Matrix metalloproteinase-13 refines pathological staging of precancerous colorectal lesions.
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ABSTRACT:
SUBMITTER: Wernicke AK
PROVIDER: S-EPMC5341998 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundApproximately 60% of colorectal cancer (CRC) precursor lesions are the genuinely-dysplastic conventional adenomas (cADNs). The others include hyperplastic polyps (HPs), sessile serrated lesions (SSL), and traditional serrated adenomas (TSAs), subtypes of a class of lesions collectively referred to as "serrated." Endoscopic and histologic differentiation between cADNs and serrated lesions, and between serrated lesion subtypes can be difficult.MethodsWe used in situ hybridization to verify the expression patterns in CRC precursors of 21 RNA molecules that appear to be promising differentiation markers on the basis of previous RNA sequencing studies.ResultsSSLs could be clearly differentiated from cADNs by the expression patterns of 9 of the 12 RNAs tested for this purpose (VSIG1, ANXA10, ACHE, SEMG1, AQP5, LINC00520, ZIC5/2, FOXD1, NKD1). Expression patterns of all 9 in HPs were similar to those in SSLs. Nine putatively HP-specific RNAs were also investigated, but none could be confirmed as such: most (e.g., HOXD13 and HOXB13), proved instead to be markers of the normal mucosa in the distal colon and rectum, where most HPs arise. TSAs displayed mixed staining patterns reflecting the presence of serrated and dysplastic glands in the same lesion.ConclusionsUsing a robust in situ hybridization protocol, we identified promising tissue-staining markers that, if validated in larger series of lesions, could facilitate more precise histologic classification of CRC precursors and, consequently, more tailored clinical follow-up of their carriers. Our findings should also fuel functional studies on the pathogenic significance of specific gene expression alterations in the initiation and evolution of CRC precursor subtypes.
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Project description:Substantial evidence implicates interstitial collagenases of the matrix metalloproteinase (MMP) family in plaque rupture and fatal thrombosis. Understanding the compensatory mechanisms that may influence the expression of these enzymes and their functions, therefore, has important clinical implications. This study assessed in mice the relative effect of the 2 principal mouse collagenases on collagen content and other plaque characteristics.Apolipoprotein E-deficient (apoE(-/-)) mice, MMP-13(-/-) apoE(-/-), MMP-8(-/-) apoE(-/-) double knockout mice, and MMP-13(-/-) MMP-8(-/-) apoE(-/-) triple knockout mice consumed a high-cholesterol diet for 10 and 24 weeks. Both double knockout and triple knockout mice showed comparable atherosclerotic lesion formation compared with apoE(-/-) controls. Analysis of aortic root sections indicated that lesions of MMP-8/MMP-13-deficient and MMP-13-deficient mice accumulate more fibrillar collagen than apoE(-/-) controls and MMP-8(-/-) apoE(-/-) double knockout. We further tested the relative effect of MMPs on plaque collagenolysis using in situ zymography. MMP-13 deletion alone abrogated collagenolytic activity in lesions, indicating a predominant role for MMP-13 in this process. MMP-13 and MMP-13/MMP-8 deficiency did not alter macrophage content but associated with reduced accumulation of smooth muscle cells.These results show that among MMP interstitial collagenases in mice, MMP-13 prevails over MMP-8 in collagen degradation in atheromata. These findings provide a rationale for the identification and selective targeting a predominant collagenase for modulating key aspects of plaque structure considered critical in clinical complications, although they do not translate directly to human lesions, which also contain MMP-1.
| S-EPMC4123424 | biostudies-literature
Project description:In this study, we validated 992 previously identified differentially methylated regions (DMRs) in colorectal precancerous lesions compared to adjacent normal mucosa in a new series of 59 prospectively collected lesions and matched normal tissue using targeted bisulfite sequencing. Strong differences in methylation level were observed across the full set of validated DMRs. Based on the mean methylation levels of a panel of 30 selected DMRs tumors could be accurately classified. We thus provide a large list of validated DNA markers to be exploited in the development of noninvasive, colorectal tumor screening assays.
