or ectopic ganglion cells are encountered.

Adenomatous Polyposis Coli↗
PubMed2005

Regulation of stromal cell cyclooxygenase-2 in the ApcMin/+ mouse model of intestinal tumorigenesis.

Cyclooxygenase-2 (Cox-2) is expressed predominantly by stromal cells in intestinal adenomas from the Apc(Min/+) mouse model of familial adenomatous polyposis. We investigated the mechanistic basis of stromal cell Cox-2 expression in Apc(Min/+) mouse adenomas, as well as Cox-2 expression and activity in histologically normal (HN) Apc(Min/+) mouse intestine, in order to gain further insights into regulation of Cox-2 as a potential chemoprevention target. Upregulation of Cox-2 in intestinal tumours is not an intrinsic feature of Apc(Min/+) macrophages as bone marrow-derived Apc(Min/+) macrophages did not exhibit an abnormality in Cox-2 expression or activity. Intestinal permeability to lactulose or mannitol was similar in Apc(Min/+) mice and wild-type littermates, implying that macrophage activation by luminal antigen is unlikely to explain stromal cell Cox-2 induction. Moreover, stromal cells exhibited differential expression of Cox-2 and inducible nitric oxide synthase, suggesting 'alternative' (M2) rather than 'classical' (M1) macrophage activation. Flow cytometric sorting of isolated stromal mononuclear cells (SMNCs), on the basis of M-lysozyme and specific macrophage marker expression, demonstrated that macrophages, neutrophils and non-myelomonocytic cells all contributed to lamina propria prostaglandin (PG) E(2) synthesis. However, the majority of PGE(2) synthesis by macrophages was via a Cox-2-dependent pathway compared with predominant Cox-1-derived PGE(2) production by non-myelomonocytic cells. SMNCs from HN Apc(Min/+) intestinal mucosa exhibited similar levels of Cox-2 mRNA and protein, but produced more Cox-2-derived PGE(2) than wild-type cells at 70 days of age. There was an age-dependent decline in PGE(2) synthesis by Apc(Min/+) SMNCs, despite tumour progression. These data suggest that other Cox-2-independent factors also control PGE(2) levels during Apc(Min/+) mouse intestinal tumorigenesis. Regulation of macrophage Cox-2 expression and other steps in PGE(2) synthesis (e.g. PGE synthase) are valid targets for novel chemoprevention strategies that could minimize or avoid systemic COX-2 inhibition.

Adenoma↗
PubMed1999

Hydronephrosis: unrecognized complication following restorative proctocolectomy with ileal pouch-anal anastomosis.

Restorative proctocolectomy with ileal pouch-anal anastamosis (IPAA) is the operation of choice to avoid permanent ileostomy in the surgical management of patients with ulcerative colitis and familial adenomatous polyposis coli. IPAA with two loops of small intestine (J-pouch) is the most common configuration. Mortality rates are low, and despite significant morbidity patient satisfaction remains high. Functional results are good in most cases. We present two cases of hydronephrosis following IPAA. Loin pain was the presenting symptom in both cases, with one patient developing impaired renal function. Hydronephrosis has not been reported following IPAA, but with other forms of pelvic and retroperitoneal surgery it is believed to remain largely asymptomatic. We discuss the etiology of this previously unrecognized complication and suggest that it may be more prevalent following IPAA than is realized.

Abdominal Pain↗
PubMed2006

Dysregulation of Reg gene expression occurs early in gastrointestinal tumorigenesis and regulates anti-apoptotic genes.

Expression of anti-apoptotic genes is frequently elevated in tumors, where they increase resistance to chemotherapeutic agents and predict poor patient outcomes. However, key cellular factors regulating anti-apoptotic genes in tumors remain unknown. Increased expression of the regenerating (Reg) genes is commonly observed in gastrointestinal (GI) malignancies including colorectal cancer (CRC). We therefore examined Reg gene expression and associated changes in anti-apoptotic genes in an animal model of GI tumorigenesis. Using real time RT-PCR, we measured expression of Reg genes in human colorectal adenocarcinoma specimens, colon adenocarcinoma cell lines and adenomas from multiple intestinal neoplasia (min) mice heterozygous for a germ-line mutation of the adenomatous polyposis coli (APC) gene. Expression of Reg genes is increased in human colorectal adenocarcinomas and in the intestine of APCmin/+ mice at four weeks of age, a time preceding the spontaneous second mutation in the APC gene. Individual Reg genes exhibited regional expression profiles across the GI tract in mice. Adenomas from 14-week old mice had significant increases in at least one member of the Reg gene family, most commonly Reg IV and an associated increase in expression of the anti-apoptotic gene, Bcl-2. Addition of exogenous recombinant human Reg IV to human colon adenocarcinoma cells significantly increased Bcl-2 and Bcl-xL expression and induced resistance to ionizing radiation. These results show that dysregulation of Reg genes occur early in tumorigenesis. Furthermore, increased expression of Reg genes, specifically Reg IV contribute to adenoma formation and lead to increased resistance to apoptotic cell death in CRC.

Adenocarcinoma↗
PubMed1996

Effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine on intestinal polyp development in Apc delta 716 knockout mice.

