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At least 883 records · Page 49Linked to original sources
PubMed2004

Tumor regionality in the mouse intestine reflects the mechanism of loss of Apc function.

Inherited colorectal cancer syndromes in humans exhibit regional specificity for tumor formation. By using mice with germline mutations in the adenomatous polyposis coli gene (Apc) and/or DNA mismatch repair genes, we have analyzed the genetic control of tumor regionality in the mouse small intestine. In C57BL/6 mice heterozygous for the Apc multiple intestinal neoplasia mutation (Apc(Min)), in which tumors are initiated by loss of heterozygosity by means of somatic recombination, tumors form preferentially in the distal region of the small intestine. By contrast, the formation of tumors initiated by allelic silencing on the AKR Apc(Min) genetic background is strongly skewed toward the ileocecal junction. A third tumor regionality is displayed by tumors that develop in MMR-deficient Apc(Min/+) mice, in which mutation of the Apc gene is responsible for tumor initiation. Thus, tumor regionality in the small intestine of Apc(Min/+) reflects the mechanism by which the wild-type allele of Apc is inactivated. We have reexamined the mechanism of Apc loss in tumors from Apc(1638N/+) mice, in which tumors of the small intestine develop in a regional pattern overlapping that of mismatch repair-deficient mice. In contrast to previous reports, we find that tumors from Apc(1638N/+) mice on a congenic C57BL/6 background maintain the wild-type allele of Apc. Our studies demonstrate a pathway-specific regionality for tumor development in mouse models for inherited intestinal cancer, an observation that is reminiscent of the regional preference for tumor development in the human colon. Perhaps, the power of mouse genetics and biology can be harnessed to identify genetic and other factors that contribute to tumor regionality.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Lack of inducible nitric oxide synthase promotes intestinal tumorigenesis in the Apc(Min/+) mouse.

BACKGROUND & AIMS: The role of the inducible isoform of nitric oxide synthase (Nos2 or iNOS) in intestinal tumorigenesis is unclear. Conflicting data also exist regarding the ability of Nos2 to modulate expression and/or activity of cyclooxygenase 2 (Cox-2), which promotes intestinal tumorigenesis. Therefore, we determined the effect of a null Nos2 genotype on intestinal tumorigenesis and Cox-2 expression/activity in the Apc(Min/+) mouse model of familial adenomatous polyposis. METHODS: Apc(Min/+)Nos2(-/-) mice were generated by successive crosses between C57BL/6-Apc(Min/+) and C57BL/6-Nos2(tm1Lau) mice. Adenoma characteristics of age-matched Apc(Min/+)Nos2(+/+) and Apc(Min/+)Nos2(-/-) mice were compared. The level and cellular localization of Nos2 messenger RNA (mRNA) expression in Apc(Min/+)Nos2(+/+) mouse intestine was determined. Cox-2 expression and activity were measured in both intestinal tissue and bone marrow-derived macrophages in vitro. RESULTS: Apc(Min/+)Nos2(-/-) mice developed significantly more intestinal adenomas than Apc(Min/+)Nos2(+/+) littermates. Epithelial cell Nos2 mRNA expression was decreased in adenomas compared with histologically normal Apc(Min/+)Nos2(+/+) intestine. There was no significant difference in Cox-2 expression or activity in either intestine or bone marrow-derived macrophages from Apc(Min/+)Nos2(+/+) and Apc(Min/+)Nos2(-/-) animals. CONCLUSIONS: Nos2 plays an antineoplastic role in the Apc(Min/+) mouse model of familial adenomatous polyposis. Nos2 does not modulate Cox-2 expression or activity in the Apc(Min/+) mouse.

Adenomatous Polyposis Coli Protein↗
PubMed2006

Cyclooxygenase-2 expression and oxidative DNA adducts in murine intestinal adenomas: modification by dietary curcumin and implications for clinical trials.

