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PubMed2002

Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy.

Prostaglandins (PGs), bioactive lipid molecules produced by cyclooxygenase enzymes (COX-1 and COX-2), have diverse biological activities, including growth-promoting actions on gastrointestinal mucosa. They are also implicated in the growth of colonic polyps and cancers. However, the precise mechanisms of these trophic actions of PGs remain unclear. As activation of the epidermal growth factor receptor (EGFR) triggers mitogenic signaling in gastrointestinal mucosa, and its expression is also upregulated in colonic cancers and most neoplasms, we investigated whether PGs transactivate EGFR. Here we provide evidence that prostaglandin E2 (PGE2) rapidly phosphorylates EGFR and triggers the extracellular signal-regulated kinase 2 (ERK2)--mitogenic signaling pathway in normal gastric epithelial (RGM1) and colon cancer (Caco-2, LoVo and HT-29) cell lines. Inactivation of EGFR kinase with selective inhibitors significantly reduces PGE2-induced ERK2 activation, c-fos mRNA expression and cell proliferation. Inhibition of matrix metalloproteinases (MMPs), transforming growth factor-alpha (TGF-alpha) or c-Src blocked PGE2-mediated EGFR transactivation and downstream signaling indicating that PGE2-induced EGFR transactivation involves signaling transduced via TGF-alpha, an EGFR ligand, likely released by c-Src-activated MMP(s). Our findings that PGE2 transactivates EGFR reveal a previously unknown mechanism by which PGE2 mediates trophic actions resulting in gastric and intestinal hypertrophy as well as growth of colonic polyps and cancers.

Animals↗

PubMed2002

Right atrial myxoma arising from the Eustachian valve in a patient with colonic polyposis.

Right atrial myxoma arising from the Eustachian valve is rare, with only two reported cases; moreover, any association with colonic polyps is uncommon, with only one such case documented. A case is described of a 68-year-old male who presented with chronic anemia; an initial investigation revealed colonic polyps, but anemia persisted after polypectomy. Further investigation revealed a right atrial myxoma arising from the Eustachian valve and prolapsing into the right ventricle through the tricuspid valve. After successful removal of the lesion, hematological indices returned to normal. In cases of persisting anemia, other rare causes such as atrial myxoma should be sought.

Adenomatous Polyposis Coli↗

PubMed1986

[Labeling index in colonic cancer, polyps and polyposis and nonspecific colitis].

Thymidine historadiography was employed to study labelling index in tumors and grossly-unaltered mucosa of large bowel in 34 cases of colorectal cancer and 67 patients with single polyps, polyposis and villous tumors of large bowel and suffering from nonspecific colitis. Mean labelling index in tumor tissue was established at 5.49, in normal mucosa of large bowel of healthy subjects--1.19, and in colitis, polyps and villous tumors--2.32, 4.24 and 5.84%, respectively. Labelling index increased with the degree of pathologic changes in mucosal epithelium of large bowel. Thymidine historadiography should be used in formation of groups at risk for large bowel cancer.

Cell Division↗

PubMed1999

[Cholesterol crystal embolisms in adenomatous polyposis coli].

Cholesterol crystal embolism is a serious complication of atherosclerosis responsible for renal, cutaneous and less often digestive manifestations. We report a case of cholesterol crystal embolization in an adenomatous colonic polyp with foci of adenocarcinoma in a patient with an abdominal aortic aneurysm taking anticoagulant therapy. This case shows that cholesterol crystal embolization may be diagnosed by microscopic examination of a colonic polyp.

Adenomatous Polyposis Coli↗

PubMed1993

[Correlation between hyperplastic and adenomatous polyps of the colon].

