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Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cellular and molecular pathology of gastric cancer and its precursors are reviewed and discussed. Gastric carcinogenesis is a multistep phenomenon, beginning with precancerous conditions. Among these, adenoma is a direct precursor, because of the dysplastic nature of its cells. However, gastric adenoma is relatively rare. Chronic atrophic gastritis (CAG) is the most common precancerous condition, in which intestinal metaplasia often occurs. Carcinoma develops in CAG through stages of hyperplasia and dysplasia involving both metaplastic and non-metaplastic glands. Molecular alterations, including replication error and p53 and APC gene mutation and aneuploidy have been found in some of these conditions, confirming their role in carcinogenesis. Carcinomas of the stomach are heterogeneous in cellular composition. Both intestinal and gastric types of cells are found in all types of tumors, indicating the unique characteristics of gastric cancer. Many molecular lesions have been found in gastric carcinomas. Basic changes involve replication errors, telomerase activity, and aberrant CD44 transcripts. Many other changes often show differences in the frequency of their occurrence between the two major histological types of gastric carcinoma: well differentiated versus poorly differentiated, or intestinal type versus diffuse type. The timing and frequency of these changes in the stomach differ from the timing and frequency in colonic carcinogeneis. Pathological evaluation remains reliable and meaningful, in basic research as well as clinical management. To obtain correlation with molecular alterations, the need for detailed pathologic classification of gastric carcinoma is recognized, taking into account its biologic behavior and grades of cell differentiation.The cellular and molecular pathology of gastric cancer and its precursors are reviewed and discussed. Gastric carcinomas are unique in their heterogeneity in both cellular composition and molecular changes.
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PMID:Cellular and molecular pathology of gastric carcinoma and precursor lesions: A critical review. 1195 42

This review compiles evidence for an alternative to the classical adenoma-carcinoma sequence in the evolution of colorectal cancer. It is suggested that between 30 and 50 of colorectal cancers are not initiated by mutation of the tumor suppressor gene APC, but through the epigenetic silencing of genes implicated in the control of differentiation, cell cycle control and DNA repair proficiency. The precursor polyps are often characterized by a serrated architecture, and include hyperplastic polyps, admixed polyps and serrated adenomas. The alternative pathway is heterogeneous and may culminate in cancers showing low or high level DNA microsatellite instability (MSI-L and MSI-H, respectively), and in cancers that are microsatellite stable (MSS). Cancers showing DNA MSI may be characterized by an accelerated evolution. Cancers in hereditary non-polyposis colorectal cancer show features of both classical (adenoma and APC mutation) and alternative pathways (rapid evolution, MSI-H and lack of chromosomal instability).
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PMID:Evolution of colorectal cancer: change of pace and change of direction. 1198 62

Curcumin, the major yellow pigment in turmeric, prevents the development of adenomas in the intestinal tract of the C57Bl/6J Min/+ mouse, a model of human familial APC. To aid the rational development of curcumin as a colorectal cancer-preventive agent, we explored the link between its chemopreventive potency in the Min/+ mouse and levels of drug and metabolites in target tissue and plasma. Mice received dietary curcumin for 15 weeks, after which adenomas were enumerated. Levels of curcumin and metabolites were determined by high-performance liquid chromatography in plasma, tissues, and feces of mice after either long-term ingestion of dietary curcumin or a single dose of [(14)C]curcumin (100 mg/kg) via the i.p. route. Whereas curcumin at 0.1% in the diet was without effect, at 0.2 and 0.5%, it reduced adenoma multiplicity by 39 and 40%, respectively, compared with untreated mice. Hematocrit values in untreated Min/+ mice were drastically reduced compared with those in wild-type C57Bl/6J mice. Dietary curcumin partially restored the suppressed hematocrit. Traces of curcumin were detected in the plasma. Its concentration in the small intestinal mucosa, between 39 and 240 nmol/g of tissue, reflects differences in dietary concentration. [(14)C]Curcumin disappeared rapidly from tissues and plasma within 2-8 h after dosing. Curcumin may be useful in the chemoprevention of human intestinal malignancies related to Apc mutations. The comparison of dose, resulting curcumin levels in the intestinal tract, and chemopreventive potency suggests tentatively that a daily dose of 1.6 g of curcumin is required for efficacy in humans. A clear advantage of curcumin over nonsteroidal anti-inflammatory drugs is its ability to decrease intestinal bleeding linked to adenoma maturation.
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PMID:Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse, a model of familial adenomatous polyposis. 1205 94