The natural polphenol, curcumin, retards the growth of intestinal adenomas in the Apc(Min+) mouse model of human familial adenomatous polyposis. In other preclinical models, curcumin downregulates the transcription of the enzyme cyclooxygenase-2 (COX-2) and decreases levels of two oxidative DNA adducts, the pyrimidopurinone adduct of deoxyguanosine (M1dG) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG). We have studied COX-2 protein expression and oxidative DNA adduct levels in intestinal adenoma tissue from Apc(Min+) mice to try and differentiate between curcumin's direct pharmacodynamic effects and indirect effects via its inhibition of adenoma growth. Mice received dietary curcumin (0.2%) for 4 or 14 weeks. COX-2 protein, M1dG and 8-oxo-dG levels were measured by Western blot, immunochemical assay and liquid chromatography-mass spectrometry, respectively. In control Apc(Min+) mice, the levels of all three indices measured in adenoma tissue were significantly higher than levels in normal mucosa. Lifetime administration of curcumin reduced COX-2 expression by 66% (P = 0.01), 8-oxo-dG levels by 24% (P < 0.05) and M1dG levels by 39% (P < 0.005). Short-term feeding did not affect total adenoma number or COX-2 expression, but decreased M1dG levels by 43% (P < 0.01). COX-2 protein levels related to adenoma size. These results demonstrate the utility of measuring these oxidative DNA adduct levels to show direct antioxidant effects of dietary curcumin. The effects of long-term dietary curcumin on COX-2 protein levels appear to reflect retardation of adenoma development.

Adenomatous Polyposis Coli↗
PubMed2004

Modulation of tumor formation and intestinal cell migration by estrogens in the Apc(Min/+) mouse model of colorectal cancer.

Epidemiological studies suggest that post-menopausal hormone replacement therapy (HRT) reduces colorectal cancer (CRC) incidence. Phytoestrogens, including the soy isoflavone genistein and coumestrol, are used by many women as alternatives to HRT. Previous studies showed that ovariectomy induced a 77% increase in intestinal adenoma number in the C57BL/6J-Min/+ (Min/+) mouse, an animal model of adenomatous polyposis coli (APC)-associated CRC. Replacement of estradiol (E(2)) in ovariectomized Min/+ mice reduced tumor number to baseline and up-regulated the expression of estrogen receptor beta (ERbeta). We hypothesized that the phytoestrogens genistein and coumestrol would inhibit intestinal tumorigenesis in ovariectomized Min/+ mice. Min/+ and Apc(+/+) (WT) mice were ovariectomized and assigned to either a control diet or treatment with E(2), genistein or coumestrol. Treatment of ovariectomized Min/+ (Min/+ OX) mice with genistein resulted in a non-significant reduction in tumor number. Min/+ OX mice treated with coumestrol had significantly fewer tumors than untreated Min/+ OX controls and the same number of tumors as non-ovariectomized Min/+ mice. Bromodeoxyuridine migration assays also demonstrated that treatment with E(2) or coumestrol improved enterocyte migration rate. Immunoprecipitation and immunohistochemistry analyses showed that impaired association of the adherens junction proteins E-cadherin and beta-catenin in Min/+ mice was improved by treatment with either E(2) or coumestrol. Immunoblot analyses also showed that expression of ERbeta was elevated in enterocytes of Min/+ OX mice treated with E(2) or coumestrol as compared with those of untreated Min/+ OX mice. In conclusion, both coumestrol and E(2) prevent intestinal tumorigenesis and ameliorate enterocyte migration and intercellular adhesion in the Apc(Min/+) mouse model of CRC.

Animals↗
PubMed1985

Remarkable improvement of clinical status in a patient with multiple lymphomatous polyposis of the gastrointestinal tract after repetitive chemotherapy.

The effect of repeated courses of chemotherapy on gastrointestinal tumors seen in a 43 year-old male patient with multiple lymphomatous polyposis involving the entire gastrointestinal tract was presented. Numerous polypoid lesions from the stomach to the rectum were the characteristic finding in this case. The biopsied specimens from polyps either of the stomach or large intestine showed diffuse lymphocytic accumulation in the submucosa, which is consistent with multiple lymphomatous polyposis of the gastrointestinal tract. Remarkable regression of the large masses in the gastrointestinal tract was obtained by two courses of VEMP therapy, along with improvement of hypoalbuminemia and a positive CRP. Recurrence of gastrointestinal masses in the cecum and rectum was also eliminated by six courses of CHOP therapy, and a total of nine courses of CHOP therapy led to complete disappearance of masses in the gastrointestinal tract. The present case is different from the others in terms of the following viewpoints that first the ensuing large masses favorably responded to repetitive chemotherapy, secondly the histopathological findings remained benign despite the fact that large nodular masses had recurred in the cecum and rectum, and thirdly the pathological changes were still confined to the gastrointestinal tract without developing systemic malignant manifestations.