PROBLEM: Although hyperplastic polyps are considered to be non-neoplastic, they nevertheless have a number of characteristics in common with adenomatous polyps. STUDY DESIGN: Since hyperplastic polyps and adenomas frequently occur together, the question arises as to whether hyperplastic polyps, found for example during sigmoidoscopy, might not be an indicator of possibly neoplastic polyps in the more proximal part of the bowel. In a retrospective analysis of first-time total colonoscopies in 685 patients, we investigated the relationship between hyperplastic and adenomatous polyps. RESULTS: Twenty-one patients proved to have only hyperplastic polyps in the rectosigmoid, while 12 of these patients (11.8%) also had adenomatous polyps in the more proximal parts of the colon. In contrast, 30.8% of the patients (n = 109) with rectosigmoidal adenomas also had adenomas in the more proximal colon. Irrespective of histology, as the size of rectosigmoidal polyps increased, so did the percentage of patients with adenomas in the proximal colon--from 22.4% in the case of small polyps not exceeding 5 mm in diameter to more than 31.2% in the case of polyps larger than 5 mm in diameter. When both hyperplastic and adenomatous polyps appeared together, hyperplastic polyps were found in larger numbers in the same or anatomically adjacent segment of the colon. CONCLUSION: The results of this study suggest that the presence of hyperplastic polyps in the rectosigmoid is not associated with an increase in the incidence of proximal adenomas, while rectosigmoidal adenomas must be considered indicators of adenomas in the more proximal parts of the bowel.

Adenomatous Polyposis Coli↗

PubMed2004

Nuclear accumulation of beta-catenin occurs commonly in the epithelial cells of juvenile polyps.

In the two conditions juvenile polyps (JPs) and juvenile polyposis coli (JPC), colonic polyps may have overlapping histologic and phenotypic appearance, but JPC confers a significant risk for colon adenocarcinoma. Although not thought to contain adenomatous polyposis coli (APC) mutations, the status of beta-catenin and full-length APC protein expression in JPs is not known. We evaluated beta-catenin and full-length APC protein expression in JPs from children with JPs and JPC. Cases were identified through endoscopic procedure records. Immunohistochemistry was performed for beta-catenin and full-length APC protein. Loss of heterozygosity at the APC gene locus on chromosome 5 was assessed using two APC-linked microsatellite markers. Polyp and normal colonic tissue were analyzed from 36 children with JPs and 9 with JPC. Both APC and beta-catenin immunoreactivity were present in epithelial cells from all samples but in different patterns. In all normal colon and polyp samples, APC expression was cytoplasmic with maximal immunoreactivity in the goblet cells. In contrast, beta-catenin immunoreactivity in epithelial cells was limited to the plasma membrane in normal colon but was both cytoplasmic and nuclear in all 45 JPs. No evidence of APC gene loss of heterozygosity was found. In polyps from children with JPs and JPC, nuclear beta-catenin accumulation is a consistent feature, and it is not due to APC gene mutation or loss of full-length APC protein expression. Thus, beta-catenin accumulation may be intrinsic to the formation of juvenile-type polyps through an as-yet-undefined mechanism.

Adenomatous Polyposis Coli Protein↗

PubMed1975

A family with atypical colonic polyposis and gastric cancer: a three-decade followup.

A three-decade followup of a family in whom multiple colonic polyps were found in 5 out of 11 members of one generation is presented. In 3 of these members, cancer was present in the colorectum. The clinical picture as well as the pathologic findings differ from those seen in familial polyposis. In the previous generation two cases of gastric cancer were found, as well as one case of colonic cancer. The high incidence of colonic polyps and cancer suggests a hereditary disease, but the mode of transmission cannot be definitely determined without following this family for a longer period.

Adolescent↗

PubMed1977

Colonoscopy in surgical practice.

Colonoscopy is a rewarding new technique with a potential for early and more accurate diagnosis. One hundred and seventy colonoscopies carried out over the past three years showed or confirmed colonic cancer in 14 patients, and solitary or multiple colonic polyps were found in 28 cases, of which 18 were excised endoscopically. A large villous adenoma was diagnosed in one patient, and the absence of a suspected sinister lesion was shown by direct examination and biopsy in 110 cases. There were 17 examination failures, including two perforations of the bowel. Colonoscopy complements rather than supplants barium enema examination and will make diagnostic laparotomy for colonic lesions unnecessary. The use of the diathermy snare allows endoscopic removal of colonic polyps and should greatly reduce the need for formal surgery in these cases. The financial saving to the Health Service will greatly outweigh the expense of the procedure, but it should be undertaken only in well organised centres as a specialist service for selected patients. In skilled hands it is safe, but potential hazards exist for the inexperienced endoscopist.

