Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study is to identify colorectal serrated lesions in the inflammatory mucosa of inflammatory bowel disease (IBD), to characterize their molecular status based on BRAF and KRAS mutations, mismatch-repair (MMR) deficiency and microsatellite instability (MSI), and to verify that these molecular alterations are specific to the 'serrated neoplasia pathway' in IBD. Neoplastic lesions from 36 patients with IBD were reviewed retrospectively, including 13 adenocarcinomas (1 mucinous and 12 conventional), 28 dysplasias [1 traditional serrated adenoma (TSA) and 27 conventional adenomas] and 1 hyperplastic polyp (HP). Both the HP and TSA exhibited the V600E BRAF mutation without MSI or MMR deficiency. The mucinous adenocarcinoma, close to the TSA, exhibited the BRAF mutation and MSI with loss of hMLH1. No KRAS mutations were found in these 3 lesions, and no BRAF mutations were found in the conventional ones. Serrated lesions exist in the inflammatory mucosa of IBD and are associated with a characteristic molecular profile, i.e. the appearance of the BRAF mutation as early as the hyperplastic polyp stage followed by MSI at the carcinoma stage. We therefore identified the serrated neoplasia pathway in IBD-related colorectal oncogenesis.
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PMID:Involvement of the serrated neoplasia pathway in inflammatory bowel disease-related colorectal oncogenesis. 1791 58

Invasive colorectal carcinomas (CRCs) with invasion confined to the lamina propria (LP) [intramucosal carcinoma (IMC)] lack access to lymphatics and therefore have no potential for metastases and local intervention (usually polypectomy) should be adequate treatment. For this reason, they are classified as "Tis" in the TNM system. It is believed that carcinomas invading the submucosa with unfavorable histology (tumors at/near the margin, and/or vascular invasion, and/or poor differentiation) require additional intervention after polypectomy, whereas those with favorable histology can be safely treated endoscopically. However, there are few data on poorly differentiated (PD) carcinomas showing invasion confined to the LP. Polypectomy is theoretically curative but in practice this has not been well demonstrated. Thus, the clinicopathologic features of 15 cases of PD CRCs with invasion limited to the LP on initial biopsies were studied to determine the best course of management for this rare subset of carcinomas. A computer search and histologic review of cases seen at Johns Hopkins Hospital was performed. Fifteen cases of PD CRC with invasion limited to the LP were identified. The clinicopathologic features of these tumors were reviewed. All 15 cases showed PD IMC with single cells infiltrating only the LP. Patients were 38 to 79 years (median, 62) of age with a male predominance (M:F=4:1). Three cases had signet ring cell differentiation, 1 had focal small cell features, and another had focal squamous differentiation. Fourteen of the cases were associated with background adenomas or adenomalike lesions including: 7 involving tubulovillous or villous adenomas, 6 involving tubular adenomas, 1 involving dysplasia associated with chronic inflammatory bowel disease. Nine of the lesions had surrounding high-grade dysplasia. One case showed no background dysplasia or adenoma. One patient was lost to follow-up and the remaining 14 were followed for 1 to 96 months (mean, 21.3 mo; median, 13 mo). Seven patients had no residual disease on follow-up colonoscopy, and no resection was performed. The remaining 7 patients were treated with partial colectomy (6) or low anterior resection (1), and of these, 5 had no infiltrating carcinoma and negative lymph nodes. One patient had a separate large colorectal (T3) carcinoma with 8/10 positive regional lymph nodes; the IMC seen on biopsy was presumably a metastasis as it was unassociated with an in situ component. Finally, the resected rectum from which an IMC had been previously detected had no residual invasive carcinoma, but the anal skin was involved by Paget disease. Thus, of the 15 cases of PD CRCs limited to the LP, 1 was a metastasis from a separate CRC and another had associated Paget disease of the anal skin. As such, even in the setting of PD carcinomas, no metastatic disease was seen arising from any of the cases that were confirmed as early primary lesions. These preliminary findings suggest that patients with isolated intramucosal PD CRCs may be managed endoscopically.
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PMID:Poorly differentiated colorectal carcinoma with invasion restricted to lamina propria (intramucosal carcinoma): a follow-up study of 15 cases. 1872 39

