Expression of metalloproteases and their inhibitors in different histological types of breast cancer.

PURPOSE: Metalloproteases (MMPs) and their tissue inhibitors of metalloproteases (TIMPs) are involved in several key aspects of tumoral growth, invasion and metastasis. The purpose of this study was to characterize on how the different histological types of breast cancer differ in the expression of several components of this enzymatic system. METHODS: An immunohistochemical study was performed in 50 ductal, 23 lobular, 14 mucinous, 7 tubular, 4 papillary and 5 medullary invasive carcinomas, using tissue arrays and specific antibodies against 7 MMPs and 3 tisullar TIMPs. Staining results were categorized by means of a specific software program (score values). RESULTS: Carcinomas of the ductal type showed higher score values for MMPs and TIMPs than the other histological types; whereas mucinous carcinomas had lower scores values for expressions of the majority of these proteins. Stromal fibroblasts were more frequently positive for MMP-1, -7 and -13 and TIMP-1 and -3, when present in carcinomas of the ductal type than in other histological types of breast carcinomas. Stromal mononuclear inflammatory cells were more frequently positive for MMP-1 and TIMP-3, but more often negative for MMP-7, -9 and -11, when located in carcinomas of the ductal type than in other histological types of breast carcinomas. CONCLUSIONS: We found variations in MMP/TIMP expressions among the different histological subtypes of breast carcinomas suggesting differences in their tumor pathophysiology.

Clinical significance of epidermal growth factor receptor content in gastric cancer.

The objective of this work was to evaluate the epidermal growth factor receptor (EGFR) content in gastric cancer, its possible relationship with clinicopathological parameters of tumors and its prognostic significance. Membranous EGFR levels were examined by radioligand binding assays in 110 patients with gastric cancer. The mean follow-up period was 30.7 months. EGFR levels of tumors ranged widely, from 0.3 to 510 fmol/mg protein. EGFR levels were significantly higher (p<0.0005) in neoplastic tissue than in paired adjacent mucosa samples (median) (n= 84; 8.7 vs. 3.9 fmol/mg protein). Intratumoral EGFR levels were significantly correlated with tumor stage (p<0.05), and were higher in patients with stage III tumors (median) (7.6, 6.4, 12.3 and 7.5 fmol/mg protein for stages I, II, III and IV, respectively). In addition, the tumor/mucosa ratios of the EGFR content were significantly higher (p<0.05) in patients with stage III tumors (1, 1.8, 3.9, and 0.92, respectively). Although there was no significant relationship between EGFR levels of tumors and overall survival, the results suggest a role for EGFR in tumor progression of gastric cancer.

C-erbB-2 oncoprotein content in gastric cancer and in adjacent mucosa.

The aim of this study was to evaluate, by means of an immunoenzymatic assay, the membranous and cytosolic c-erbB-2 oncoprotein contents in primary tumors and in adjacent mucosa from gastric cancer patients. Fifty-two patients with primary gastric adenocarcinomas were enrolled in this prospective study. c-erbB-2 protein levels were significantly higher in membranous than in cytosolic samples, both in neoplastic tissues (median: 3602 vs 525 NHU/mg protein; p<0.0001) and in adjacent mucosa samples (median: 3174 vs 509 NHU/mg protein; p<0.0001). Nevertheless, there was a significant positive relation between membranous and cytosolic c-erbB-2 protein contents in both neoplastic tissue (p<0.001) and adjacent mucosa (p<0.001) samples. There was no significant difference in the membranous c-erbB-2 protein content between neoplastic tissues and adjacent mucosa samples. However, the cytosolic c-erbB-2 content was significantly higher in neoplastic tissues than in adjacent mucosa (p<0.05). Finally, the results did not show any significant correlations of these oncoprotein contents with patient characteristics, clinicopathologic parameters and overall survival of the study population.

Expression and prognostic significance of pepsinogen C in gastric carcinoma.

