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

The Paneth cell lineage is one of four epithelial lineages derived from the adult mouse small intestine's multipotent stem cell. Mature Paneth cells secrete antimicrobial peptides (cryptdins), growth factors, as well as two gene products, a secreted phospholipase A2 and matrilysin, that has been implicated as modifiers of adenoma formation in mice containing a mutation in the tumor suppressor Apc. Immature Paneth cells are located just above and below the cell layer, in intestinal crypts, that has been proposed to contain the multipotent stem cell. Paneth cells differentiate during a downward migration to the crypt base. The location and direction of Paneth cell migration, their high density and long residency time at the crypt base, and the nature of their secreted gene products, suggest that they may influence the structure and/or function of the stem cell niche. Paneth cell ablation can therefore be viewed as an experimental manipulation of the cellular microenvironment that purportedly contains the stem cell and its immediate descendants. Two types of ablation experiments were performed in transgenic mice. Nucleotides -6500 to +34 of the mouse cryptdin-2 gene (CR2) were used to express an attenuated diphtheria toxin A fragment. Light and electron microscopic immunohistochemical analyses of several pedigrees of postnatal day 28 to 180 animals established that ablation of Paneth cells is accompanied by an increase in the proportion of undifferentiated crypt base columnar cells. These cells normally co-exist with Paneth cells. The ablation does not produce a detectable effect on the proliferation or terminal differentiation programs of the other three lineages or on host-microbial interactions. The last conclusion is based on the ability of crypts to remain free of microbes detectable by Gram and Warthin-Starry stains and by retention of the normal crypt-villus distribution of components of the diffuse gut-associated lymphoid tissue. CR2-directed expression of simian virus 40 large T antigen also results in a loss of mature Paneth cells but produces a marked amplification of crypt cells having a morphology intermediate between Paneth and granule goblet cells. EM immunohistochemical analyses suggest that intermediate cells can differentiate to mature goblet cells but not to Paneth cells, as they migrate up the crypt-villus axis. Our findings suggest that (i) stemness in the crypt is not defined by instructive interactions involving the Paneth cell; (ii) expressing a Paneth cell fate may require that precursors migrate to the crypt base; (iii) antimicrobial factors produced by Paneth cells are not required to prevent colonization of small intestinal crypts; and (iv) this lineage does not function to maintain the asymmetric crypt-villus distribution of components of the diffuse gut-associated lymphoid tissue.
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PMID:Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice. 929 17

The synovial fluid or group II secretory phospholipase A2 (sPLA2) has been implicated in various inflammatory processes and has been shown to release arachidonic acid for prostaglandin biosynthesis. In human colorectal cancer, both arachidonic acid and eicosanoid levels are elevated. Recently, sPLA2 has been identified as a candidate gene that modifies the Apc gene in the Min mouse, a murine model for familial adenomatous polyposis (FAP). Loss of sPLA2 gene function results in susceptibility to the Min phenotype and the formation of multiple intestinal polyps, whereas mice expressing an active sPLA2 gene are resistant to polyp formation. Therefore, there are two potentially contrasting roles for sPLA2 in colon cancer; one is protection against polyp formation, and the other, the release of arachidonic acid for prostaglandin production and subsequent tumor promotion. To investigate these contrasting dual roles of sPLA2, we have examined the expression and sequence of the sPLA2 mRNA in normal mucosa and duodenal and colorectal polyps from FAP patients. In 11 of 14 patients, there was a significant increase in sPLA2 mRNA levels in the adenoma over the normal tissue. In some cases, there was over 100-fold increase in mRNA levels in the adenoma compared with normal tissue. Analysis of multiple adenomatous polyps from individual patients revealed that not all polyps contained elevated levels of sPLA2 mRNA. Immunoblot analysis also showed that sPLA2 protein expression was elevated in adenoma over normal tissue in five of six FAP patients analyzed. Furthermore, sequence analysis of sPLA2 mRNA present in these samples did not reveal mutations in the coding region. The implications of the up-regulation of sPLA2 in FAP is not clear, but unlike the Min mouse model, it does not seem to have a significant effect on polyp formation. In contrast, the high level of sPLA2 expression is more likely contributing to the elevated levels of arachidonic acid found in colorectal cancer and, in conjunction with the elevated expression of cyclooxygenase-2, could be another factor in tumor formation.
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PMID:Overexpression of the nonpancreatic secretory group II PLA2 messenger RNA and protein in colorectal adenomas from familial adenomatous polyposis patients. 945 96

Apc(Min) mice have provided an example of a locus (Modifier of Min1; Mom1) modifying adenoma numbers in the intestines of inbred strains. Linkage analysis located Mom1 on chromosome 4, and further investigation identified secretory phospholipase A2 (Pla2g2a) as a candidate gene. Because of unknown variation introduced by a single founding male mouse, our Min stock, although Pla2g2a(Mom1-s), was not on a pure C57BL/6J background and exhibited several polymorphic loci, including a region on chromosome 18 distal to Apc. Through selective breeding for homozygosity for distal chromosome 18 markers, six recombinant lines that presented with limited intraline variation in adenoma numbers were established. One line (V) showed a particularly severe phenotype (mean adenoma number +/- SEM, 370 +/- 21) compared with the other lines that recorded significantly lower means (3- to 5-fold; P < 10(-3), t test). Intercrosses between lines I and V showed suppression of the severe phenotype in the N1 generation. In N2 (and subsequent) backcrosses, tumor multiplicity depended on the origins of the WT and Min Apc alleles. Mice carrying both alleles from line V had a severe phenotype; others had mild disease very similar to line I (likelihood ratio statistic > 49.0; likelihood of odds > 10; P < 10(-5)). Frequency of allele loss at Apc was increased significantly in adenomas of mice with more severe disease. We propose that a modifier gene close to Apc or structural variation on chromosome 18 modifies polyp numbers in our mice, possibly by altering the frequency of WT Apc allele loss.
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PMID:Genetic basis of variation in adenoma multiplicity in ApcMin/+ Mom1S mice. 1571 Aug 76

The secreted phospholipase A2 type IIA (Pla2g2a) gene was previously identified as a modifier of intestinal adenoma multiplicity in Apc Min/+ mice. To determine if intestinal secreted phospholipase A2 (sPLA2) activity was also attenuated in susceptible strains, we developed a sensitive assay to directly quantitate sPLA2 activity in the murine intestinal tract utilizing a fluorescent BODIPY-labeled phospholipid substrate. Here, we report assay conditions that distinguish between secreted and cytosolic PLA2 enzyme activities in extracts of intestinal tissue. The small intestine exhibited higher activity levels than the large intestine. Consistent with predictions from the sPLA2-IIA gene sequence in inbred strains, we detected low levels of enzyme activity in inbred strains containing sPLA2-IIA mutations; these strains were also associated with greater numbers of intestinal polyps. Additionally, the assay was able to distinguish differences in levels of sPLA2 activity between neoplasia-resistant strains, which were then shown by sequencing to carry variant wild-type sPLA2-IIA alleles. Immunohistochemical analyses of intestinal tissues were consistent with sPLA2-IIA activity levels. This approach enables further studies of the mechanisms of sPLA2 action influencing the development and tumorigenesis of the small intestine and colon in both mice and humans.
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PMID:Diversity in secreted PLA2-IIA activity among inbred mouse strains that are resistant or susceptible to Apc Min/+ tumorigenesis. 1600 93