The cyclooxygenase (COX) is a key enzyme in the conversion of arachidonic acid to prostaglandins. COX-1 is constitutively expressed and is a critical housekeeping gene, whereas COX-2 is rapidly upregulated by growth factors and cytokines and thus responsible for inflammation. COX-2 is frequently overexpressed in colonic adenoma and carcinoma. Specific inhibitors of COX-2 have been shown to induce apoptosis in tumor cells and to inhibit tumor growth in animal models and in humans. Long-standing IBD patients have increased risk of developing colorectal cancer compared to general population. IBD-associated colorectal carcinogenesis is probably promoted by chronic inflammation and closely related to COX-2. In a recent study, powerful chemopreventive ability of selective COX-2 inhibitor was observed in colitis-related colon carcinogenesis in mouse model. But it was reported that even selective COX inhibitors aggravated the DSS-induced colonic inflammation. It is assumed that endogenous PGs are involved in the mucosal defense against DSS-induced colonic ulcerations which are produced by COX-1 at early phase and by COX-2 at late phase. Long-term use of COX-2 inhibitors for the chemoprevention of colitic cancer is needed to define their mechanism of action, that reduce side effects and have specific tumor target.
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PMID:[COX-2 inhibitors in inflammatory bowel disease: friends or foes?]. 1815 71

Localized inflammation of the sigmoid colon or segmental colitis associated with diverticulosis (SCAD syndrome) is an increasingly recognized, apparently uncommon, clinical and pathological disorder usually described in older adults. In the present study, 24 symptomatic patients, including 14 males, (58.3%) and 10 females (41.7%) were evaluated over a 20-year period with follow-up intervals ranging from 2 to 16 years. In most, initial clinical symptoms appeared after age 40 years and included rectal bleeding, diarrhea, and abdominal pain. Most (21 of 24, over 80%) initially responded with long-term resolution of their disease after treatment only with a 5-aminosalicylate. In addition, however, spontaneous remissions without any form of drug therapy were documented. In some, persistent, chronically active disease or true episodic recurrences were seen, leading to use of corticosteroids and/or resective surgery. Evidence here also suggested that colonic neoplasia, including adenoma development and cancer, were not related to the presence of this uniquely localized mucosal inflammatory process defined within the sigmoid colon. This study documents the natural history and long-term clinical behavior of this unusual segmental inflammatory process, associated with diverticulosis, and provides additional strong evidence that the SCAD syndrome is very distinct and can be readily separated from other forms of chronic inflammatory bowel disease.
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PMID:Natural history and long-term clinical behavior of segmental colitis associated with diverticulosis (SCAD syndrome). 1833 65

It is well established that the intestinal microbiota plays a key role in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC) collectively referred to as inflammatory bowel disease (IBD). Epidemiological studies have provided strong evidence that IBD patients bear increased risk for the development of colorectal cancer (CRC). However, the impact of the microbiota on the development of colitis-associated cancer (CAC) remains largely unknown. In this study, we established a new model of CAC using azoxymethane (AOM)-exposed, conventionalized-Il10(-/-) mice and have explored the contribution of the host intestinal microbiota and MyD88 signaling to the development of CAC. We show that 8/13 (62%) of AOM-Il10(-/-) mice developed colon tumors compared to only 3/15 (20%) of AOM- wild-type (WT) mice. Conventionalized AOM-Il10(-/-) mice developed spontaneous colitis and colorectal carcinomas while AOM-WT mice were colitis-free and developed only rare adenomas. Importantly, tumor multiplicity directly correlated with the presence of colitis. Il10(-/-) mice mono-associated with the mildly colitogenic bacterium Bacteroides vulgatus displayed significantly reduced colitis and colorectal tumor multiplicity compared to Il10(-/-) mice. Germ-free AOM-treated Il10(-/-) mice showed normal colon histology and were devoid of tumors. Il10(-/-); Myd88(-/-) mice treated with AOM displayed reduced expression of Il12p40 and Tnfalpha mRNA and showed no signs of tumor development. We present the first direct demonstration that manipulation of the intestinal microbiota alters the development of CAC. The TLR/MyD88 pathway is essential for microbiota-induced development of CAC. Unlike findings obtained using the AOM/DSS model, we demonstrate that the severity of chronic colitis directly correlates to colorectal tumor development and that bacterial-induced inflammation drives progression from adenoma to invasive carcinoma.
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PMID:Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. 1955 Nov 44

