Search PubMed⌕ Search

Biomedical subjects

H M Collins

Publications and source records attributed to H M Collins.

12 recordsLinked to original sources
PubMed2003

Helicobacter pylori upregulates matrilysin (MMP-7) in epithelial cells in vivo and in vitro in a Cag dependent manner.

BACKGROUND AND AIMS: Matrix metalloproteinase-7 (MMP-7) is important in normal and pathological remodelling of epithelial-matrix interactions, and is upregulated in gastric cancer. Helicobacter pylori infection is the first stage in gastric carcinogenesis, and therefore our aim was to determine if H pylori upregulated gastric MMP-7 expression and if this was affected by strain virulence. METHODS: We took gastric biopsy specimens at endoscopy from H pylori infected (n = 17) and uninfected (n = 18) patients and assessed MMP-7 expression by ELISA, real time polymerase chain reaction (PCR), and immunohistochemistry (concentrating on epithelial cells in the proliferative zone). We PCR typed H pylori for cagE and vacA. We performed H pylori/cell line coculture studies with wild-type pathogenic and non-pathogenic H pylori strains and with CagE(-) and VacA(-) isogenic mutants. RESULTS: Gastric biopsy specimens from H pylori+ patients expressed higher levels of MMP-7 at the protein and mRNA levels in the antrum and corpus (for example, by ELISA: H pylori+ 0.182 OD units vH pylori- 0.059; p = 0.009 antrum). Epithelial cells from H pylori+ patients stained more intensely for MMP-7 than those from uninfected patients, including in the proliferative zone containing pluripotent cells (p<0.03 antrum, p<0.04 body). Upregulation of MMP-7 in epithelial cells was confirmed at the protein and mRNA levels by H pylori/cell line coculture. These experiments also showed that MMP-7 upregulation was dependent on an intact H pyloricag pathogenicity island but not on the vacuolating cytotoxin. CONCLUSION: We speculate that increased expression of MMP-7 in H pylori gastritis may contribute to gastric carcinogenesis.

Aged↗
PubMed2001

Spectrum of matrix metalloproteinase expression in primary and metastatic colon cancer: relationship to the tissue inhibitors of metalloproteinases and membrane type-1-matrix metalloproteinase.

The matrix metalloproteinases, MMP-2 and MMP-9, are capable of degrading components of the basement membrane, a vital barrier breached during the progression of colorectal cancer. The regulation of MMP-2 activation and subsequent targets is vital to understanding the metastatic process. MMP-2 was not expressed by colorectal cancer cells (C170 and C170HM(2)) in vitro but by stromal fibroblasts (46BR.1GI). There was induction of this MMP upon transwell co-cultivation of the colon cancer cells with the fibroblasts but in vivo growth did not lead to a similar increase in the metastatic tumour cells (C170HM(2)), MMP-2 again being attributed to the stromal cells. MMP-2 mRNA was overexpressed in human colorectal tumours compared to normal colorectal tissue, which correlated with Dukes' stage and immunolocalized to the stromal compartment of the tumour tissue. The active form of the MMP-2 enzyme was also present in the colorectal tumour tissue (7/8) but essentially absent in all normal colon samples examined (1/8). MMP-2 activation was not related to an increase in MT-1-MMP mRNA or a decrease in the specific inhibitor TIMP-2 in human tissue. There was however an increase in MMP-2/TIMP-2 ratio in tumour compared to normal. MMP-9, a target of active MMP-2, was present in the metastatic cell line but expression was down-regulated in the tumour cells in vivo, gelatin analysis revealed that MMP-9 was almost entirely attributable to the murine host, confirmed by PCR. There was no increase in mRNA for MMP-9 or its specific inhibitor TIMP-1 in colorectal tumour tissue compared to normal, MMP-9 protein localized to the inflammatory infiltrate. Fibroblast cells may provide malignant epithelial cells with a ready source of enzyme which is crucial to the metastatic process.

Colonic Neoplasms↗
PubMed2001

Matrix metalloproteinases 2 and 9 in otitis media with effusion.

A qualitative and quantitative study of the presence of matrix metalloproteinase 2 (MMP 2) and matrix metalloproteinase 9 (MMP 9), in the effusions of otitis media with effusion (OME), was performed. The activity of the above enzymes was compared in thick and thin effusions, and concentrations compared in samples from children with one, two, three and four sets of ventilation tubes. The activity of both MMP 2 and MMP 9 was higher in thick than thin effusions, P = 0.07 and P = 0.04, respectively. The concentrations of MMP 9 did not vary with the number of tube insertions but those of MMP 2 did (ANOVA P < 0.05). MMPs may be involved in tympanic membrane damage and prognosis of OME.

Child↗
PubMed2000

Increased type-IV collagenase (MMP-2 and MMP-9) activity following preoperative radiotherapy in rectal cancer.