Colon↗

PubMed2006

Selenomethionine induces p53 mediated cell cycle arrest and apoptosis in human colon cancer cells.

While there is an increasing interest in selenium chemoprevention against human colon polyp recurrence and other cancers, the mechanism(s) by which these agents inhibit carcinogenesis are uncertain. Some of the proposed mechanisms include the inhibition of cytosine methyltransferases, carcinogen bioactivation, and inhibition of cyclooxygenase (COX). More recently, it has been suggested that selenium may exert growth inhibitory effects by activating p53. However, the molecular mechanisms of action of selenomethionine, an organoselenium compound present in selenized yeast and currently being investigated in human clinical trials for colon polyp prevention, are unclear. In the present study we tested the hypothesis that selenomethionine might affect colon cancer cell growth by p53 mediated apoptosis and/or cell cycle regulation. Four human colon cancer cell lines including HCT116 and RKO (wild type p53), HCT116-p53KO (isogenic control of HCT116 cells with p53 knocked out) and Caco-2 (mutant p53) were treated with 0-100 microM of selenomethionine for 24, 48 and 72 h. Cell viability rates were determined by the MTT assay. Cell cycle analysis was performed by flow cytometry and apoptosis measured by Annexin V-Cy5 staining. Expression of p53 protein was determined by Western blotting and immunofluorescence assays. All cell lines showed concentration and time dependent growth inhibition with selenomethionine, although HCT116 and RKO cells were the most sensitive to such treatments. Interestingly, although HCT116 and HCT116-p53KO are isogenic cell lines, selenomethionine caused a G2/M cell cycle arrest in HCT116 and RKO cells, but not in HCT116-p53KO cells. Similarly, both HCT116 and RKO demonstrated a significant increase in apoptosis (100-170%; p < 0.01) with 50-100 microM selenomethionine. Cell cycle arrest and apoptosis observed in HCT116 and RKO cell lines were accompanied by a marked increase in p53 protein expression following selenium treatment. These results clearly suggest that selenomethionine exerts p53 dependent growth inhibitory effects in colon cancer cells by inducing G2/M cell cycle arrest as well as apoptosis.

Apoptosis↗

PubMed1990

[Diagnosis of tumors of the large intestine by colonic ultrasound].

Retrograde instillation of liquid into the colon allows a specific, percutaneous sonographic examination of the colon to be performed. As part of a prospective study of the diagnosis of colonic tumors in 260 patients, this form of colon sonography was examined together with colonoscopy. Sonographically, colonic polyps and carcinomas of the colon manifested as echogenic, parietal masses. Using colonic sonography, it was possible to identify 96% of the carcinomas that had been diagnosed colonoscopically. The sonographic diagnosis of polyps was insufficient if they were smaller than 6 mm: if they were larger than 7 mm, however, diagnostic sensitivity was 91%. The results of this study show that colon sonography is a new, sensitive method in the diagnosis of colonic tumors.

Cecal Neoplasms↗

PubMed2001

The changed histologic paradigm of colorectal polyps.