We experienced an unusual case of duodenal adenocarcinoma associated with Peutz-Jeghers syndrome (PJS). A 34-year-old woman was admitted to our hospital with abdominal pain. She had been diagnosed as having PJS at 21 years of age, based on the presence of mucocutaneous pigmentation of the lip and fingertips, and colonic hamartomatous polyps. Abdominal computed tomography revealed a tumor in the third portion of the duodenum extending into the pancreas head. As the tumor was pathologically determined to be adenocarcinoma at the time of surgery, pylorus-preserving pancreaticoduodenectomy was performed. We carried out molecular analyses of this patient to examine the pathway of carcinogenesis in PJS. The tumor did not show somatic mutation of the APC and K-ras genes, which is a critical step for the adenoma-carcinoma sequence in colon cancer. Importantly, a germline mutation of the STK11 gene was detected at codon 281 delC in exon 6. Moreover, the tumor showed loss of heterozygosity of the 19p marker near STK11 and somatic mutation of the p53 gene. These findings suggest that STK11 is a tumor suppressor gene regulating the development of hamartomas, and that somatic mutation of p53 subsequently promotes gastrointestinal cancer at a later stage in PJS.
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PMID:Duodenal cancer in a patient with Peutz-Jeghers syndrome: molecular analysis. 1205 37

Colorectal cancer (CRC) represents a significant cause of morbidity and mortality worldwide. Recently, ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) have exhibited promise in the treatment of CRC. For example, activation of PPARgamma reduces the proliferation of cultured CRC cells grown in vitro or in vivo using the nude mouse xenograft model of tumor growth. Furthermore, agonists of the receptor also reduce the development of preneoplastic lesions in a model of carcinogen-induced CRC in rats. However, ligands for the receptor paradoxically enhance intestinal adenoma formation in another murine model of intestinal polyposis, the APC(Min) mice. These disparate results may be due to the inherent limitations of the APC(Min) mouse as a model for humans with CRC. Finally, genetic studies identifying loss of function mutations of PPARgamma in human CRC specimens strongly suggest a tumor suppressive role for the receptor during the development of CRC.
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PMID:Controversy: PPARgamma as a target for treatment of colorectal cancer. 1212 72

