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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an attempt to demonstrate the relationship between aberrant crypt foci (ACF) and subsequent colonic neoplasms, we investigated the distribution of ACF in the dimethylhydrazine (DMH) model of colonic carcinogenesis in the rat. DMH was given to male Wistar rats by s.c. injection in a dosage of 15 mg/kg body weight once a week for 19 weeks. As a result, eight poorly differentiated, mucin-secreting carcinomas, two well-differentiated tubular adenocarcinomas, and four adenomas developed in 35 rats autopsied at 24 weeks after the first injection of DMH. The location of each type of tumor was site specific. Poorly differentiated, mucin-secreting carcinomas of signet-ring type occurred only in the proximal colon; the mean location of these lesions was 17.6 +/- 3.8% (SE; range, 0-39%) of the length of the colon. Well-differentiated tubular adenocarcinomas and adenomas developed in the distal colon; the mean location of these lesions was 76.7% +/- 4.9 (SE; range, 60-90%) of the length of the colon. There was a mean number of 276 +/- 29 (SE) ACF per colon; these were present at between 40 and 90% of the colonic length, peaking at 70%. We conclude that ACF are marker lesions for colonic neoplasms, but only in the distal colon where tumors follow the adenoma-carcinoma sequence; this is not so for the proximal colon, where poorly differentiated, mucin-secreting carcinomas are found. These findings suggest that these latter tumors well may arise de novo and indicate that studies that attempt to correlate ACF with subsequent tumor formation must take cognizance, not only of the site, but also of the tumor type.
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PMID:The incidence of aberrant crypt foci and colonic carcinoma in dimethylhydrazine-treated rats varies in a site-specific manner and depends on tumor histology. 937 61

In order to establish an animal model for studying the cause and prevention of esophageal adenocarcinoma (EAC) and its frequent precursor, Barrett's esophagus (BE), factors affecting the pathogenic processes were investigated in an esophagoduodenal anastomosis model with rats. Experiments by us and others have shown that surgical treatment produced reflux esophagitis with cell hyperproliferation, but not EAC. Additional treatment with a carcinogen has been shown to be necessary for the development of EAC, squamous cell carcinomas (SCC) or EAC/SCC mixtures. We found that the surgically treated animals developed anemia due possibly to reduced iron absorption. When the operated animals were supplemented with iron, EAC occurred at a high rate (73%) after 30 weeks, and treatment with N'-nitrosonornicotine did not enhance the rate of tumorigenesis. Treatment with carcinogen, however, induced SCC in the group of rats killed after 22 weeks. The results suggest that iron overload, which is known to cause oxidative damage, is an enhancing factor for adenocarcinogenesis. The pathogenesis of EAC in the iron-supplemented, non-carcinogen treated group resembles human esophageal adenocarcinogenesis in many features. All the BE was the specialized type with goblet cells (containing sialomucin or sulfomucin) and columnar cells (containing acid or neutral mucin) as well as an incompletely developed brush border. Almost all of the BE was located at the bottom of the esophagus and was continuous with the duodenal mucosa; dysplasia became more frequent at later time points. All of the cancers were well-differentiated mucinous EAC, and most of the EAC had an adjacent area of BE with dysplasia. The results are consistent with the proposed human sequence for pathogenic events of BE progression to 'BE with dysplasia' and then to EAC. Esophagoduodenal anastomosis and iron treatment in rats produces a high rate of BE and EAC which are morphologically similar to human BE and EAC; this may be a useful animal model to study the development and prevention of EAC in humans.
Carcinogenesis 1997 Nov
PMID:Development of esophageal metaplasia and adenocarcinoma in a rat surgical model without the use of a carcinogen. 939 30

In a previous study, we obtained a novel monoclonal antibody (F1 alpha-75) directed against a synthetic mucin antigen termed F1 alpha, and demonstrated that this antigen was expressed in a high percentage (80.2%; 89/111) of gastric carcinomas. In the present study, we compared the expression of F1 alpha with that of sialyl-Tn antigen, a mucin antigen similar to F1 alpha, in 54 human early gastric carcinomas, intestinal metaplasia and adenomatous polyps of the stomach to determine how differences in the expression of these antigens correlated with gastric carcinogenesis. The rate of expression of F1 alpha in early gastric carcinoma tissues, 81.5%, was higher than that of sialyl-Tn antigen, 57.4%. No correlation was found between the rate of expression and histological type, depth of cancerous invasion or lymph node metastasis. Sialyl-Tn antigen was extensively expressed in 77.5% of specimens of complete intestinal metaplasia and in 78.6% of those of incomplete intestinal metaplasia; however, the expression of F1 alpha in those specimens was rare and sporadic, with rates of only 25.0 and 27.7%, respectively. In adenomatous polyps, the rate of expression of F1 alpha is 6.25% and that of sialyl-Tn antigen is 43.8%. Our findings indicate that F1 alpha is a more specific antigen for gastric cancer than sialyl-Tn antigen, and that F1 alpha is an antigen associated with carcinogenesis of the stomach.
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PMID:F1 alpha: a novel mucin antigen associated with gastric carcinogenesis. 942 79