BACKGROUND: Previous literature has recorded the preponderance of hyperplastic over neoplastic polyps. This study evaluated the histopathologic characteristics of colonic polyps, excised during colonoscopic polypectomy, and further determined their relationship to age, location, and gender. METHODS: Of 5132 colonoscopies reviewed between 1976 and 1999, 757 were performed on 582 patients who had polyp removal. Patients with previous colon resection or incomplete cecal intubation were excluded. RESULTS: The mean age was 67 +/- 11 years for men and 66 +/- 11 years for women. Of the 1050 lesions histologically analyzed, 871 (83.0%) were neoplastic, 129 (12.3%) were hyperplastic, and 50 (4.8%) were miscellaneous lesions (29 inflammatory polyps, 14 lipomas, 2 leiomyomas, 1 juvenile polyp, and 4 no pathology identified). Hyperplastic polyps were always less than 1 cm (with one exception) and were located predominantly in the left colon, the majority residing in the sigmoid colon. Peak prevalence of hyperplastic polyps occurred in the 50-70 years old age group. Of the neoplastic polyps, 566 (65.0%) were tubular, 225 (25.8%) villotubular, 63 (7.2%) villous adenomas, 4 (0.5%) mixed adenomatous hyperplastic polyps, and 12 (1.4%) invasive carcinomas. The peak prevalence of neoplastic polyps occurred in the same age group as did hyperplastic polyps. Even though adenomatous polyps outnumbered hyperplastic polyps throughout the colon and within each age group, a greater percentage of hyperplastic polyps were found distally and in younger patients compared to location and age groups for neoplastic polyps. CONCLUSION: Adenomatous polyps outnumber hyperplastic polyps 7:1, even in the distal colon. Even small polyps seen during colonoscopy should be removed and subjected to histologic analysis because of the advisability of follow-up examinations of patients with neoplastic polyps. The increase in the incidence of neoplastic polyps beginning at the age of 50 years supports the need for colonoscopy in these individuals.

Adenomatous Polyps↗

PubMed2004

Risk factors for colorectal cancer: an epidemiologic descriptive study of a series of 333 patients.

AIM: The purpose of the research was to evaluate several risk factors for colonic neoplasia and to institute a specialized colorectal cancer (CRC) registry in the 3rd Medical and Surgical Clinics Cluj-Napoca. MATERIAL AND METHODS: The study comprised 333 patients,155 women, mean age 61.32 +/- 12.42 years and 178 men, mean age 64.31 +/- 10.39 years, admitted to the 3rd Medical Clinic and 3rd Surgical Clinic Cluj-Napoca and diagnosed with CRC between January 2001 - September 2003. The diagnosis was made on the basis of clinical, endoscopical and histopathological findings. Age, geographical patterns, tumor location, family history, personal history and several lifestyle factors: dietary habits (intake of fat and red meat), long term smoking (more than 20 years), heavy alcohol consumption were analyzed. Evaluation was made using family history and epidemiologic lifestyle questionnaires. RESULTS: CRC occurred more frequently in the 7th decade. There was a strong correlation between age and CRC development. In the 5th decade, females developed CRC more frequently than males. The median age for developing right-sided tumors was significantly higher in males. Patients living in an urban area were dominant (69%). Family history was present in 1/3 of females and 1/4 of males. Personal history of colon polyps was more common in men, particularly among smokers for more than 20 years and among those with an excessive intake of fat. The cholecystectomized women had an increased frequency of sigmoidian tumors. All the patient's information was included in a specialized colon cancer registry. CONCLUSION: High fat intake and cigarette smoking favour colon polyp development. CRC development and location of the tumor are associated with an older age (in men) and personal history of cholecystectomy (in women). Inheritance was significant in our study group.

Adult↗

PubMed2005

Anxiety, depression and psychotropic medication use in patients with persistent upper and lower gastrointestinal symptoms.

BACKGROUND: Limited information is available about anxiety, depression and psychotropic medication use in patients referred for gastrointestinal endoscopy. AIM: To determine anxiety and depression and its association with endoscopic findings in a representative sample of patients with persistent gastrointestinal symptoms prior to endoscopy. METHODS: Patients referred to the hospital for endoscopy between February 2002 and February 2004 were asked to score anxiety and depression on the Hospital Anxiety and Depression Scale 2 weeks prior to endoscopy. Information about endoscopic diagnoses was obtained from medical files. RESULTS: A total of 1298 subjects was studied (600 upper gastrointestinal endoscopies and 698 lower gastrointestinal endoscopies). Patients referred for upper gastrointestinal endoscopy used most psychotropic agents (24%; odds ratio = 3.1; 95% confidence interval = 2.3-4.2), especially patients with an organic abnormality when compared with patients without an organic abnormality (42% versus 8%; odds ratio = 8.6; 95% confidence interval = 5.4-14.0). Patients with colonic polyps were more anxious (odds ratio = 1.7; 95% confidence interval = 1.0-2.9) and depressed (odds ratio = 1.8; 95% confidence interval = 1.1-3.1) than other patients referred for lower gastrointestinal endoscopy. CONCLUSIONS: There is no difference in anxiety nor depression between patients with and without organic abnormalities at endoscopy. Patients with colonic polyps are more anxious and depressed than other patients referred for lower gastrointestinal endoscopy. Psychotropic medication use is highest among patients with an organic abnormality in the proximal gastrointestinal tract.

