Noriko Oda

Expression of osteoprotegerin correlates with aggressiveness and poor prognosis of gastric carcinoma.

Osteoprotegerin (OPG), identical with osteoclastogenesis inhibitory factor, is a member of a subgroup of the tumor necrosis factor (TNF)-receptor superfamily, which functions as a soluble decoy receptor. It has been reported that OPG expression is associated with bone metastasis of cancer of the breast and prostate. In the present study, we examined the expression of OPG in gastric carcinomas using immunohistochemistry and reverse-transcription polymerase chain reaction methods, and compared with clinicopathological parameters. The expression of OPG mRNA was confirmed in a gastric carcinoma cell line (MKN-7) and gastric carcinoma tissues. Immunohistochemically, strongly positive staining of OPG was found in 65% (67/103) of gastric carcinomas, whereas OPG protein was not detected in non-neoplastic mucosal epithelia. The expression of OPG protein in gastric carcinoma tissues correlates significantly with depth of tumor invasion, nodal metastases and advanced tumor stage. Furthermore, the prognosis of the cases with strong OPG expression was significantly worse than those with weak or no expression of OPG. These results suggest that OPG may participate in stomach carcinogenesis, invasion and metastasis, and may serve as a novel molecular marker for aggressive gastric cancer.

Tubular adenoma of the human stomach. An immunohistochemical analysis of gut hormones, serotonin, carcinoembryonic antigen, secretory component, and lysozyme.

A total of 49 gastric tubular adenomas and 6 tubular adenomas with foci of adenocarcinoma from surgically resected stomachs were examined histologically and immunohistochemically for gut peptide hormones, serotonin, Carcinoembryonic antigen (CEA), secretory component (SC), and lysozyme. A variety of endocrine cells were detected in tubular adenoma with mild to moderate atypia. Both the frequency and distribution density were highest for serotonin‐containing EC cells, often showing hyperplasia, followed by glicentin‐containing L cells, somatostatin‐containing D cells and motilin‐containing Mo cells in the order given. Adenoma cells with SC immunoreactivity were more dominant than those with CEA immunoreactivity. In tubular adenoma with severe atypia, endocrine cells were markedly decreased, whereas adenoma cells with CEA immunoreactivity were increased. The distribution density of lysozyme‐containing cells in tubular adenoma of the intermediate zone and fundus was significantly higher than that of the antrum. In the subjacent mucosa of the adenoma, L cells and SC‐positive epithelial cells were detected in 24 and 33 cases, respectively. These findings suggest that gastric tubular adenoma develops from intestinal metaplasia. In addition, gastric tubular adenoma showed a tendency to lose various intestinal markers with increase of histologic atypicality.

DNA ploidy pattern and amplification of ERBB and ERBB2 genes in human gastric carcinomas

SummaryThe DNA ploidy pattern and amplification of ERBB and ERBB2 genes were examined in paraffinembedded tissue from gastric carcinomas using flow cytometry and a slot-blot hybridization technique. The incidence of aneuploidy in well differentiated adenocarcinomas (56%) was significantly higher (p<0.05) than that in poorly differentiated adenocarcinomas (21%). The DNA ploidy pattern was not remarkably different between the primary tumors and metastatic deposits in lymph nodes. Of the nine specimens having an aneuploid stem cell line in the primary tumor and/or in metastases, three showed ERBB2 gene amplification and one showed ERBB gene amplification. The incidence of epidermal growth factor (EGF) immunoreactivity in tumor cells showed no difference between diploid and aneuploid tumors. These findings indicate that aneuploidy is frequently associated with amplification of ERBB and ERBB2 genes.

Expression of Cbl linking with the epidermal growth factor receptor system is associated with tumor progression and poor prognosis of human gastric carcinoma

Cbl proteins play important roles in downregulation of growth factor receptors by acting as ubiquitin ligases and multi-adapter proteins. Ligand-induced desensitization of the epidermal growth factor receptor (EGFR) has been shown to be controlled by Cbl. In the present study, we examined the expression of Cbl in gastric carcinomas and studied the correlation of Cbl expression with clinicopathological characteristics as well as EGFR expression. Cbl protein was expressed in 67% (82/122) of gastric carcinomas, and diffuse expression of Cbl was detected in 29% (35/122) of the cases. The incidence of cases with diffuse expression of Cbl was significantly higher in advanced cases (28/70, 40%) than in early cases (7/52, 14%) (P=0.0010). Diffuse expression of Cbl was significantly associated with metastasis of tumor cells in lymph nodes (P=0.0318). Diffuse expression of EGFR was significantly associated with depth of invasion (P=0.0057), lymph-node metastasis (P=0.0371) and tumor stages (P=0.0278). As the grades of Cbl expression became stronger, the cases with diffuse EGFR expression increased, the positive correlation being significant (P=0.049). All the cases with diffuse expression of Cbl and EGFR were found to show nodal metastasis and to be at an advanced stage. Moreover, the prognosis of the patients with synchronous diffuse expression of Cbl and EGFR was significantly poorer than that of the patients negative for Cbl and focal or negative for EGFR (P=0.0086). The expression of Cbl protein was clearly induced in gastric carcinoma cell lines by transforming growth factor-α treatment. These results suggest that Cbl in connection with the EGFR system may be associated with stomach carcinogenesis, invasion and metastasis. Cbl may serve as a novel molecular marker for aggressive gastric carcinoma.

