Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neoplastic progression of colorectal epithelial cells from benign adenomas to malignant carcinomas appears to result from a series of genetic alterations involving both oncogenes and tumor suppressor genes. This progression was recently found to be associated with expression of splice variant isoforms of CD44, a cell surface hyaluronate receptor implicated in carcinogenesis. In this study we examined the relationship of CD44 expression to somatic genetic events in the adenoma-carcinoma sequence: point mutation of K-ras in codons 12 and 13 and overexpression of p53 protein as a marker of gene mutation. Among 22 small adenomas, CD44 was present in 9 (41%), of which only 1 contained a K-ras mutation. CD44 was absent in the other 2 small adenomas positive for K-ras mutation or p53 overexpression. In contrast to the early expression of CD44 in small adenomas, mutations of K-ras and p53 were detected preferentially in large adenomas and late-stage adenomas containing carcinoma. The frequent expression of CD44 prior to K-ras and p53 gene alterations in colorectal neoplasia suggests that activation of CD44 gene expression is related to earlier events in the adenoma-carcinoma sequence, possibly cell activation and proliferation following APC gene mutation or alteration of DNA methylation.
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PMID:CD44 expression in colorectal adenomas is an early event occurring prior to K-ras and p53 gene mutation. 751 84

Variant CD44 has recently been shown to serve as a metastasis marker in human breast cancer. Certain variant epitopes on primary tumors predict poor survival probabilities for the patients. In this study, immunohistochemical analysis of 16 uterine cervical carcinomas showed strong expression of several CD44 variant epitopes in all samples. In normal cervical epithelia from 5 patients, expression of these epitopes was restricted to particular cell layers, with expression being strong in basal and spinal cells but absent in superficial cells. Fifteen of 16 cancer samples were stained strongly with an antibody which recognizes one particular CD44 epitope that is encoded by both variant exons v7 and v8. This epitope was not detectable in normal cervical epithelium. CD44-mRNA splicing analysis showed qualitative and quantitative differences between malignant and normal tissues with a much more complex splice pattern and high expression of a large CD44 isoform containing variant exons v3 to v10 (including the v7/v8 transition epitope) in about one-half of the cancer samples. Interestingly, patients with lymph node metastases were in this group only. These differences in CD44 epitope expression and mRNA splicing in cervical carcinoma reveal dynamic changes in CD44 expression during carcinogenesis. Such changes could provide metastatic cells with a selective advantage during the carcinogenic process. Furthermore, the v7/v8 epitope may be suitable for screening early stages of cervical cancer.
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PMID:Surface protein expression and messenger RNA-splicing analysis of CD44 in uterine cervical cancer and normal cervical epithelium. 751 19

Using immunostaining, immunoblot, reverse-transcriptase polymerase chain reaction and Southern blot, we found that expressions of CD44 isoforms and E-cadherin were very closely linked and were correlated with the differentiation status in human urothelial cell lines and clinical specimens of transitional cell carcinoma. Normal urothelium, well to moderately differentiated cell lines and surgical samples expressed E-cadherin and large CD44 isoforms containing exon v6, which was pivotal in metastasis of rat pancreatic cell line model. Poorly differentiated cell lines and surgical samples, were E-cadherin-negative and expressed primarily standard form CD44, which did not contain exon v6. We concluded that CD44v6 isoforms and E-cadherin were both down-regulated during the carcinogenesis of urothelium. The large exon v6 containing CD44 isoforms were readily detected in normal urothelium, therefore, were not likely linked to cancer metastasis. E-cadherin and CD44v6 may be used as differentiation markers for human urothelial tumors. Immunohistochemical study solely with antibody against epitopes encoded by exon v6 alone is not informative enough as other alternatively spliced exons may change the function of CD44v6 isoforms.
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PMID:Correlation of expression of CD44 isoforms and E-cadherin with differentiation in human urothelial cell lines and transitional cell carcinoma. 753 58