Adolescent↗

PubMed2000

Optimization of CT colonography technique: prospective trial in 180 patients.

PURPOSE: To assess the added benefits of prone positioning in addition to supine positioning and oral iodinated contrast medium for help in the detection of colonic polyps at computed tomographic (CT) colonography. MATERIALS AND METHODS: CT colonography was performed in prone and supine positions in 180 patients with polyps or risk factors for colonic neoplasia. Patients were randomly assigned to receive a standard bowel preparation or a standard preparation plus oral iodinated contrast medium. One radiologist interpreted supine images alone, and another analyzed supine and prone images. All patients subsequently underwent colonoscopy. RESULTS: At colonoscopy, 121 large (> or =1-cm-diameter) polyps and 142 smaller (0.5-0.9-cm) polyps were identified. Prone positioning resulted in increased sensitivity for identification of patients with large (> or =1-cm) polyps (increase from 70% to 85%, P: =.004) and of patients with polyps 0.5 cm or larger (increase from 75% to 88%, P: <.005), with no change in specificity. Use of oral contrast medium did not significantly improve polyp detection even in the subset of patients in whom colonic fluid attenuation was markedly increased. CONCLUSION: Acquisition and review of supine and prone CT colonographic images significantly improves the ability to identify patients with polyps 0.5 cm in diameter or larger. Administration of oral iodinated contrast medium does not significantly improve polyp detection.

Colon↗

PubMed1994

Colonic hamartomatous polyposis associated with hypertrophic osteoarthropathy.

A 7-year-old girl with an unremarkable family history was admitted with complaints of diarrhea containing mucus and blood, abdominal pain, weight loss and fever for 10 months. Although her symptoms, physical examination and laboratory results were highly suggestive of inflammatory bowel disease, radiologic studies and colonoscopy demonstrated multiple colonic polyps. A bilateral and symmetric lamellar periosteal reaction and osteopenia were present on her extremity radiographs. The chest radiograph and thoracic CT scan were normal. The histologic nature of the polyps was determined as hamartoma. One month after subtotal colectomy, the patient's symptoms resolved and she gained 7 kg in weight. The association of generalized juvenile polyposis and hypertrophic osteoarthropathy has previously been described in five cases; arteriovenous malformations were present in four of them. In our case the polyps were hamartomatous and localized in the colon, without associated arteriovenous malformation.

Child↗

PubMedDate not supplied

[Endoscopic excision of malignant colorectal polyps. Study of a series of 82 cases].

The management of malignant colonic polyps removed by endoscopic polypectomy is a controversial subject. We reported a series of 81 patients with 82 malignant polyps removed by endoscopic polypectomy between 1977 and 1984. 15 polyps contained carcinoma in situ and were treated by endoscopic polypectomy alone. 36 polyps contained superficial cancer; 35 were treated by EP alone; 1 was treated by endoscopic polypectomy and colectomy. 26 polyps contained invasive carcinoma and 2 were classified as polypoid adenocarcinomas. 19 had clear resection margins at polypectomy and seven had involved resection margins: 17 were treated by endoscopic polypectomy alone, 9 were treated by endoscopic polypectomy and colectomy. The patients were followed with colonoscopy. Follow-up has been 6 to 74 months (mean 32 months). The patients whose polyps were treated by endoscopic polypectomy alone, had had no evidence of recurrent tumor at the polypectomy site. Of the 12 patients undergoing colectomy, 4 had residual tumor at the polypectomy site. No patients had involved lymph nodes. There was no evidence of recurrence in any of these cases. Polyps containing contained carcinoma in situ and superficial cancer, polyps containing invasive carcinoma and clear resection margins can be treated with endoscopic polypectomy alone. Polyps with invasive carcinoma and involved resection margins should undergo segmental colonic resection. This approach must be weighed against the age of the patient, the medical status and the morbidity and mortality of the surgical procedure.