Innervation of the gastric mucosa plays an important role in its defense mechanism. In a previous study, gastrectomy with denervation promoted tumorigenesis in the gastric body in rats after administration of a carcinogenic agent. In this study we investigated the induced gastric mucosal changes from the viewpoint of mucin histochemistry. Gastrectomy with denervation promoted the development of intestinal metaplasia, dysplasia, and carcinoma in the gastric body. Proliferating cell nuclear antigen labeling indexes as a marker for cell kinetics were significantly elevated in the denervated group. Analysis of mucin histochemistry by staining with paradoxical concanavalin A (PCA) and galactose oxidase-Schiff (GOS), which are markers for expression of the gastric phenotype, revealed that these mucins were positive in submucosal adenocystic proliferation and carcinoma at the anastomotic site. Conversely, in the gastric body these mucins disappeared with progression of dysplasia, and carcinoma cells contained neither PCA- nor GOS-positive mucins. These results suggest that there are two different processes of carcinogenesis in the gastric remnant, depending on the location, and that denervation of the remnant gastric mucosa promotes the development of cancer-related lesions in the gastric body.
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PMID:Denervation promotes the development of cancer-related lesions in the gastric remnant. 947 39

Monoclonal antibodies TKH2 and B72.3, which react with the mucin-associated sialyl-Tn(STn) antigen, preferentially bind to cancerous but not normal colonic tissues. If O-acetyl groups are removed by saponification of tissues, MAb TKH2 will react with normal colonocytes, whereas MAb B72.3 remains non-reactive. To explain this difference in binding specificity, we tested both MAbs against synthetic constructs of single (monomeric) or clustered (trimeric) STn epitopes by enzyme immunoassay. Both MAb TKH2 and MAb B72.3 reacted with trimeric STn, but MAb TKH2 demonstrated greater binding than MAb B72.3 to monomeric STn. This suggests that normal colonic mucosa expresses monomeric STn epitopes, but that with transformation to malignancy, clustered STn epitopes appear. The appearance of clustered STn epitopes during colonic carcinogenesis represents a novel pattern of carbohydrate antigen expression and implicates alterations at the level of apomucins and/or glycosyltransferases responsible for cluster epitope formation.
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PMID:Different modes of sialyl-Tn expression during malignant transformation of human colonic mucosa. 953 Sep 54

Lung cancer is largely a site-of-entry disease caused by inhaled carcinogenic agents, especially tobacco smoke. Two major groups of procarcinogens, tobacco-specific nitrosamines and polycyclic aromatic hydrocarbons, are putative agents, but their relative contributions are disputed. An important indicator of relative potency for these compounds is the dose to the target epithelial cells. Although we have reported the dose of polycyclic aromatic hydrocarbons to the canine tracheal epithelium [Gerde et al., Carcinogenesis (Lond.), 18: 1825-1832, 1997; Gerde et al., Carcinogenesis (Lond.), in press, 1998], the purpose of the current study was to characterize the absorption and metabolism of low levels of one tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in the canine trachea. One hundred ng of tritiated NNK were instilled in the distal trachea of the dog. Blood was repeatedly sampled from the azygous vein and both sides of the systemic circulation from 15 s to 30 min after instillation. Tissues were then removed and analyzed for the tritiated NNK and its metabolites. Autoradiography was used to determine the depth distribution of tritium in the tracheal mucosa. Most NNK appeared rapidly in the blood draining the airway mucosa, but there was also a slow clearance phase. During absorption, NNK was distributed within the entire depth of the mucosa to the tracheal cartilage; however, a portion was conspicuously bound to the mucin component of the mucous lining layer. Reversible binding to mucin may be largely responsible for the slow clearance phase. Despite the rapid absorption of most of the tritium, NNK was nonetheless extensively metabolized in the tracheal mucosa. Systemic metabolism was also rapid: within 18 min of instillation, the NNK parent compound had disappeared from the systemic circulation, and 45 min after instillation, no NNK was found in the trachea or any distal tissue. Although the rapid absorption and distribution of NNK and its metabolites ensured widespread and extensive distal binding in all tissues, first-pass metabolism and activation of NNK in the airway mucosa were sufficiently rapid to cause levels of binding at the site of absorption to be approximately 20-fold those of distal tissues. NNK may thus act as a site-of-entry carcinogen. This observation may be important in estimating the contribution of NNK to lung cancer relative to other carcinogens and for explaining increased incidences of oral cancers in users of snuff and chewing tobacco in which NNK is present in high concentrations.
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PMID:A relevant dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is extensively metabolized and rapidly absorbed in the canine tracheal mucosa. 953 42

