W. van Duijn

Matrix metalloproteinase-2 is a consistent prognostic factor in gastric cancer.

In a pioneer study, we showed 10 years ago that enhanced tissue levels of the matrix metalloproteinases (MMPs) MMP-2 and MMP-9 in gastric cancers, as determined by zymography, were related with worse overall survival of the patients. To corroborate these observations, we now assessed MMP-2 and MMP-9 with new techniques in an expanded group of gastric cancer patients (n=81) and included for comparison MMP-7, MMP-8 and the tissue inhibitors of MMPs, TIMP-1 and -2. All MMPs and TIMP-1 were significantly increased in tumour tissue compared to normal gastric mucosa. Matrix metalloproteinase-7, -8 and -9, and the TIMPs showed some correlations with the clinicopathologic parameters TNM, WHO and Laurén classification, but their levels were not related with survival. Regardless of the determination method used, that is, enzyme-linked immunosorbent assay or bioactivity assay, an enhanced tumour MMP-2 level did not show a significant correlation with any of the clinicopathological parameters, but was confirmed to be an independent prognostic factor in gastric cancer.

Value of Serology (ELISA and Immunoblotting) for the Diagnosis of Campylobacter pylori Infection

Fifty-two unselected patients referred to for upper gastrointestinal endoscopy were evaluated in several ways to determine the presence of Campylobacter pylori. Antibodies against this microorganism were measured to assess the value of serology for the diagnosis of C. pylori infection. Five antral biopsy specimens were taken in each patient for culture and bacteriological determinations, histology [morphology and Warthin-Starry (WS) staining] and the urease test (2, 3 and 24 h). Serum antibodies against a sonicate of 6 strains of microorganisms were assayed by enzyme-linked immunoassay (ELISA) and an immunoblotting technique. In 14 of the 52 patients the histology of the antrum was normal, 18 patients had chronic active gastritis and 20 had chronic gastritis without polymorphonuclear infiltration. In the group with normal histology, only 1 patient was positive for C. pylori with all methods, and 1 other subject was positive for IgG and 2 for IgA only with ELISA. In the group with chronic active gastritis, 14 were positive with all methods, 1 was negative by WS only and another was negative for IgA according to ELISA, WS and antibodies. Among the patients with chronic gastritis, 7 were positive and 7 negative with all tests; in the other 6 patients the results obtained with the various tests were divergent. Four serological tests were studied and validated against culture, WS and urease test which were considered to be the reference methods. The serological tests showed high sensitivity and specificity for the detection C. pylori-associated active chronic gastritis of the antrum, and can therefore serve as noninvasive methods to identify individuals with this condition.

Tissue level, activation and cellular localisation of TGF-β1 and association with survival in gastric cancer patients

Transforming growth factor-β1 (TGF-β1), a tumour suppressing as well as tumour-promoting cytokine, is stored as an extracellular matrix-bound latent complex. We examined TGF-β1 activation and localisation of TGF-β1 activity in gastric cancer. Gastric tumours showed increased stromal and epithelial total TGF-β1 staining by immunohistochemistry. Active TGF-β1 was present in malignant epithelial cells, but most strongly in smooth muscle actin expressing fibroblasts. Normal gastric mucosa from the same patient showed some staining for total, and little for active TGF-β1. Active TGF-β1 levels were determined by ELISA on tissue homogenates, confirming a strong increase in active TGF-β1 in tumours compared to corresponding normal mucosa. Moreover, high tumour TGF-β1 activity levels were significantly associated with clinical parameters, including worse survival of the patients. Total and active TGF-β1 levels were not correlated, suggesting a specific activation process. Of the different proteases tested, active TGF-β1 levels were only correlated with urokinase activity levels. The correlation with urokinase activity suggests a role for plasmin in TGF-β1 activation in the tumour microenvironment, resulting in transformation of resident fibroblasts to tumour promoting myofibroblasts. In conclusion we have shown localisation and clinical relevance of TGF-β1 activity levels in gastric cancer.

MMP-2 geno-phenotype is prognostic for colorectal cancer survival, whereas MMP-9 is not

The prognostic significance of single-nucleotide polymorphisms (SNPs) and tumour protein levels of MMP-2 and MMP-9 was evaluated in 215 colorectal cancer patients. Single-nucleotide polymorphism MMP-2−1306T and high MMP-2 levels were significantly associated with worse survival. Extreme tumour MMP-9 levels were associated with poor prognosis but SNP MMP-9−1562C>T was not. Tumour MMP levels were not determined by their SNP genotypes.

MMP-2 and MMP-9 in normal mucosa are independently associated with outcome of colorectal cancer patients.

Background:Upregulation of the matrix metalloproteinases MMP-2 and MMP-9 in various cancers has been associated with worse survival of the patients.Methods:We assessed MMP-2 and MMP-9 levels in normal colorectal mucosa from colorectal cancer patients in relation to the course of the disease.Results:A high protein expression of MMP-2 as well as MMP-9 in normal mucosa was found to be correlated with worse 5-year survival. The combination of both parameters was an even stronger prognostic factor. These protein levels were found not to be related to the corresponding single nucleotide polymorphisms of MMP-2 (−1306C>T) and MMP-9 (−1562C>T). Multivariate analyses indicated that the MMP-2 and MMP-9 levels in normal mucosa are prognostic for survival, independent of TNM classification.Conclusion:MMP-2 and MMP-9 levels in normal mucosa are indicative of the course of disease in colorectal cancer patients.

Negative Humoral Response to Adenovirus 12 in Coeliac Disease

It has been suggested that an encounter of the immune system with antigenic determinants produced during intestinal Ad12 viral infection may be important in the pathogenesis of coeliac disease (CD).