Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a presumed activator of MMP2, which is one of the major proteinases in tumor cell invasion. In this study, we determined the clinico-pathologic significance of MT1-MMP expression in 68 human gastric carcinomas. The tumor-normal ratio (T/N ratio) of MT1-MMP expression was determined by reverse transcription-polymerase chain reaction analysis. To visualize the localization of MT1-MMP, an immunohistochemical study was performed. In addition, a gelatin zymography was done to examine the activation ratio of MMP2, and a correlation between MT1-MMP expression and activation of MMP2 was studied. The expression of MT1-MMP mRNA was higher in tumor tissue than in corresponding normal tissue in most cases. The mean value of the T/N ratio was 4.8. Twenty cases with T/N H 4.8 showed significantly deeper invasion and higher frequency of lymph node metastasis than 48 cases with T/N F 4.8. MT1-MMP expression was an independent factor influencing both tumor invasion of the gastric wall and lymph node metastasis. Although MT1-MMP expression was not an independent prognostic factor, the patients with T/N H 4.8 showed a significantly worse prognosis than those with T/N Cancer cell metastasis to distant organs is the major cause of death in cancer patients. Metastasis is a multi-step process, and the initial step is considered to be the invasion of surrounding stromal tissue by cancer cells. Matrix metalloproteinases (MMPs), which contain a zinc atom in a highly conserved active site, are chiefly responsible for this step, and they are frequently overexpressed in a variety of tumors (Davies et al., 1993;Emmert-Buck et al., 1994;Mori et al., 1995a;Sato H. et al., 1992).Overexpression of MMPs in tumor tissues themselves does not mean actual function of the enzymes, since several of these are secreted as latent pro-enzymes that need modification or removal of the aminoterminal domain for the expression of activity (Cao et al., 1995;Emonard et al., 1992;Sato et al., 1994). Of 12 MMPs so far identified, MMP2 (gelatinase A) and MMP9 (gelatinase B) are believed to play a major role in tumor invasion by degradation of type IV collagen, which is the main component of the extracellular matrix (Cao et al., 1995;Emonard et al., 1992). MMP9 is activated by other proteases such as trypsin, stromelysin or collagenase. On the other hand, MMP2 has been shown to be activated by membrane-type 1 MMP (MT1-MMP), which possesses a functional transmembrane domain (Sato et al., 1994). To our knowledge, 4 MT-MMPs have been reported at present (Puente et al., 1996;Sato et al., 1994;Takino et al., 1995;Will and Hinzmann, 1995). These 4 enzymes have similar molecular structures, and 2 of these activate pro-MMP2. The first MT1-MMP discovered, which was described as MT1-MMP-1, is the focus of our study.Overexpression of MT1-MMP has been observed in cervical cancers and lung cancers as being associated with invasiveness of the cancer cells, probably via activation of MMP2 (Gilles et al., 1996;Tokuraku et al., 19...

ObjectiveThe human genes MAGE-1 and -3 encode tumor-specific peptide antigens, which are recognized by autologous cytotoxic T lymphocytes. The antigens coded by those genes may be useful for cancer immunotherapy. There is, however, little information on the expression of these genes in human colorectal carcinomas. MethodThe expression of MAGE-1, -2, and -3 genes in 54 pairs of tumor and corresponding normal tissue specimens of the colorectum was determined by means of reverse transcription polymerase chain reaction. The induction of MAGE-1, -2, -3, and -4 gene expression in eight colorectal carcinoma cell lines also was examined by use of a demethylating agent, 5-Aza-2'-deoxycytidine (DAC). ResultsThe expression of MAGE genes was not recognized in normal colorectal tissues at all. In tumor tissue specimens, the expression of MAGE-1, -2, and -3 was recognized in 16 (30%), 15 (28%), and 11 (20%) patients, respectively. The expression was seen frequently in patients with liver metastasis (p < 0.01). Although MAGE-1 or -3 genes were not induced by DAC, MAGE-2 or -4 genes were induced in three of four MAGE-2 negative cell lines or three of seven MAGE-4 negative cell lines, respectively. ConclusionsThe MAGE genes were expressed exclusively in tumor tissues of one third of patients with colorectal carcinoma. The identification of such tumor rejection antigens is considered to uncover a new possibility for the specific immunotherapy of colorectal carcinoma. The demethylating agent may increase the number of patients who might be candidates for MAGE-specific immunotherapy.183

From 1988 to 1990, 53 patients with squamous cell carcinoma of the thoracic oesophagus underwent subtotal oesophagectomy after either preoperative hyperthermo-chemoradiotherapy (HCR therapy) or chemoradiotherapy without hyperthermia (CR therapy), in a prospective randomized trial carried out to examine the effects of hyperthermia given preoperatively. The two groups (27 patients given HCR therapy and 26 given CR therapy) were found to be comparable with regard to prognostic factors of age, site of carcinoma, TNM stage, etc. Following preoperative evaluation by an upper GI series and endoscopy, a subtotal oesophagectomy was done for all 53 patients. All the resected specimens, including the lymph nodes, were histopathologically examined, and the effects of preoperative treatment were evaluated by findings in the upper GI series and endoscopy, as well as based on the histopathology of the excised tissues. There were no viable cancer cells in the resected specimens of seven patients in the HCR therapy group (26.9%) and of two patients in the CR therapy group (7.7%). In addition, no hyperthermia complications were observed. The study suggests that preoperative HCR therapy may be a more beneficial therapy than preoperative CR therapy in patients with squamous cell carcinoma of the oesophagus who undergo a subtotal oesophagectomy.

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Recent studies have shown that microsatellite instability (MSI) may play an important role in the development of various types of cancer. However, there have been only 2 reports describing MSI in esophageal carcinoma and the clinicopathologic significance of MSI in this malignancy has not yet been clarified. To better elucidate the role of genetic instability in the development of esophageal carcinoma, we investigated the presence of MSI in 32 cases of esophageal cancer using paired samples of fresh frozen tumor and normal tissue by a method based on the polymerase chain reaction. MSI was defined as occurring in tumors which showed altered banding patterns at one or more microsatellite loci. The incidence of MSI in esophageal carcinoma was 6 out of 32 patients. MSI was observed more frequently in cases with small-cell carcinoma (2 out of 2) than in cases with squamous-cell carcinoma (4 out of 29). No cases with adenocarcinoma or Barrett's metaplasia were included in our series. No significant correlations between MSI and other clinicopathologic parameters were observed. The present study suggests that (1) some Japanese esophageal carcinomas certainly correlate with DNA replication error, and (2) MSI may be more frequent in small-cell carcinoma of the esophagus than in squamous-cell carcinoma of the esophagus.