Adult↗
PubMed1999

Genotype-phenotype correlation in murine Apc mutation: differences in enterocyte migration and response to sulindac.

The adenomatous polyposis coli (APC) gene product mediates coordinated cell growth in the intestinal mucosa. In humans, germ-line mutations of APC are associated with colorectal carcinogenesis, a process that varies in severity depending on the length of the protein resulting from the mutant allele. In a previous study of the C57BL/6J-Min/+ (Min/+) mouse, we found that the protein fragment resulting from truncation at codon 850 of murine Apc was associated with changes in enterocyte migration, proliferation, apoptosis, and beta-catenin expression. This effect was reversed upon treatment of Min/+ mice with the chemopreventive drug sulindac sulfide. In this study, we measured enterocyte migration in the Apc1638N mouse, an animal with an Apc mutation that yields no detectable APC protein. We found no difference in enterocyte migration, proliferation, apoptosis, or beta-catenin levels in the Apc1638N mouse when compared to wild-type littermates bearing two normal Apc alleles. Furthermore, administration of sulindac sulfide to Apc1638N mice did not alter enterocyte migration. These observations suggest that a dominant negative effect altering cell migration is exerted by the truncated APC protein present in the Min/+ mouse. These data also suggest that the effectiveness of chemopreventive agents in preventing Apc-related tumor formation may depend on which type of mutation is present.

Adenomatous Polyposis Coli↗
PubMed2006

Activation of Wnt signaling in the intestinal mucosa of Apc +/min mice does not cause overexpression of the receptor tyrosine kinase Met.

The receptor tyrosine kinase MET is overexpressed in human colorectal adenomas and carcinomas, suggesting an instrumental role for MET signaling in the onset and progression of colorectal cancer. To corroborate this role, animal models are needed. To study the expression of Met in the normal and neoplastic mouse intestine, we generated an Armenian hamster monoclonal antibody against mouse Met. By using this antibody in immunohistochemical studies, we observed strong Met expression in fetal mouse intestinal epithelial cells. In contrast, in the intestines of adult mice, Met expression was very low whereas the protein was undetectable on the neoplastic epithelium of intestinal adenomas in Apc+/min mice. By immunoblotting, we were also unable to detect Met in intestinal adenomas, whereas Met mRNA levels in microdissected adenomas were very low. The absence of detectable Met protein expression in adenomas of Apc+/min mice contrasts sharply with the vast overexpression of the protein in adenomas of humans with familial adenomatous polyposis or sporadic colorectal carcinomas. Our results imply that deregulation of Wnt signaling in mouse--unlike in human--intestinal epithelium does not result in Met overexpression. Our findings thus reveal important interspecies differences in the regulation of Met expression during intestinal tumorigenesis.

Adenomatous Polyposis Coli Protein↗
PubMed2003

Primary follicular lymphoma of the gastrointestinal tract: a study of 25 cases and a literature review.

BACKGROUND: To describe better the clinical, biological, endoscopic and pathological presentations, as well as the outcome, of primary follicular lymphoma (FL) of the gastrointestinal (GI) tract. PATIENTS AND METHODS: From November 1983 to February 2001, 25 eligible patients with primary FL of the GI tract were retrieved from several French Departments of Pathology departments based on histological diagnosis and immunophenotype. Median age was 56 years (range 44-71) with a sex ratio female/male of 2 (17/8). RESULTS: Abdominal pain was the main presenting symptom followed by intestinal obstruction. The small intestine was the most common site of involvement. Lesions were unifocal in the majority of patients (15/25). A pattern similar to lymphomatous polyposis was observed in 50% (7/14) of patients. Twelve patients had stage I, 10 patients stage II and three patients stage IV disease, and there was minimal extra intestinal involvement. Lymphoma tissues were composed of neoplastic follicles, most of which were grade 1 according to the World Health Organization (WHO) classification. The immunophenotype of the lymphoma cells was CD20+, CD10+, bcl2+ and CD5-. In tissue samples, IgH/bcl2 rearrangement at the MBR locus was present in 11 of 14 patients tested. Seven patients did not receive any treatment; four of them progressed after a median follow-up of 37.5 months. Treatment was otherwise heterogeneous, and complete remission was obtained in 15 patients which lasted for a median of 31 months. Relapses were either in the GI tract (n = 3) or outside the GI tract (n = 3). After a median follow-up of 34 months (range 5-203), 22 patients were still alive (complete remission, 11; partial remission, three; stable disease, six; progressive disease, two). CONCLUSIONS: Primary FL of the GI tract is a predominantly female lymphoma that most frequently involves the small intestine. Since the endoscopic and clinical presentation may not be different from lymphomatous polyposis, which is often associated with mantle cell origin of tumor cells, it is mandatory to perform an immunohistological and, if possible, a molecular analysis of GI lymphoma. The course of the disease is indolent and does not differ from nodal FL. Thus, therapy may not be required unless significant clinical symptoms are present or until disease progression.