2023-03-30 | E-MTAB-12612 | biostudies-arrayexpress
Project description:Endoscopic mucosal resection (EMR) is a technique allowing efficacious and minimally invasive resection of precancerous lesions across the entire gastrointestinal tract. However, conventional EMR, involving injection of fluid into the submucosal space, is imperfect, given the high rate of recurrence of post-endoscopic resection adenoma, especially after piecemeal resection. In light of these observations, modifications of the technique have been proposed to overcome the weakness of conventional EMR. Some of them were designed to maximize the chance of en bloc resection-cap-assisted EMR, underwater EMR, tip-in EMR, precutting, assisted by ligation device-while others were designed to minimize the complications (cold EMR). In this review, we present their modes of action and summarize the evidence regarding their efficacy and safety.
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Project description:Little is known about the immunoediting process in precancerous lesions. We explored this aspect of benign colorectal adenomas with a descriptive analysis of the immune pathways and immune cells whose regulation is linked to the morphology and size of these lesions. Two series of polypoid and nonpolypoid colorectal adenomas were used in this study: 1) 84 samples (42 lesions, each with matched samples of normal mucosa) whose gene expression data were used to quantify the tumor morphology- and size-related dysregulation of immune pathways collected in the Molecular Signature Database, using Gene Set Enrichment Analysis; 2) 40 other lesions examined with immunohistochemistry to quantify the presence of immune cells in the stromal compartment. In the analysis of transcriptomic data, 429 immune pathways displayed significant differential regulation in neoplasms of different morphology and size. Most pathways were significantly upregulated or downregulated in polypoid lesions versus nonpolypoid lesions (regardless of size). Differential pathway regulation associated with lesion size was observed only in polypoid neoplasms. These findings were mirrored by tissue immunostaining with CD4, CD8, FOXP3, MHC-I, CD68, and CD163 antibodies: stromal immune cell counts (mainly T lymphocytes and macrophages) were significantly higher in polypoid lesions. Certain markers displayed significant size-related differences regardless of lesion morphology. Multivariate analysis of variance showed that the marker panel clearly discriminated between precancerous lesions of different morphologies and sizes. Statistical analysis of immunostained cell counts fully support the results of the transcriptomic data analysis: the density of infiltration of most immune cells in the stroma of polypoid precancerous lesions was significantly higher than that observed in nonpolypoid lesions. Large neoplasms also have more immune cells in their stroma than small lesions. Immunoediting in precancerous colorectal tumors may vary with lesion morphology and stage of development, and this variability could influence a given lesion's trajectory to cancer.
| S-EPMC4956166 | biostudies-literature
Project description:Epigenetic silencing of protein-encoding genes is common in early-stage colorectal tumorigenesis. Less is known about the methylation-mediated silencing of genes encoding microRNAs (miRNAs), which are also important epigenetic modulators of gene expression. Using quantitative PCR, we identified 56 miRNAs that were expressed in normal colorectal mucosa and in HT29 colorectal cancer cells treated with demethylating agents but not in untreated HT29 cells, suggesting that they probably undergo methylation-induced silencing during colorectal tumorigenesis. One of these, miR-195, had recently been reported to be underexpressed in colorectal cancers and to exert tumor-suppressor effects in colorectal cancer cells. We identified the transcription start site (TSS) for primary miRNA (pri-miR)-497/195, the primary precursor that yields miR-195 and another candidate on our list, miR-497, and a single CpG island upstream to the TSS, which controls expression of both miRNAs. Combined bisulfite restriction analysis and bisulfite genomic sequencing studies revealed monoallelic methylation of this island in normal colorectal mucosa (50/50 samples) and full methylation in most colorectal adenomas (38/50; 76%). The hypermethylated precancerous lesions displayed significantly downregulated expression of both miRNAs. Similar methylation patterns were observed at two known imprinted genes, MEG3 and GNAS-AS1, which encode several of the 56 miRNAs on our list. Imprinting at these loci was lost in over half the adenomas (62% at MEG3 and 52% at GNAS-AS1). Copy-number alterations at MEG3, GNAS-AS1 and pri-miR-497/195, which are frequent in colorectal cancers, were less common in adenomas and confined to tumors displaying differential methylation at the involved locus. Our data show that somatically acquired, epigenetic changes at monoallelically methylated regions encoding miRNAs are relatively frequent in sporadic colorectal adenomas and might contribute to the onset and progression of these tumors.