The aim of this study was to investigate the effect of preoperative high-dose radiotherapy (25 Gy in 5 fractions over 5 days) on the type-IV collagenase protein profile, in patients with resectable rectal cancer, by gelatin zymography. Biopsy samples of tumour and distant normal mucosa from 12 patients with resectable rectal cancer were obtained pre- and post-radiotherapy. Expression of type-IV collagenases (both pro- and active forms) was studied using gelatin zymography. Enzyme levels were normalized for total protein content of each sample. Rectal cancer specimens expressed both pro (72 kDa) and active (62 kDa) forms of MMP-2 but only the pro form of MMP-9 (92 kDa). Normal mucosa showed expression of the pro forms of MMP-2 and MMP-9 while no active form of either enzyme was detected in any of the samples. A significant three- to fourfold increase (P < 0.01) of active matrix metalloproteinases (MMP)-2 (62 kDa) was seen in malignant rectal mucosa after radiotherapy. The effect of radiotherapy also led to a twofold increase (P = 0.047) of pro MMP-2 (72 kDa) and a two- to threefold increase (P = 0.03) of the precursor form of MMP-9 (92 kDa). In contrast, in normal mucosa expression of the precursor form of MMP-9 (92 kDa) did not change after radiation, and no significant effect on the levels of pro MMP-2 (72 kDa) was observed. Preoperative high-dose radiotherapy leads to an increase in activity of type-IV collagenases in patients with resectable rectal cancer. Type-IV collagenase inhibition may be a useful therapeutic adjunct to radiotherapy in rectal cancer.

Adenocarcinoma↗
PubMed1999

Inhibition of tumour growth by marimastat in a human xenograft model of gastric cancer: relationship with levels of circulating CEA.

Inhibition of matrix metalloproteinases (MMPs) is an attractive approach to adjuvant therapy in the treatment of cancer. Marimastat is the first orally administered, synthetic MMP inhibitor to be evaluated, in this capacity, in the clinic. Measurement of the rate of change of circulating tumour antigens was used for evaluating biological activity and defining optimum dosage in the early clinical trials of marimastat. Although tumour antigen levels have been used in the clinical management of cancer for many years, they have not been validated as markers of disease progression. In order to investigate the relationship between the effects of marimastat on tumour growth and circulating tumour antigen levels, mice bearing the human gastric tumour, MGLVA1, were treated with marimastat. The MMP inhibitor exerted a significant therapeutic effect, reducing tumour growth rate by 48% (P = 0.0005), and increasing median survival from 19 to 30 days (P = 0.0001). In addition, carcinoembryonic antigen (CEA) levels were measured in serum samples from animals sacrificed at regular intervals, and correlated with excised tumour weight. It was shown that the natural log of the CEA concentration was linearly related to the natural log of the tumour weight and that treatment was not a significant factor in this relationship (P = 0.7). In conclusion, circulating CEA levels were not directly affected by marimastat, but did reflect tumour size. These results support the use of cancer antigens as markers of biological activity in early phase trials of non-cytotoxic anticancer agents.

Animals↗
PubMed1999

Experimental studies with Stronglyloides papillosus in goats.

Unusual clinical and pathological observations in the field in goats and sheep suffering from Strongyloides papillosus infection prompted experimental work on this parasite. Goats were infected percutaneously with either single or multiple, low or high levels of S. papillosus. Young goats up to 12 months of age were found to be the most susceptible. Some animals, however, showed substantial resistance to infective doses. Clinical signs included transient diarrhoea, misshapen, elongated faecal pellets terminally, dehydration, anorexia, cachexia, gnashing of teeth, foaming at the mouth, anaemia and nervous signs such as ataxia, a wide-based stance, stupor and nystagmus. A 'pushing syndrome' was seen in 22% of the animals. The pathological changes are described and included enteritis, status spongiosus in the brain, hepatosis leading to rupture of the liver, nephrosis, pulmonary oedema, interstitial pneumonia and pneumonia. About 6% of the goats died acutely from fatal hepatic rupture. The development of an acquired immunity was determined. The immunity elicited an allergic skin reaction at the application site of larvae or injection sites of larval metabolites. This immunity, however, could be breached by large doses of larvae. The most profound clinicopathological changes induced by the parasites were an anaemia (most pronounced in the young goats) and hypophosphataemia. Trace element analyses provided evidence of Cu, Mn and possibly Se deficiencies in some goats.

Animals↗
PubMed1998

Gelatinase (MMP-2 and -9) expression in gastrointestinal malignancy.

The aim of the study was to investigate expression of the active and inactive gelatinases (MMP-2 and -9) in colorectal neoplasia and gastric cancer compared with normal mucosa. A total of 53 colorectal cancers and corresponding normal mucosa were studied using gelatin zymography as well as 15 colorectal adenomas and 13 gastric cancers with corresponding normal mucosa. Overexpression of all the gelatinases occurs in both colorectal and gastric cancer, with activation of MMP-2 appearing to be a feature of the malignant phenotype. Overexpression of MMP-9 occurs in colorectal adenomas. The gelatinases are overexpressed in gastrointestinal neoplasia, suggesting that these enzymes may have an important role in tumour invasion and metastasis.

Adenoma↗
PubMed1997

Matrix metalloproteinases.

BACKGROUND: The matrix metalloproteinases (MMPs) have a role in gastrointestinal malignancy. This role is reviewed, with particular reference to the gelatinase subgroup of enzymes. METHODS: All relevant papers derived from the Medline and Enbase databases between 1984 and early 1996 were reviewed. RESULT AND CONCLUSION: There is now strong evidence that MMPs play a major role in tumour invasion and metastasis. The development of MMP inhibitors may lead to important new treatment for the control of malignant disease.

Clinical Trials as Topic↗