Adult↗
PubMed1994

Gene alterations in intestinal metaplasia and gastric cancer.

PURPOSE: To review genetic alterations in precancerous lesions and adenocarcinoma of the stomach. RESULTS: Telomere reduction, tpr-met oncogenic rearrangement, overexpression of cripto, p53 mutations, adenomatous polyposis coli gene mutations and K-ras mutations, which are frequently associated with the well differentiated or intestinal type of stomach cancer, were found in intestinal metaplasia and adenoma of the stomach. CONCLUSIONS: Among these genetic alterations, reduction of telomere repeat arrays might be the initial step in the genetic instability of stomach carcinogenesis. Some of the well differentiated type stomach cancers may develop by an accumulation of multiple gene changes similar to those of colorectal cancer.

Base Sequence↗
PubMed1997

Loss of the PLA2G2A gene in a sporadic colorectal tumor of a patient with a PLA2G2A germline mutation and absence of PLA2G2A germline alterations in patients with FAP.

The Min (multiple intestinal neoplasia) mouse with a germline mutation in the adenomatous polyposis coli gene serves as an animal model for familial adenomatous polyposis coli (FAP). The number and age at onset of colorectal adenomas varies in the offspring of Min mice crossed with other strains. The murine gene for the secretory phospholipase A2 (PLA2G2A) was found to be the main candidate for these variations. To test the hypothesis of a correlation between PLA2G2A gene alterations and human tumor development, we screened 14 patients with FAP and 20 patients with sporadic colorectal cancer for germline and somatic PLA2G2A gene mutations. None of the individuals with FAP showed PLA2G2A germline alterations. However, a germline mutation was observed in one patient with an apparently sporadic colorectal tumor; the wildtype allele was somatically lost in the tumor of this patient.

Adenomatous Polyposis Coli↗
PubMed1990

Laser-induced fluorescence spectroscopy of human colonic mucosa. Detection of adenomatous transformation.

To evaluate the potential of laser-induced fluorescence spectroscopy for the detection of premalignant lesions of the gastrointestinal tract, the hypothesis that adenomatous transformation of colonic mucosa results in an alteration of laser-induced fluorescence that enables its differentiation from normal or hyperplastic tissue was tested. A fiberoptic catheter coupled to a helium-cadmium laser (325 nm) and an optical multichannel analyzer were used to obtain fluorescence spectra (350-600 nm) from 35 normal colonic specimens and 35 resected adenomatous polyps. A score based on six wavelengths was derived by stepwise multivariate linear regression analysis of the spectra. The mean score (+/- SEM) was + 0.86 +/- 0.06 for normal mucosa and -0.86 +/- 0.06 for adenomatous polyps (P less than 0.001). Spectra from an additional 34 normal specimens, 16 adenomatous polyps, and 16 hyperplastic polyps were prospectively classified with accuracies of 100%, 100%, and 94%, respectively. The mean score for hyperplastic polyps was significantly different from adenomatous (P less than 0.001) but not from normal tissue. Thus, quantitative analysis of fluorescence spectra enables the detection of adenomatous transformation in colonic mucosa.

Adenomatous Polyposis Coli↗
PubMed2006

Induction of inflammatory bowel disease accelerates adenoma formation in Min +/- mice.