BACKGROUND: In this study we evaluated the expression and clinical significance of pepsinogen C, an aspartic proteinase involved in the digestion of proteins in the stomach, in patients with gastric cancer. METHODS: Pepsinogen C expression was examined by immunohistochemical methods in a series of 95 gastric carcinomas. The prognostic value of pepsinogen C was retrospectively evaluated by multivariate analysis taking into account conventional prognostic parameters. Follow-up period of patients was 21.4 months. RESULTS: A total of 25 (26.3%) gastric carcinomas stained positively for pepsinogen C. The percentage of pepsinogen C-positive tumors was higher in well-differentiated (50%) than in moderately differentiated (19.5%) and poorly differentiated (21.9%) tumors (P < .05). Similarly, significant differences in pepsinogen C immunostaining were found between node-negative and node-positive tumors (47.1% vs. 14.7%; P < .001). In addition, statistical analysis revealed that pepsinogen C expression was associated with clinical outcome in gastric cancer patients. Low pepsinogen C levels predicted short overall survival periods in the overall group of patients with gastric cancer (P < .001), and in 71 patients with resectable carcinomas (P < .005). Multivariate analysis according to Cox's model indicated that pepsinogen C immunostaining was an independent predictor of outcome for both overall and resectable gastric cancer patients (P < .05, for both). CONCLUSIONS: The expression of pepsinogen C in gastric cancer may represent a useful biological marker able to identify subgroups of patients with different clinical outcomes.

Tissue-type plasminogen activator (tPA) content in colorectal cancer and in surrounding mucosa: relationship with clinicopathologic parameters and prognostic significance.

The aim of this study was to evaluate the cytosolic tissue-type plasminogen activator (tPA) content in colorectal cancer, its possible relationship with the clinicopathologic parameters of tumors, and its prognostic significance. We have therefore examined by immunoenzymatic assay the cytosolic tPA content in tumors and paired surrounding normal mucosa samples from 162 colorectal cancer patients. Cytosolic tPA levels were significantly higher in surrounding normal mucosa samples than in neoplastic tissues (4.01 +/- 5.07 vs 2.63 +/- 5.82 ng/mg protein; p < 0.0001). By contrast, no significant correlation was found between tPA content and clinicopathologic tumor parameters such as location, Dukes' stage, histologic grade, and DNA content or S-phase fraction. However, the results indicated that a high cytosolic tPA content (> 0.75 ng/mg protein) in tumors predicted for a shorter relapse-free and overall survival (both p < 0.05) in 123 resectable colorectal cancer patients who were prospectively evaluated during a mean follow-up period of 32.2 months. This suggests that tPA may give additional information to that provided by other biochemical markers currently used in colorectal cancer.

Comparative study of carbohydrate antigen 195 and carcinoembryonic antigen for the diagnosis of pancreatic carcinoma.

The expression CA195 in serum, defined by monoclonal antibody CC3C195 (IgM), was studied in 67 patients with pancreatic cancer and in 138 patients with biliary or pancreatic benign disease. The results were compared with carcinoembryonic antigen (CEA) expression. The overall sensitivity of the CA195 assay (> 12 U/ml) was higher than that for CEA (89.5% vs. 53.7%) (p < 0.001). Sensitivity was increased to 92.5% with the simultaneous use of the two antigens, but the difference was statistically significant only with CEA (p < 0.001). The specificity of CA195 calculated from all patients with benign diseases was lower than that of CEA (73.1% vs. 89.8%). However, using a cutoff value of 100 U/ml for CA195, the specificity of this antigen (82%) was higher than that of CEA. These results demonstrate that marked elevations of tumor antigen CA195 are relatively specific for pancreatic carcinoma, and that this antigen is superior to CEA for diagnosing pancreatic cancer by virtue of its higher sensitivity.

Preoperative carbohydrate antigen 195 (CA195) and CEA serum levels as prognostic factors in patients with colorectal cancer.

We evaluated in 214 patients with primary colorectal cancer the prognostic value of the preoperative serum levels of CEA and CA195. For CEA these levels were above the cutoff of 6 ng/ml in 31.3% of patients, whereas for CA195 they were higher than 12 U/ml in 35.9% of patients. The simultaneous use of both antigens increased the sensitivity to 49%, which was significantly higher than that of CEA (p < 0.001) and CA195 (p < 0.01) taken singly. The mean preoperative CEA levels were significantly (p < 0.001) correlated with Dukes' stage only, while there was a significant correlation between preoperative serum levels of CA195 and Dukes' stage (p < 0.001), grade of differentiation (p < 0.01) and tumor location (p < 0.05). The results indicated that high preoperative serum levels of CEA and CA195 were associated with a shorter overall survival (p < 0.0001). In addition, separate Cox multivariate analysis showed that preoperative CA195 was, after Dukes' stage, the strongest factor to predict overall survival (p < 0.0001).