Alternative splicing of ten different variant exons (v1-v10) is responsible for the creation of a large number of different CD44 surface proteins. Some of these proteins play decisive roles in the metastatic spread of rat tumours. Also in human cancers, CD44 splice variants are frequently expressed in advanced states of tumorigenesis. In breast cancer and in non-Hodgkin's lymphomas expression of exon v6 is correlated with poor prognosis of patient survival. In colorectal carcinogenesis, expression of exon v5 is an early tumour marker since it is already detectable on small dysplastic polyps (but not on normal colon epithelium). In contrast, exon v6 expression occurred with increased frequency with tumour progression, and its expression on colorectal tumours indicated reduced survival probability. Most likely, tumours carrying the CD44 v6 epitope acquire selective advantage during tumour progression and metastasis formation. This could be a proliferative advantage since mice transgenic for the CD44 isoform CD44v4-v7 on T lymphocytes show an accelerated T-dependent immune response as compared with non-transgenic siblings.
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PMID:CD44 in colon cancer. 757 2

Gastric cancer involves changes in multiple oncogenes and multiple suppressor genes, and it causes genetic instability. Aberrant expression and amplification of the c-met gene, inactivation of the p53 gene, and CD44 abnormal transcripts are common events of both well differentiated and poorly differentiated gastric cancers. Amplification of the cyclin E gene is also observed in gastric cancer regardless of histologic type. Decreased expression of the pic1 (p21) gene occurs independent of the p53 mutations. In addition, K-ras mutations, c-erbB-2 gene amplification, loss of heterozygosity (LOH) and mutations of the APC gene, LOH of the bcl-2 gene, and LOH at the DCC locus are preferentially associated with well differentiated gastric cancer. Moreover, LOH on chromosome 1q is involved in the progression of well differentiated cancer. Precancerous lesions, including hyperplastic polyp, intestinal metaplasia, and adenoma, share genetic changes found in well differentiated cancers. Conversely, genetic instability may be involved in the first step of stomach carcinogenesis of the poorly differentiated type. Reduction or loss of cadherin and catenins, K-sam gene amplification, and c-met gene amplification are necessary for the development and progression of poorly differentiated or scirrhous carcinoma. Interaction between cell-adhesion molecules in the c-met expressed tumor cells and hepatocyte growth factor from stromal cells is implicated in the morphogenesis of two types of gastric cancer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular biology of gastric cancer. 767 88

A recently described splice variant of CD44 expressed in metastasizing cell lines of rat tumors has been shown to confer metastatic potential to a non-metastasizing rat pancreatic carcinoma cell line and to non-metastasizing sarcoma cells. Homologues of this variant as well as several other CD44 splice variants are also expressed at the RNA level in human carcinoma cell lines from lung, breast, and colon, and in immortalized keratinocytes. Using antibodies raised against a bacterial fusion protein encoded by variant CD44 sequences, we studied the expression of variant CD44 glycoproteins in normal human tissues and in colorectal neoplasia. Expression of CD44 variant proteins in normal human tissues was readily found on several epithelial tissues including the squamous epithelia of the epidermis, tonsils, and pharynx, and the glandular epithelium of the pancreatic ducts, but was largely absent from other epithelia and from most non-epithelial cells and tissues. In human colorectal neoplasia CD44 variant proteins, including homologues of those which confer metastatic ability to rat tumors, were found on all invasive carcinomas and carcinoma metastases. Interestingly, focal expression was also observed in adenomatous polyps, expression being related to areas of dysplasia. The distribution of the CD44 variants in human tissues suggests that they play a role in a few restricted differentiation pathways and that in colorectal tumors one of these pathways has been reactivated. The finding that metastasis-related variants are already expressed at a relatively early stage in colorectal carcinogenesis and tumor progression, i.e., in adenomatous polyps, suggests the existence of a yet unknown selective advantage linked to CD44 variant expression. The continued expression in metastases would be compatible with a role in the metastatic process.
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PMID:A human homologue of the rat metastasis-associated variant of CD44 is expressed in colorectal carcinomas and adenomatous polyps. 841 89