Colorectal cancer (CRC) can be prevented by screening programs in the population at average risk (men and women aged between 50 and 74 years) and at high risk (first degree relatives, CRC hereditary syndromes and chronic inflammatory bowel disease). Early CRC (with submucosal invasion) and advanced adenomas (size > or =10mm, with severe dysplasia or >20% villous component) produce intermittent microscopic blood losses that can be detected through chemical and immunological testing for fecal occult blood (C-FOBT and I-FOBT). Among the screening strategies in the population at average risk, annual or biannual fecal occult blood testing is the most widely used due to its non-invasiveness and low cost. Four randomized clinical trials have shown that annual or biannual screening with guaiac-based tests (C-FOBT) reduces overall mortality due to CRC by 16% and CRC incidence by 20% and 17% respectively. However, these tests have major drawbacks, especially their low sensitivity in detecting early CRC and advanced adenoma, their lack of specificity in detecting human hemoglobin (Hb), and their high fecal Hb detection threshold (>300microgHb/gfeces). In the last few years, major developments have occurred in immunological tests (I-FOBT), based on an antigen-antibody reaction that specifically detects human Hb, and these tests are currently available as an alternative to C-FOBT. Their main advantages are as follows: firstly, I-FOBT specifically detect human Hb in stools and at much lower levels (40-300microgHb/gfeces) than C-FOBT; secondly, automated analysis avoids subjectivity in reading qualitative tests and allows large population groups to be studied in a short time, making I-FOBT ideal for population-based screening; thirdly, I-FOBT fairly accurately selects individuals for colonoscopy so that approximately half of patients with an I-FOBT test show clinically significant colorectal neoplasia (advanced adenoma or invasive CRC); fourthly, the cut-off point for fecal Hb detection can be modified, depending on the availability of endoscopic resources; fifthly, when cut-off points for fecal Hb of 50-150microgHb/gfeces are used, more than twice the number of CRC and advanced adenomas are detected than with C-FOBT, with a reasonable false-positive rate; and sixthly, I-FOBT are better accepted by the population due to their simplicity and ease of use, increasing participation in screening programs. For all these reasons, the current recommendation is that the new quantitative I-FOBT tests replace C-FOBT tests when the strategy of population-based screening through annual or biannual fecal occult blood testing is considered.
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PMID:[Chemical or immunological tests for the detection of fecal occult blood in colorectal cancer screening?]. 1957 40

Colorectal cancer fulfils the conditions required for mass screening. Data from controlled studies indicate that it is possible to reduce colorectal cancer mortality at a population level using faecal occult blood testing. Screenings rely on biennial testing in between 50 and 74average risk subjects. Compliance must be over 50%. Colorectal cancer mortality decrease in this case between 15 and 18% in the general population, 33 and 39% among participants to screening. The European Commission, on the basis of available data recommended to organise colorectal cancer screening in the European Union. Generalisation of screening has become a reality in France. Epidemiological studies allow us to define subjects at very high risk (genetic origin) and high risk for colorectal cancer. Colonoscopy screening is recommended in first degree relatives of patients with colorectal cancer or large adenoma diagnosed before 60years or with two affected first-degree relatives, in subjects with an extended inflammatory bowel disease, or with a personal history of large bowel cancer or large adenoma. Promising research strategies are arising: immunochemical tests in the short term, stool-based DNA tests in stools and proteome-based approach in the long term.
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PMID:[Colorectal cancer: from diagnosis to screening]. 1970 33

Inflammatory bowel disease (IBD) includes Crohn's disease (CD) and ulcerative colitis (UC). The recognition of typical morphological features usually allows to distinguish CD from UC. Several infectious diseases like tuberculosis as well as other disorders can mimic IBD and need to be excluded before immunosuppressive treatment is started or surgical intervention planned. IBD is associated with an increased risk for the development of colorectal adenocarcinoma. There is a strong relationship between the presence of intraepithelial neoplasia (IEN) in patients with CD or UC and colon cancer. Thus, the differentiation between biopsies with reactive atypia, low-grade IEN and high-grade IEN is of great importance. Furthermore, distinction between dysplasia-associated lesions or masses (DALM) and sporadic adenoma-like masses (ALM) is crucial as prophylactic colectomy is usually recommended for DALM and polypectomy may be sufficient for ALM. Various features like localization of the lesion, architecture, inflammation and immunohistochemical evaluation of additional markers, e.g. p53 and beta-catenin, may be helpful in the distinction of DALM versus ALM. Finally, the use of modern immunosuppressive therapies may go along with an increased susceptibility towards infections, e.g. cytomegalovirus colitis or Epstein-Barr virus-induced lymphoproliferative disorders, and a high degree of awareness by clinicians and pathologists is required in order not to miss these life-threatening complications of IBD.
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PMID:Diagnostic standards in the pathology of inflammatory bowel disease. 1989 78