Adult↗

PubMed2000

Uroguanylin treatment suppresses polyp formation in the Apc(Min/+) mouse and induces apoptosis in human colon adenocarcinoma cells via cyclic GMP.

The enteric peptides, guanylin and uroguanylin, are local regulators of intestinal secretion by activation of receptor-guanylate cyclase (R-GC) signaling molecules that produce cyclic GMP (cGMP) and stimulate the cystic fibrosis transmembrane conductance regulator-dependent secretion of Cl- and HCO3-. Our experiments demonstrate that mRNA transcripts for guanylin and uroguanylin are markedly reduced in colon polyps and adenocarcinomas. In contrast, a specific uroguanylin-R-GC, R-GCC, is expressed in polyps and adenocarcinomas at levels comparable with normal colon mucosa. Activation of R-GCC by uroguanylin in vitro inhibits the proliferation of T84 colon cells and elicits profound apoptosis in human colon cancer cells, T84. Therefore, down-regulation of gene expression and loss of the peptides may interfere with renewal and/or removal of the epithelial cells resulting in the formation of polyps, which can progress to malignant cancers of the colon and rectum. Oral replacement therapy with human uroguanylin was used to evaluate its effects on the formation of intestinal polyps in the Min/+ mouse model for colorectal cancer. Uroguanylin significantly reduces the number of polyps found in the intestine of Min/+ mice by approximately 50% of control. Our findings suggest that uroguanylin and guanylin regulate the turnover of epithelial cells within the intestinal mucosa via activation of a cGMP signaling mechanism that elicits apoptosis of target enterocytes. The intestinal R-GC signaling molecules for guanylin regulatory peptides are promising targets for prevention and/or therapeutic treatment of intestinal polyps and cancers by oral administration of human uroguanylin.

Adenocarcinoma↗

PubMed2004

Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation.

Heterozygous germline DNA mismatch repair gene mutations are typically associated with hereditary nonpolyposis colorectal cancer. The molecular hallmark of this syndrome is high-frequency microsatellite instability in the tumors. Rare childhood cases with homozygous or compound heterozygous DNA mismatch repair gene mutations have a described predisposition to leukemia, lymphoma, and brain tumors but not to gastrointestinal cancer. We have now characterized a family in which 2 children with a homozygous germline DNA mismatch repair gene mutation developed early-onset gastrointestinal cancers. The 11-year-old proband had café-au-lait macules and developed metastatic duodenal adenocarcinoma that arose in a tubulovillous adenoma. His 9-year-old sister with café-au-lait macules and axillary freckling presented with malignant colon polyps. A 6-year-old sister with café-au-lait macules, hairy nevi, and a plexiform neurofibroma of the tongue has no malignancies to date. The family history did not fulfill the Amsterdam criteria for hereditary nonpolyposis colorectal cancer, but 2 relatives in their 60s had gastric cancer and colorectal cancer, whereas the parents, who are first cousins, remain cancer free. The proband's metastatic duodenal cancer and his sister's malignant colon polyps had high-frequency microsatellite instability but had detectable MLH1, MSH2, and MSH6 proteins by immunohistochemistry. Because some germline DNA mismatch repair gene deficiencies are associated with apparently intact immunohistochemical DNA mismatch repair gene expression in tumors, we proceeded to DNA sequencing, which showed that all 3 children had a germline homozygous MLH1 missense mutation (exon 18, codon 687, CGG-->TGG), whereas both parents were heterozygous for this mutation.

Adaptor Proteins, Signal Transducing↗