Colorectal cancer is the most common malignant tumor in the french population. This tumor represents 45% of the cancers of the digestive tract in female and 60% in male. It is one of the main problem in the field of Public Health but recent progress for research, prophylaxis and treatment have been performed. There are two different pathogenic pathways for colorectal cancer. In chromosomal instability a sequence of rearrangements leads step by step from normal to adenoma and to carcinoma. It is the common pathway observed in 85% of colorectal cancers, mainly localized in left colon. In genic nucleotidic instability loss of tumor-suppresor genes and activation of cellular oncogenes are the consequence of DNA mismatch repair system, which is controlled by several genes. The defect of DNA mismatch repair leads to a hypermutable state in which simple repetitive DNA sequences are specially instable. This is the basis for a test to demonstrate nucleotidic instability. This pathway is found in the remaining 15% of colorectal cancers which are mainly localized on right colon. A mutational inactivation of both alleles of APC gene is considered as an initial gatekeeper event although some cancers begin with a mutation in beta-catenin gene which has the same functional impact. APC expression plays central role in regulating the rate of beta-catenin degradation. Destruction of beta-catenin prevents its translocation into the nucleus where it promotes cellular proliferation. About 5% of colorectal cancer are developed in a high risk population, Familial Adenomatous Polyposis coli (FAP) or Hereditary Non Polyposis Colon Cancer (HNPCC). FAP is caused by a germline mutation in APC gene. Every cell harbors a mutation of an APC allele which insures that a large number of adenomas will occur once an inactivating event occurs on the other wild-type APC allele. The demonstration of a constitutional mutation in a family allows to limit the survey only to the carriers. The phenotypic expression (attenuated, profuse, associated with extra-intestinal lesions) is correlated with the site of the APC mutation. Thus the determination of this site occurs in the choice of the treatment. HNPCC is suggested on clinical and genealogical criterions (young age of onset of cancer, multiple family members affected with cancer in multiple generations, the association of certain tumors in an individual of family, multiple tumors). A biological test may be useful to demonstrate the nucleotidic instability (MSI: microsatellite instability). Constitutional mutations on the mismatch repair genes, mainly MSH2 and MLH1, cause HNPCC syndrome. Endometrial and urethelial malignant tumors are frequent in an individual or in the family. The proven or suspected carriers of mutations undergo colonoscopic surveillance every 1 to 2 years, starting at age 25. An anti-tumoral action of the non steroidal antiinflammatory drugs (NSAID) is now recognized. Firstly observed in animal models of colon cancer the suppressive action was demonstrated in patient with Familial Adenomatous Polyposis. From the results of several epidemiological studies the suppressive action can be generalized to common intestinal tumors. This effect is in relation with the cyclooxygenase 2 inhibition. Other independent pathways intervene: NSAID interfere with beta-catenin, decreasing its action on cellular division. The indication of NSAID and more specifically of COX2 inhibitors in the prophylaxis of colo rectal cancer are yet questioned. The results of trials in progress are expected.
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PMID:[Recent notions on intestinal cancerogenesis, their implications in genetic risk screening and preventive action of non-steroid anti-inflammatory agents]. 1214 48

Gastric cancer is common among the world, but genetic mechanisms of gastric carcinogenesis are not well understood. Gastric polypoid adenomas and flat dysplasias are regarded as precursor lesions. However, a detailed molecular study of these lesions has not been done to determine their role as precancerous lesions. We investigated mutations of the APC, beta-catenin, and K-ras genes, and microsatellite instability (MSI) status in 35 adenomas and 47 flat dysplasias without adenocarcinoma, 35 adenomas/dysplasias associated with adenocarcinomas, and 39 adenocarcinomas (20 diffuse type and 19 intestinal type). Somatic APC gene mutations were identified in 76% (59 of 78) of adenomas or flat dysplasias without associated adenocarcinoma, but in only 3% (1 of 30) of adenomas/dysplasias associated with adenocarcinoma, and in only 4% (3 of 69) of adenocarcinomas (P < 0.000001). No mutations of beta-catenin were found in adenocarcinomas, or adenomas/dysplasia without APC mutation. K-ras mutations were detected in 5% (4 of 82) of gastric adenomas/dysplasia without carcinoma, 3% (1 of 39) of adenocarcinomas without associated adenoma/dysplasia, and not in 32 adenocarcinomas with associated adenoma/dysplasia. High level of MSI (MSI-H) was more frequent in gastric adenoma/dysplasia associated with carcinoma (17%, 6 of 35) than in adenomas/dysplasia without carcinoma (3%, 2 of 75; P = 0.01). MSI-H was also more frequent in intestinal type adenocarcinoma (20%, 11 of 54) than in diffuse type (0%, 0 of 20; P = 0.03). APC gene mutations were present in six of nine (67%) of gastric adenomas/dysplasias with low level of MSI, but in none of the eight adenomas/dysplasia with MSI-H phenotype (P = 0.009). Our results indicate that somatic mutation of the APC gene plays an important role in the pathogenesis of gastric adenoma and dysplasia but has a limited role in neoplastic progression to adenocarcinoma. Gastric adenomas or dysplasias without APC mutations but with or without MSI may have a different biological behavior, and are precursors of intestinal-type of gastric adenocarcinomas.
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PMID:Inverse relationship between APC gene mutation in gastric adenomas and development of adenocarcinoma. 1216 85