| S-EPMC3740287 | biostudies-literature
Project description:Matrix metalloproteinase-13 (MMP-13) has been implicated as the protease responsible for collagen degradation in cartilage during osteoarthritis (OA). Compounds that inhibit the metalloproteinase at the Zn binding site typically lack specificity among MMP family members. Analogs of the low-micromolar lead MMP-13 inhibitor 4, discovered through high-throughput screening, were synthesized to investigate structure-activity relationships in this inhibitor series. Systematic modifications of 4 led to the discovery of MMP-13 inhibitors 20 and 24 which are more selective than 4 against other MMPs. Compound 20 is also approximately fivefold more potent as an MMP-13 inhibitor than the original HTS-derived lead compound 4.
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Project description:Osteoarthritis (OA) is the most common joint degenerative disease affecting the joint structure, leading to loss of joint function and tissue destruction. Recent studies have demonstrated that miRNAs are involved in many pathological conditions, including OA. The study was to investigate the role of miR-411 in the pathogenesis of OA. The expression of miR-411 was downregulated in OA cartilage compared with in normal cartilage. Conversely, the expression of MMP-13 was upregulated in OA cartilage compared with in normal cartilage. IL-1? treatment repressed miR-411 expression in chondrocytes. Moreover, we identified MMP-13 as a direct target gene of miR-411 in chondrocytes and overexpression of miR-411 inhibited the MMP-13 expression. Furthermore, overexpression of miR-411 increased the expression of type II collagen and type IV collagen expression in chondrocytes. MiR-411 is a crucial regulator of MMP-13 in chondrocytes and may response to the development of OA.
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Project description:Matrix metalloproteinase 13 (MMP13) is a key enzyme implicated in the degradation of the extracellular matrix in osteoarthritis. Clinical administration of broad spectrum MMP inhibitors such as marimastat has been implicated in severe musculo-skeletal side effects. Consequently, research has been focused on designing inhibitors that selectively inhibit MMP13, thereby circumventing musculo-skeletal toxicities. A series of pyrimidine dicarboxamides were recently shown to be highly selective inhibitors of MMP13 with a novel binding mode. We have applied a molecular ruler to this exosite by dual inhibition studies involving a potent dicarboxamide in the presence of two metal chelators of different sizes. A larger hydroxamate mimic overlaps and antagonizes binding of the dicarboxamide to the exosite whereas the much smaller acetohydroxamate synergizes with the dicarboxamide. These studies elucidate the steric requirement for compounds that fit exclusively into the active site, a mandate for generating highly selective MMP13 inhibitors.
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Project description:The assembly and degradation of extracellular matrix (ECM) molecules are crucial processes during bone development. In this study, we show that ECM remodeling is a critical rate-limiting step in endochondral bone formation. Matrix metalloproteinase (MMP) 13 (collagenase 3) is poised to play a crucial role in bone formation and remodeling because of its expression both in terminal hypertrophic chondrocytes in the growth plate and in osteoblasts. Moreover, a mutation in the human MMP13 gene causes the Missouri variant of spondyloepimetaphyseal dysplasia. Inactivation of Mmp13 in mice through homologous recombination led to abnormal skeletal growth plate development. Chondrocytes differentiated normally but their exit from the growth plate was delayed. The severity of the Mmp13- null growth plate phenotype increased until about 5 weeks and completely resolved by 12 weeks of age. Mmp13-null mice had increased trabecular bone, which persisted for months. Conditional inactivation of Mmp13 in chondrocytes and osteoblasts showed that increases in trabecular bone occur independently of the improper cartilage ECM degradation caused by Mmp13 deficiency in late hypertrophic chondrocytes. Our studies identified the two major components of the cartilage ECM, collagen type II and aggrecan, as in vivo substrates for MMP13. We found that degradation of cartilage collagen and aggrecan is a coordinated process in which MMP13 works synergistically with MMP9. Mice lacking both MMP13 and MMP9 had severely impaired endochondral bone, characterized by diminished ECM remodeling, prolonged chondrocyte survival, delayed vascular recruitment and defective trabecular bone formation (resulting in drastically shortened bones). These data support the hypothesis that proper ECM remodeling is the dominant rate-limiting process for programmed cell death, angiogenesis and osteoblast recruitment during normal skeletal morphogenesis.
| S-EPMC2771178 | biostudies-literature