Damage to the human adenomatous polyposis coli (APC) gene is responsible for not only familial adenomatous polyposis but also many sporadic cancers of the entire digestive tract. Using homologous recombination in embryonic stem cells, we recently constructed gene knockout mice with a truncation mutation in the Apc gene. These heterozygous mice developed intestinal polyps. We found that all microadenomas dissected from the earliest polyps had already lost the wild-type allele, indicating loss of heterozygosity (LOH) (Oshima et al., Proc. Natl. Acad. Sci. USA 92:4482-4486, 1995). Using these knockout mice, we investigated the effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP), one of the most abundant heterocyclic amines found in cooked meat and fish. When PhIP was fed to these mice at 400 ppm for 8 wk, the polyp distribution shifted to a larger size range, although the total polyp number did not change significantly. Similar, but weaker, effects were observed with the other heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline. On the other hand, intraperitoneal injections of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhlP) at a higher dose (50 mg/kg) for five consecutive days increased the polyp number significantly. This increment was not associated with mutations in the Apc gene; however, most polyps showed loss of the full-length Apc allele (LOH). These results suggest that PhIP affects intestinal polyp development by accelerating the growth rate of microadenomas. It is also possible that high doses of N-OH-PhIP increase the frequency of Apc gene LOH.

Age Factors↗
PubMed1989

Current experiences with the continent intestinal reservoir.

From November 1986 through October 1987, 71 patients received a continent intestinal reservoir at the Mississippi Baptist Medical Center. The mean age was 37 years (a range of 13 to 65 years). Coloproctectomy was necessary because of ulcerative colitis in 60, Crohn's colitis in eight and familial polyposis in three. A conventional ileostomy was converted to a continent intestinal reservoir in 54, while 13 received a continent intestinal reservoir at the time of the coloproctectomy. In four, the continent intestinal reservoir was constructed after removal of an ileoanal J pouch. Operative maneuvers of importance during valve construction included an intestinal collar, an isoperistaltic valve, stapling of the valve and electrocautery scarification of the serosa. Two patients experienced valve dessusception. The over-all operative revision rate for valve and pouch problems was 7 per cent. There were no deaths and no reservoirs have been removed. An improved quality of life was reported by almost all of those patients converted from a conventional ileostomy. The continent intestinal reservoir represents an attractive option for certain patients after coloproctectomy.

Adenomatous Polyposis Coli↗
PubMed2002

Cyclooxygenase-2 expression in fibroblasts and endothelial cells of intestinal polyps.

Cyclooxygenase-2 (COX-2), the inducible COX isozyme, plays a key role in intestinal tumorigenesis. We have demonstrated recently that COX-2 protein is induced in the polyp stroma near the intestinal luminal surface in the Apc(Delta716) mouse, a model for human familial adenomatous polyposis, and stimulate tumor angiogenesis. However, the precise cell types that express COX-2 are still to be determined. By immunohistochemical analysis, here we show that the majority of COX-2-expressing cells in the intestinal polyps of Apc(Delta716) mice are fibroblasts and endothelial cells. Furthermore, the COX-2-expressing cells in human familial adenomatous polyposis polyps are also fibroblasts and endothelial cells. In contrast, bone marrow-derived cells such as macrophages and leukocytes express little COX-2 protein in the intestinal polyps. These results clearly indicate that fibroblasts and endothelial cells play important roles in polyp expansion by expressing COX-2, resulting in tumor angiogenesis.

Actins↗
PubMed2003

Transcriptional profiling of the transition from normal intestinal epithelia to adenomas and carcinomas in the APCMin/+ mouse.

Mutations in the adenomatous polyposis coli (APC) gene that result in excessive beta-catenin-induced cell signaling are implicated in the risk of colon cancer. Although the mechanism of APC-mediated tumorigenesis is known, the pathways that translate beta-catenin signaling into tumor growth in vivo are undefined. To address this, gene expression profiles of normal intestinal epithelial cells were compared with those from adenomas and carcinomas from APC(Min/+) mice, a model of APC-related colorectal cancer. The gene expression profiles of adenomas and carcinomas were very similar, which is consistent with the theory that carcinomas progress from adenomas in this model system. Tumors had altered transcript abundance for members of several pathways that influence cell growth and proliferation including growth factors/receptors, molecules involved in apoptosis, and protein processing and catabolism enzymes. Comparison of gene expression between adenomas and carcinomas revealed nine differentially expressed transcripts. These included members of three growth-regulating pathways, and the results are consistent with the increased growth potential of carcinomas. SRY-box containing gene 17 (Sox 17), a negative regulator of beta-catenin signaling, and calbindin-D9K, a factor that enhances calcium transport, were more highly expressed in adenomas than carcinomas (approximately 4-fold and 15- to 22-fold, respectively). Transcript abundance for insulin-like growth factor binding protein 5, which mediates insulin-like growth factor function, was 2.6-fold greater in carcinomas. Because the changes in gene expression observed in this study are directly associated with a deficiency in APC, the data provide new insights into how loss of this important tumor suppressor translates into benign and malignant tumor growth.

Adenoma↗
PubMed2004

The influence of matrix metalloproteinase-7 on early mammary tumorigenesis in the multiple intestinal neoplasia mouse.

The multiple intestinal neoplasia (Min/+) mouse, which carries a mutant adenomatous polyposis coli (Apc) allele, is a model for human familial colon cancer. Like the human syndrome caused by mutant APC, the Min/+ mouse syndrome shows susceptibility to tumors of other tissues, including the mammary gland. The matrix metalloproteinase (MMP) MMP-7 (matrilysin) gene is transcriptionally induced by signal transduction pathways resulting from loss of APC function, and contributes to the progression of benign and malignant intestinal epithelial cells. Mammary tumors that develop in Min/+ mice express MMP-7. To investigate whether mutant APC and MMP-7 can cooperate in mammary tumorigenesis, we compared N-ethyl-N-nitrosourea (ENU)-enhanced mammary tumor formation in Min/+ mice that were either wild-type or deficient in MMP-7. Min/+ mice lacking MMP-7 demonstrate a 60% reduction in the number of early focal lesions in the mammary gland at early, but not later, timepoints. We conclude that MMP-7 transiently influences early stage mammary tumorigenesis.

Animals↗