LT97, a permanent cell line consisting of epithelial cells with an early premalignant genotype was established from small colorectal polyps. LT97 cells have lost both alleles of the APC tumour suppressor gene. In addition, they carry a mutated Ki-ras oncogene, while TP53 is normal. LT97 growth characteristics are thus representative of early adenomas. They had to be passaged as multicellular aggregates indicating a dependency of survival on cell-cell contact and in accordance with their premalignant genotype were not capable of growth in soft agar. LT97 cells did express both the EGF-receptor and small amounts of TGF(alpha) establishing an autocrine growth or survival pathway. However, in spite of autocrine TGF(alpha) production, growth was strongly dependent on exogenous growth factors--mainly EGF, insulin and HGF. Inhibition of the EGF-receptor kinase induced apoptosis at an IC(50) concentration of 4 micromolar indicating that TGF(alpha) activated survival pathways in the early adenoma cell.
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PMID:Cells obtained from colorectal microadenomas mirror early premalignant growth patterns in vitro. 1220 77

We investigated the adenoma-carcinoma sequence in intraductal papillary-mucinous neoplasm from the aspect of genetic changes. The formalin-fixed paraffin-embedded tumors and surrounding normal pancreatic tissues from patients with 16 intraductal papillary-mucinous adenoma of the pancreas (IPMA) and 10 intraductal papillary-mucinous carcinoma of the pancreas (IPMC) were provided for DNA extraction after microdissection. SSCP-DNA sequencing analysis demonstrated K-ras mutations at codon 12 in 75% of IPMA and 70% of IPMC, while those at codon 13 were observed neither in IPMA nor IPMC. There were no characteristic K-ras mutation types in IPMA and IPMC and no significant differences in incidence of K-ras mutations between the two categories. The frequencies of p53 mutations analyzed by SSCP-DNA sequencing were not high in IPMA (18.8%) and IPMC (30%), showing no significant difference between them. LOHs of APC in IPMA and IPMC were infrequent (6.3 and 20%, respectively) and showed no significant difference in incidence between the two categories. The LOH frequencies of DCC in IPMA and IPMC were 31.3 and 40%, respectively, and were not statistically different from each other. Taken together, genetic changes such as K-ras, p53, APC and DCC mutations may not be associated with adenoma-carcinoma sequence in intraductal papillary-mucinous neoplasm of pancreas.
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PMID:Genetic alterations in adenoma-carcinoma sequencing of intraductal papillary-mucinous neoplasm of the pancreas. 1237 Jul 56

Identification of the adenoma-carcinoma sequence with its corresponding molecular genetic alterations has significantly increased our understanding of the pathogenesis of colorectal carcinoma (CRC). This route of carcinogenesis, hallmarked by genetic instability at the chromosomal level, is conventionally called the "suppressor pathway" because it is frequently accompanied by biallelic loss or inactivation of specific tumor suppressor genes (APC, p53 etc.). However, not all genetic alterations involved in carcinogenesis in the colon fit into this linear tumor progression model. In part, hereditary and sporadic CRC develops from a genetic instability at the DNA level (detected as microsatellite instability, MSI). This route of carcinogenesis in the colon is also termed the "mutator pathway". While familial adenomatous polyposis (FAP) is grouped into the "suppressor pathway" category, hereditary nonpolyposis colorectal cancer (HNPCC) typically follows the "mutator pathway". Whereas most MSI cancers presumably develop from colorectal adenomas, emerging evidence indicates that some MSI tumors may develop from certain hyperplastic polyps via a "serrated adenoma" (termed the "serrated pathway"). This review shall present the different ways that colon cancer can develop and illustrate the molecular alterations and morphological and clinical correlates that characterize these carcinogenesis pathways. The review shall conclude with a discussion of aspects relevant to clinical practice.
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PMID:[Pathogenesis of colorectal carcinoma]. 1239 9


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