BACKGROUND: The accelerated incidence of colorectal carcinoma in individuals with inflammatory bowel disease suggests that cellular perturbation triggered by chronic inflammation is linked to the development of dysplasia and neoplastic transformation. To test the mechanistic links between these processes, we employed the following murine strains: (1) multiple intestinal neoplasia (Min) +/- mice, bearing a mutation in the adenomatous polyposis coli (APC) gene; (2) mice deficient in interleukin 10 (IL-10), which normally develop enterocolitis; and (3) Min +/-/IL-10 null mice, first developed in our laboratory. METHODS: Mice with either parental strain or the cross were sacrificed at time points ranging from 10 to 30 weeks of age. The small bowel and colon of 170 IL-10 null mice, 31 Min +/- mice, and 120 Min +/-/IL-10 null mice were examined microscopically. RESULTS: The number of flat adenomas was increased in the colons of the Min +/-/IL-10-/- mice, compared with the Min +/- mice (P = .0005). Neither colitis-type dysplasia nor carcinoma was increased in the Min +/-/IL-10 -/-, compared with the IL-10 null mice (P = .18). Mice deficient in IL-10 developed colitic-type dysplasia (P = .0001) or carcinoma (P = .0001) correlated with increasing inflammation. CONCLUSIONS: Breeding the Min +/- genotype into the IL-10 -/- background increased the incidence of colonic adenomas. Our studies demonstrate that acceleration of dysplasia and progression to invasion were associated with the degree of the inflammatory response in mice deficient in IL-10. These findings provide a novel system to dissect the pathways by which inflammatory mechanisms accelerate adenoma formation.

Adenoma↗
PubMed2001

Chemopreventive agents inhibit aberrant proliferation of the aneuploid phenotype in a colon epithelial cell line established from Apc 1638N [+/-] mouse.

Loss of function of the adenomatous polyposis coli (APC) tumor suppressor gene predisposes for familial adenomatous polyposis (FAP) syndrome. The Apc gene knockout mice exhibit accelerated intestinal carcinogensis modifiable by diverse pharmacological agents. Present experiments utilized the Apc[+/-] 1638N COL colon epithelial cell line (origin: histologically normal colon) as the model. Retinoid receptor modulator 9-cis-retinoic acid (9-cis-RA), ornithine decarboxylase inhibitor difluoromethyl ornithine (DFMO), and nonselective cyclooxygenase inhibitor sulindac (SUL) represented the chemopreventive test compounds. Population doubling, cell cycle progression, and anchorage-independent growth provided mechanistic end points for chemopreventive efficacy. Treatment of 1638N COL cells with 9-cis-RA, DFMO and SUL produced a dose-dependent cytostatic growth arrest by decreasing the number of population doublings and altering aneuploid G0/G1:S+G2/M ratio. The clonally expanded 1638N-Cl1 cells selected for anchorage-independent growth exhibited decreased anchorage-independent colony formation in response to treatment with the three test compounds. Susceptibility of preneoplastic 1638N COL cells to mechanistically distinct chemopreventive agents validates a unique epithelial cell culture model for FAP syndrome, and facilitates investigations on Apc regulated colon carcinogenesis and cancer prevention.

Alitretinoin↗
PubMed1991

Multiple primary malignant neoplasms.

The occurrence of multiple malignant tumours has been recorded, usually as individual cases but also in groups from tumour registries or autopsy studies. A personal series of 71 cases encountered in the follow-up clinics of two District General Hospitals is presented. Cases of multiple skin tumours, and of intestinal growths associated with pernicious anaemia, ulcerative colitis and familial polyposis have been excluded. Review of the literature has been carried out and possible aetiological factors have been considered. The importance of the functions of the tumour surveillance mechanism is emphasized, and the possibility of depression of the defence mechanism by major surgery, is considered to be of importance. Assessment of the patient's defence mechanisms may be as important as grading and staging the tumours.

Adult↗
PubMed1978

[Precancerous lesions in the gastrointestinal tract].

In the large intestine, the pathologist has to differentiate between multiple polyps and polyposis (more than 100 polyps), further between adenomatosis (coli) and non-neoplastic (tumorlike) polyposis. Without prophylactic colectomy, in about 80% of adenomatosis patients an evolution of cancer is observed. Patients with extensive or total ulcerative colitis and a long history have an increased risk for developing carcinoma. Precancerous dysplasia can be demonstrated in rectoscopic and/or colonoscopic biopsies. Cancers complicating adenomatosis or ulcerative colitis account for only a very small proportion of large bowel carcinoma. The "adenoma-cancer sequence" is of greater importance. Colorectal polyps should be removed endoscopically whenever possible. Most gastric polyps are non-neoplastic and have no carcinomatous potential. The true adenoma and the so-called borderline lesion only can be considered as precursor of the gastric carcinoma.

Colitis, Ulcerative↗