ABSTRACT
BACKGROUND: Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), are expressed in the gastrointestinal tract by different cellular types. Nevertheless, the imbalance between MMPs and TIMPs plays an important role in the physiopathology of diverse intestinal inflammatory processes. METHODS: An immunohistochemical study was performed using tissue arrays and specific antibodies against MMPs -1, -2, -7, -9, -11, -13, -14, and TIMPs -1, -2 and -3. Immunohistochemical staining of intestinal samples from surgical interventions from 30 patients with complicated Crohn's disease (CD) and 25 patients with diverticulitis were performed at the inflamed mucosa and in adjacent noninflamed mucosa. A reverse-transcription polymerase chain reaction (RT-PCR) analysis was performed to confirm the results obtained by immunohistochemistry. In addition, western blot experiments were carried out. RESULTS: CD inflamed mucosa showed higher global expression of MMP-2, MMP-9, and MMP-13 than diverticulitis inflamed mucosa. However, inflamed and noninflamed diverticulitis mucosal samples showed higher global expression of MMP-1, TIMP-1, and 3 than the CD samples. Epithelial cells of inflamed mucosa showed higher expression of MMP-2, 9, and 13 in CD than diverticulitis. However, the latter showed higher expression of TIMP-1. Similar differences for fibroblast-like cells and mononuclear inflammatory cells were found. CD samples presented an increased expression of MMPs and a decreased expression of TIMPs compared to diverticulitis. CONCLUSIONS: These results indicate a differential pattern of expression of MMPs and TIMPs in CD and diverticulitis and the necessity to study the potential role of MMP inhibitors as new protective agents in both diseases.
Subject(s)
Crohn Disease/metabolism , Crohn Disease/surgery , Diverticulitis/complications , Diverticulitis/metabolism , Matrix Metalloproteinases/metabolism , Tissue Inhibitor of Metalloproteinases/metabolism , Adult , Blotting, Western , Colon/metabolism , Crohn Disease/genetics , Diverticulitis/genetics , Female , Humans , Image Processing, Computer-Assisted , Immunoenzyme Techniques , Intestinal Mucosa/metabolism , Male , Matrix Metalloproteinases/genetics , Middle Aged , Prognosis , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Tissue Array Analysis , Tissue Inhibitor of Metalloproteinases/geneticsABSTRACT
Studies on metastasic lesions from human carcinomas are scarce. Therefore there is a need for such studies to identify the expression of the biological factors that will help in the assessment of the natural history of breast cancer. Here an immunohistochemical study was performed using tissue arrays and specific antibodies against matrix metalloproteinases (MMPs)-1, 2, 7, 9, 11, 13, 14 and tissue inhibitors of metalloproteases (TIMPs)-1, 2 and 3 in 39 patients with breast cancer. Specimens from 39 patients with node-positive carcinomas were examined and the analysis was performed at the central core of the tumour, at the invasive front, and in the metastasic axillary lymph nodes (MALNs). Global expression of MMP-1, 7 and 14, TIMP-1, and 3, were significantly higher at the centre of the tumour compared with the invasive front or the MALNs. Significantly higher expression of MMP-7 and 14, and TIMP-3, by fibroblast-like cells and mononuclear inflammatory cells (MICs) was seen in MALNs. In addition, in the tumour centre, the expression of MMP-11 and TIMP-1 and 2 by MICs, as well as TIMP-2 expression by fibroblast-like cells, were associated significantly with the occurrence of distant metastasis. In contrast, TIMP-3 expression by tumour cells or by fibroblast-like cells in this same tumour locations, as well as TIMP-1 expression by fibroblast-like cells at the invasive front, were associated significantly with poor prognosis. However, the expression of all of these biological factors in MALNs was not associated with the development of distant metastasis. Our data suggest that there is prognostic relevance to the expression of MMPs and TIMPs in the stromal cells of primary tumours, rather than to the expression of these enzymes in MALNs.
Subject(s)
Breast Neoplasms/enzymology , Carcinoma, Ductal, Breast/enzymology , Lymph Nodes/enzymology , Matrix Metalloproteinases, Secreted/analysis , Tissue Inhibitor of Metalloproteinases/analysis , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Carcinoma, Ductal, Breast/mortality , Carcinoma, Ductal, Breast/secondary , Carcinoma, Ductal, Breast/therapy , Cluster Analysis , Disease-Free Survival , Female , Humans , Lymph Nodes/pathology , Lymphatic Metastasis , Middle Aged , Neoplasm Invasiveness , Neoplasm Staging , Proportional Hazards Models , Risk Assessment , Risk Factors , Stromal Cells/enzymology , Survival Analysis , Time Factors , Treatment OutcomeABSTRACT
AIMS: To evaluate hyaluronan expression at different stages of tumoral progression in primary breast cancer. METHODS: Hyaluronan expression was evaluated by histochemical techniques in 42 cases of pure DCIS, in 15 cases of DCIS with a microinvasive component, and in 32 cases of invasive ductal carcinoma of the breast. Staining results were evaluated by calculating the percentage of stained areas by means of a specific software program. RESULTS: Our results show higher values of hyaluronan expression in invasive breast carcinomas [median of percentage of stained areas 41.1 (range 8-69.2)] and in DCIS with a microinvasive component [48.6 (16.8-62.8)] than in pure DCIS [14.5 (1-44.4)] (p < 0.001, for both). CONCLUSIONS: Our study indicates a proportionally higher area of hyaluronan expression in DCIS with a microinvasive component than in pure DCIS, suggesting a key role of this glycosaminoglycan in the early invasive phase of breast carcinomas. Thus, hyaluronan could play an important function in determining the migratory phenotype of cancer cells. Larger size tumors appear to demonstrate an intricate balance between hyaluronan synthesis and degradation, thus conditioning intratumoral heterogeneity in the hyaluronan metabolism.
Subject(s)
Breast Neoplasms/metabolism , Carcinoma, Intraductal, Noninfiltrating/metabolism , Hyaluronic Acid/metabolism , Breast Neoplasms/pathology , Carcinoma, Intraductal, Noninfiltrating/pathology , Disease Progression , Female , Humans , Middle Aged , Neoplasm InvasivenessABSTRACT
BACKGROUND AND AIMS: Cathepsin D (Cath-D) is an aspartyl protease involved in protein catabolism and tissue remodelling. In the present article, we evaluate the tumor content of Cath-D in resectable gastric carcinomas and its relation with clinical and pathological parameters, as well as its prognostic significance. METHOD: This prospective study included a series of 60 patients with primary gastric adenocarcinoma, who first underwent a complete surgical resection of their tumors and then were evaluated for disease recurrence and survival status during a mean follow-up period of 41.5 months. Cath D was measured in cytosolic samples using an immune-radiometric assay which determined the total amount of Cath-D (52K, 48K, and 34K). RESULTS: The tumor content of Cath-D ranged from 4 to 247 pmol/mg protein and from 6.4 to 97.7 pmol/mg protein in adjacent non-neoplastic mucosa samples. Cytosolic Cath-D levels were significantly higher in neoplastic tissues (P < 0.001). Statistical analysis also demonstrated that younger patients showed lower Cath-D tumor levels than older ones. Likewise, patients with lower tumor levels of Cath-D had better survival than those with intermediate or high Cath-D tumor content (P = 0.002). This finding showed an independent prognostic value on survival (P = 0.02). CONCLUSIONS: The present study demonstrates the presence of higher Cath-D content in gastric carcinomas than in adjacent non-neoplastic mucosa, and that high intratumor Cath-D levels identify a subgroup of resectable gastric cancer patients with a high probability of relapse as well as worse survival.