Interaction between lymphocytes and epithelial cells may play a key role in Helicobacter pylori (H. pylori)-associated gastric mucosal inflammation. This interaction process is at least partially mediated by various cell adhesion molecules. The aims of the present study were to assess using flow cytometric analysis whether H. pylori directly or supernatants from H. pylori-activated peripheral blood mononuclear cells (PBMC) can affect the expression of adhesion molecules on the gastric epithelial cell line AGS in vitro. The results showed that resting AGS cells expressed CD44 and ICAM-1. Co-culture of AGS with H. pylori or cytokine-rich supernatants from H. pylori-activated PBMC resulted in up-regulation of expression of CD44 and ICAM-1 on AGS cells. These data suggest that H. pylori directly and indirectly through inflammatory cytokines may contribute to alternations in adhesion molecule expression on gastric epithelial cells. This may be of pathological significance in H. pylori-associated gastric mucosal inflammation and carcinogenesis.
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PMID:Up-regulation of CD44 and ICAM-1 expression on gastric epithelial cells by H. pylori. 853 34

Splice variants of the cell surface glycoprotein CD44 (CD44v) have been implicated in the progression of various human tumors. In the present study, we have examined the expression pattern of a CD44v epitope encoded by the adjacent variant exons v7 and v8 during human cervical carcinogenesis. While only l/ll normal cervical squamous epithelia was positive for this epitope by immunohistochemistry, 4/21 samples of low-grade squamous intra-epithelial lesions (LSIL), 17/35 samples of high-grade squamous intra-epithelial lesions (HSIL), 11/12 samples of the HSIL subgroup of carcinomas in situ and 17/17 cases of invasive cervical carcinoma showed CD44v7/8 epitope expression. In addition to CD44 variant expression, we have analyzed 67 lesions for the presence of HPV16/18-DNA using PCR. Most of the samples expressing the v7/8 epitope were also HPV16-positive (29/32), whereas only 17/35 of the v7/8-negative samples were HPV16-positive. HPV18 DNA was found in only one invasive carcinoma. Our data suggests that high-risk HPV infection may precede CD44v7/8 expression and that the number of samples expressing the CD44v7/8 epitope increases during carcinogenesis and reaches nearly 100% at the carcinoma in situ stage. This CD44 epitope could, therefore, serve as a diagnostic marker of cervical squamous cell carcinomas and as a possible target for CD44v7/8 epitope-directed therapies.
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PMID:Increasing incidence of CD44v7/8 epitope expression during uterine cervical carcinogenesis. 860 87

Alterations in the structure and function of oncogenes and tumor suppressor genes, as well as genetic instability at several other genetic foci may be responsible for stomach carcinogenesis. The particular combination of multiple gene changes found in gastric cancer differs depending on the two histological types, strongly indicating that different genetic pathways exist for well differentiated or intestinal type and poorly differentiated or diffuse type gastric cancers. In general, genetic instability, telomerase activity, CD44 abnormal transcripts, and p53 mutation, all of which are common events of two types of gastric cancer, may be involved mainly in the early stage of stomach carcinogenesis, whereas activation of oncogenes and overexpression of the epidermal growth factor-related growth factor system may chiefly confer progression on gastric cancer. A new strategy of molecular diagnosis of gastrointestinal cancer, which has been implemented as a routine service in the Hiroshima University Clinical Laboratory, may provide new opportunities for early cancer diagnosis and more accurate evaluation of prognosis or grade of malignancy.
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PMID:Molecular biological observations in gastric cancer. 865 14

The scenario of multistep of stomach carcinogenesis differs depending on the two histological types, well differentiated adenocarcinoma and poorly differentiated adenocarcinoma, because the two types may have different genetic pathways. Genetic instability, reactivation of telomerase and abnormal transcript of CD44 including intron 9 are common events of both well and poorly differentiated type carcinomas. These occur at early stage of carcinogenesis, even in precancerous lesions such as intestinal metaplasia and adenoma. Inactivation of APC, activation of K-ras, amplification of c-erbB2, and allelic loss of DCC locus are associated with well differentiated type, while amplification of K-sam and functional loss of cadherin/catenin are characteristics of poorly differentiated type. HGF/c-met system plays a pivotal role in morphogenesis of both histological types through interaction with cell-cell adhesion molecules. Reactivation of telomerase or genetic instability may be an initial event for accumulation of multiple genetic alterations during the progression of stomach carcinogenesis.
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PMID:[Genetic alterations in stomach cancer]. 869 39


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