REG4, the latest member of the regenerating gene family, is overexpressed in inflammatory bowel diseases and gastrointestinal carcinomas. To date, its pathophysiologic role has not been well established. Using HT-29 models, we previously identified REG4 as being overexpressed in colorectal tumor cells displaying a drug-resistance phenotype; some also displayed invasive properties. Thus, we investigated the potential functions of REG4 in biological processes involved in colorectal tumor progression such as cell proliferation, migration and invasion. Colon cancer cells secreting REG4 (HT29-5M21, HT29-5F7 and HT29/REG4-8) or not (HT-29, HT29/CT1 and Caco-2/TC7) were used to analyze the autocrine and paracrine effects of REG4. REG4 was continuously secreted into the culture medium of colon cancer cells. REG4 stimulated cell growth in a paracrine manner after 24 h of treatment. Notably, REG4 promoted migration and invasion of tumor cells in both an autocrine and paracrine manner, and these effects were significantly decreased by concomitant treatment with an anti-REG4 antibody. Using pharmacological inhibitors, we showed that PI3K/Akt, PKAs, PKCs and Rho-like GTPases, but not MAPK, are involved in REG4 invasion signals. In addition, REG4 expression was found to be increased in tissues harboring proliferation and migration properties such as the developing intestine and tissues from inflammatory bowel disease, hyperplastic polyps, adenoma and colorectal cancers. In various situations, REG4 expression was not confined to proliferating cells, regenerating cells or cells of the invasive front of metastatic tumors, suggesting that extracellular REG4 may act on epithelial cells in a paracrine manner. Altogether, our results indicate that REG4 is a multifunctional secreted protein which acts on colorectal cancer cells in an autocrine and paracrine manner. According to its biological functions and tissue expression, REG4 may play an important role in the development and progression of colorectal cancer, as well as in intestinal morphogenesis and epithelium restitution.
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PMID:REG4 acts as a mitogenic, motility and pro-invasive factor for colon cancer cells. 2012 89

Soluble human leukocyte antigen-G (sHLA-G) has been reported in malignancies and is implicated in mediating immune surveillance of tumor. The aim of our study is to detect serum sHLA-G levels in colorectal cancer and to determine whether sHLA-G may be helpful in distinguishing colorectal cancer from benign colorectal diseases. Serum sHLA-G levels were determined using enzyme-linked immunosorbent assay. Receiver operating characteristic (ROC) curve was used to evaluate the feasibility of sHLA-G in differentiating colorectal cancer from benign colorectal diseases. Median sHLA-G concentrations were significantly higher in colorectal cancer compared to normal colorectum, hyperplastic polyp, inflammatory bowel disease and adenoma (all at p < 0.001, respectively). ROC curve for sHLA-G revealed an area under the curve of 84.2%, and when 88.6 U/mL was used as cutoff, a sensitivity of 72.2% and a specificity of 87.8% were achieved. Comparison of sHLA-G and carcinoembryogenic antigen ROC curves indicated that sHLA-G was superior to CEA in differentiating colorectal cancer from benign colorectal diseases (p < 0.001). ROC curves analysis of the combined sHLA-G and CEA showed a higher detection capacity (area under the ROC curve, 87.4%) than that of markers considered singly. These findings reveal that serum levels of sHLA-G are significantly increased in colorectal cancer which may serve as a potent mediator of immune escape in colorectal cancer, and sHLA-G may be a useful indicator in differentiating colorectal cancer from benign colorectal diseases.
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PMID:Serum sHLA-G levels: a useful indicator in distinguishing colorectal cancer from benign colorectal diseases. 2047 65


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