Mucins are high molecular weight glycoproteins which are heavily glycosylated with many carbohydrate side chains. In epithelial cancers such as colorectal cancer, both qualitative and quantitative alterations in carbohydrate and polypeptide moieties of mucin glycoproteins occur. These changes in mucin glycoproteins are one of the most common phenotypic markers of colorectal carcinogenesis and may play an important pathobiological role. The expression of some of the sialylated carbohydrate antigens appears to correlate with a poor prognosis and increased metastatic potential in colorectal cancer. The increased exposure of peptide epitopes of mucin glycoproteins in colorectal cancer appears to be due to either abnormal glycosylation and/or altered levels of mucin gene transcription. In addition, dysregulation of tissue specific mucin genes occurs in colorectal cancers. This information is currently being exploited for further elucidation of the molecular mechanisms involved in carcinogenesis, tumor progression and metastasis, and the development of novel methods of colorectal cancer diagnosis and therapy.
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PMID:Mucin glycoproteins in colonic neoplasia. 956 May 27

Evaluation of the role of somatic genetic alterations in cancer development is best performed by examining small tumors in the earlier stages of carcinogenesis. We examined the relationship between allelic deletions of 4 microsatellites linked to the adenomatous polyposis coli (APC) gene and differential histogenetical phenotypes in 34 intramucosal carcinomas of the stomach, of which, structurally, 24 cases were the gland-forming type (so-called "intestinal type") and 10 were the diffuse type. Using mucin and immunohistochemical staining techniques specific for gastric- and intestinal-type mucins, the phenotype of each tumor was histogenetically classified as exclusively gastric, predominantly gastric, predominantly intestinal or exclusively intestinal. There was generally a free combination between structural types and phenotypic mucin expression. Allelic deletions were detected in 6 carcinomas of the exclusively intestinal phenotype. The incidence of allelic deletions was significantly higher in the predominantly and exclusively intestinal phenotypes (6/16, 37.5%) than in the predominantly and exclusively gastric phenotypes (0/18) (p = 0.0060, Fisher's test). Taking the high frequency of allelic deletions in 5q in invasive stomach carcinomas, the present study suggests that genetic alteration in this region is a very early event in stomach carcinomas with intestinal differentiation but a relatively late event in those with gastric differentiation.
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PMID:Intramucosal carcinomas of the stomach: phenotypic expression and loss of heterozygosity at microsatellites linked to the APC gene. 968 49

Existence of the organ stem cell population seems to decide on ability of the tissue to regenerate and, likewise, on carcinogenesis. The source of the organ specific stem cells may be perivascular mesenchyma of thin-walled vascular channels. Our previous study on the breast cancer indicates that the perivascular mesenchyma of thin-walled vessels appears to be source of myoid cells (myofibroblasts) from which cancer cells arise. Similar results have been observed in the cancers of lung, salivary gland and colon, investigated in the current study. The perivascular cells of thin-walled channels are the source of myoid cells with expression of synaptophysin (Syn) and/or chromogranin A (Chg A), and from these cells neoplastic cells could originate. Syn and/or Chg A positive neoplastic cells were particularly well visible in connection with the vascular channels on the peripheries of tumors while other parts of tumors were only weak positive or negative for those neuroendocrine markers. Similarly as in breast cancers, the S100-protein positive dendritic cells with various of distribution were seen, expressing intimate connection with neoplastic cells. The epithelial pearls especially abundant in non-small cell lung carcinomas demonstrated immunohistochemical analogy to Hassall's bodies: they had monocytogenic cell inside and they displayed thymosin alpha 1 (TA1), as well as mucin secretion and minute calcification. Some epithelial cells expressed desmin and Syn. All types of investigated cancers demonstrated TA1. Results of our present study suggest that the perivascular cells have a differentiation defect. Such defect may initiate abnormal stromal environment, commonly observed in neogenesis, however, the presence of thymic growth factors may favor tumor growth.
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PMID:Epithelial-mesenchymal cell interactions and participation of the neuroendocrine markers in tumor development. Immunohistochemical study. 977 91

Based on the multistage and multifocal nature of colorectal carcinogenesis, it is likely that reduction of cancer mortality through early detection and identification of new prognostic markers is an attainable goal. Well-documented changes occur in mucin glycoconjugates during neoplastic progression in the colon, and the nonneoplastic colonic mucosa in colon cancer patients is morphologically and histochemically abnormal. In this retrospective study, 152 archival colorectal tissues from 49 patients were studied for changes in mucin secretions as detected by the galactose oxidase-Schiff's (GOS) sequence. Intensity of the stain was evaluated in histological sections by semiquantitative analysis, and the area percentage of epithelium stained was quantified by image cytometry. The correlation between gender or tumor size, location and reactivity with peanut agglutinin and quantitative expression of GOS-reactive mucins was determined as well as intratumor and inter individual variability. Reactivity with GOS: (a) decreased during neoplastic progression and malignant conversion in the neoplasm; (b) increased in the normal colonic mucosa of patients with progressively more advanced disease; and (c) was of prognostic significance for patient survival or recurrence both in the normal colon of cancer patients and in invasive neoplasms. These data are consistent with the conclusion that GOS reactivity in the normal colonic mucosa is a dosimeter of exposure to environmental/lifestyle colorectal carcinogens rather than a marker for an oncodevelopmental cancer-associated antigen.
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PMID:Validation of the galactose oxidase-Schiff's reagent sequence for early detection and prognosis in human colorectal adenocarcinoma. 981 34


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