Serotonin in tubular adenomas, adenocarcinomas and endocrine tumours of the stomach. An immunohistochemical study.

Serotonin was examined immunohistochemically in seven tubular adenomas, 194 adenocarcinomas and 41 endocrine cell tumours of the stomach. In tubular adenomas, serotonin-containing cells showing argentaffinity were present in the lower portion of the adenomatous glands and were considered to be an expression of intestinal character. Scattered serotonin-containing tumour cells were found in 60 (30.9%) of 194 adenocarcinomas regardless of their histological type. Cell fusions between carcinoma and enterochromaffin (EC) cells might be a possible mechanism for the occurrence of serotonin-containing cells within the tumour. In 17 (54.8%) of 31 endocrine cell carcinomas, serotonin-containing tumour cells were observed in a variable degree in contrast to the absence of these cells in classical carcinoid. Moreover, diffuse serotonin reactivity was found in four cases of scirrhous endocrine cell carcinoma. The histogenesis and the occurrence of serotonin-containing cells in each type of gastric tumour is also discussed.

Effect of epidermal growth factor on rat stomach carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine.

The effect of epidermal growth factor (EGF) on rat stomach carcinogenesis induced by N‐methyl‐N′‐nitro‐N‐nitro‐soguanidine (MNNG) was studied. Male Wistar rats given MNNG for 30 weeks in drinking water (80 μg/ml) were treated with S.C. injections of human EGF (10 μg/kg, once daily) at various stages of the carcinogenesis. Four (30.8%) out of 13 rats treated with EGF immediately after cessation of the MNNG treatment had stomach tumors including one adenocarcinoma, one adenoma and two carcinoids. No stomach tumor was found in rats treated with MNNG alone or in those treated with MNNG and EGF for different periods such as synchronously for 10 weeks, for 30 weeks or throughout the experiment. These findings suggest a possible enhancing effect of EGF on stomach carcinogenesis in rats. Acta Pathol Jpn 40: 165‐171, 1990.

EXPRESSION OF Ha-ras ONCOGENE PRODUCT IN RAT GASTROINTESTINAL CARCINOMAS INDUCED BY CHEMICAL CARCINOGENS

The expression of Haras oncogene product in rat gastrointestinal carcinomas induced by N‐methyl‐N‐nitro‐N‐nitrosoguanidine (MNNG) or 1, 2‐dimethylhydrazine (DMH) was studied by Western blotting and immunohistochemistry using anti‐Haras p 21 oncoprotein antibody. In Western blotting, high levels of c‐Haras p 21 were found in serially transplantable rat duodenal carcinomas induced by MNNG and rat colon carcinomas induced by DMH. mmunohistochemically, c‐Haras p21 immunoreactivity was detected in 3 (16.7%) of 17 MNNG‐induced stomach carcinomas and in 21 (63.6%) of 33 DMH‐induced colon carcinomas, respectively. In the colon carcinomas, c‐Ha‐ras p 21 immunoreactivity in deeply invasive tumors was stronger than that in superficially invasive tumors and was expressed in all subserosal tumors. Moreover, all of the metastatic colon carcinomas had c‐Ha‐ ras p 21 immuno‐reactive tumor cells. These findings suggest that c‐Ha‐ ras p21 expression plays an important role in tumor proliferation, invasion and metastasis of DMH‐induced colon carcinoma. ACTA PATHOL. JPN. 37: 1731–1741, 1987.

Histopathological observation of the heart with diffuse and abnormal proliferation of mitochondria in myocardial cells (mitochondrial cardiomyopathy): Report of an adult case

SummaryAn autopsy case of idiopathic dilated cardiomyopathy with abnormal proliferation of mitochondria in the myocardial cells is reported. The case is that of a 39-year-old male with congestive heart failure. The heart was 700 g and showed marked dilatation of all cardiac chambers with myocardial fibrosis of the left ventricular myocardium and interventricular septum, especially in the basal portion of the left ventricular posterior wall. Myocardial cells were hypertrophied with a marked increase of fine-granular sarcoplasm, containing numerous mitochondria, seen by electron microscopy. The mitochondria were usually round or oval and ranged in size from 0.3 to 1.2 µm in diameter. The cristae of these mitochondria frequently showed a concentric lamellar or reticular configuration. Myofibrils were unusually scarce, but the sarcomere structure and arrangement of myofilaments were well-preserved. Epicardial and intramural coronary vessels were almost normal. From these findings, we consider this to be an adult case of mitochondrial cardiomyopathy.