Yutaka Kohgo

Clonality and field cancerization in intraductal papillary-mucinous tumors of the pancreas

Multiple lesions of intraductal papillary‐mucinous tumor of the pancreas (IPMT) in the same pancreas often are encountered. To elucidate field (multicentric) cancerization and clonality of IPMT, clonal analyses of IPMT and its precursor lesion of ductal hyperplasia were performed. K‐ras codon 12 mutations and X‐chromosome inactivation of human androgen receptor gene (HUMARA) were investigated.

Reduced expression of syndecan-1 affects metastatic potential and clinical outcome in patients with colorectal cancer.

Syndecan‐1 is a transmembrane heparansulfate proteoglycan which regulates cell‐to‐cell or cell‐to‐extracellular matrix interactions and may influence malignant cell behavior. We investigated the alterations of syndecan‐1 expressions in colorectal cancers and analyzed the relationship between histological and clinical characteristics. Syndecan‐1 protein expression in colorectal cancer tissues was investigated with immunohistochemical staining of resected specimens. In situ hybridization was performed using syndecan‐1 riboprobe to confirm the transcriptional signals. Syndecan‐1 mRNA expression in cancer cell lines cultured with or without methylation inhibitor was also analyzed by quantitative PCR. Out of 105 specimens tested, less than 25% of tumor cells were stained with anti‐syndecan‐1 monoclonal antibody in 36 (34.3%). In situ hybridization showed a similar staining profile to that of immunohistochemistry. Syndecan‐1 mRNA expression was increased by the methylation inhibitor 5‐aza‐2′‐deoxycytidine, suggesting that the hypermethylation is involved in the suppression of syndecan‐1 expression. Clinically, the incidence of metastasis to lymphnode or liver in patients with syndecan‐1‐negative tumors was significantly high. Among Tl colorectal cancers displaying a primary invasive phase, lymphnode metastasis, undifferentiated characters and ‘budding’ of cancer cells were more common in syndecan‐1‐negative tumors. The survival rate in patients with syndecan‐1‐negative tumors was decreased significantly in a stage‐independent manner. These results suggest that the reduction of syndecan‐1 expression in colorectal cancer cells, which is supposed to be regulated at the transcription level, is closely related to invasive character. The evaluation of syndecan‐1 expression in colorectal cancer may allow prediction of patients survival after surgery

Effect of Ecabet Sodium Enema on mildly to moderately active ulcerative proctosigmoiditis: an open-label study

OBJECTIVES:Ecabet sodium (ES), a nonabsorbable antigastric ulcer agent, has been shown to adhere to the region of an ulcer. It topically enhances gastric mucosal defensive factors such as the endogenous prostaglandins, capsaicin-sensitive sensory nerves, nitric oxide, and mucin. All of these mucosal defensive factors play an important role in maintaining the mucosal integrity of the colon and rectum. Therefore, we investigated the effect of ES in patients with mildly to moderately active ulcerative proctosigmoiditis.METHODS:In an open-label study, seven patients with mildly to moderately active ulcerative colitis (UC) who had an inflamed mucosa in the rectum and/or sigmoid and were resistant to 4-wk topical and systemic standard treatment were treated with an ES enema b.i.d. for 14 days. The enema consisted of ES (1 g) and tepid water (20 or 50 ml). These patients were assessed by the Clinical Activity Index, colonoscopically, and histologically before and after the ES therapy. The ES therapy was started after obtaining informed consent from the patients.RESULTS:Six of the seven patients responded to therapy and achieved clinical, endoscopic, and histological remissions. One patient was withdrawn because of increased stool frequency. All six patients who completed the study showed a significant change in the mean Clinical Activity Index score from 5.3 ± 1.4 (mean ± SD) to 0.5 ± 0.8 (p < 0.05), in the colonoscopic score from 3.0 ± 0.9 to 0.8 ± 0.4 (p < 0.05), and in the histological score from 2.7 ± 0.5 to 0.5 ± 0.6 (p < 0.05), and achieved remission at the end of the study. There were no side effects attributable to the ES therapy. Five of the six patients are still in clinical remission after a median follow-up period of 5 months.CONCLUSIONS:The ES enemas proved to be a safe and potentially useful adjuvant therapy currently available for treating patients with mildly to moderately active ulcerative proctosigmoiditis. A controlled study is necessary to confirm our results.

Expression of syndecan-1 is common in human lung cancers independent of expression of epidermal growth factor receptor

In order to determine syndecan-1 expression in lung cancer, we examined 115 lung cancer specimens and 17 lung cancer cell lines. Syndecan-1 was immunohistochemically stained with a polyclonal antibody in 115 paraffin-embedded specimens; 84 cases out of 97 non-small cell lung cancer (NSCLC) and eight cases out of 18 small cell lung cancer (SCLC) were positively stained. Simultaneously, epidermal growth-factor receptor (EGFR) was stained; 47 cases out of 97 NSCLC and one case of 18 SCLC were positively stained. No significant correlation was shown between EGFR and syndecan-1 expression (P=0.68). Syndecan-1 mRNA was detectable in 16 of 17 lung cancer cell lines and EGFR mRNA in nine of 17. Eight cell lines had syndecan-1 mRNA as well as EGFR mRNA. PR-39 (1 microM) and 80 pM transforming growth factor-beta(1) (TGF-beta(1)), did not increase expressions of syndecan-1 mRNA and EGFR in five lung cancer cell lines. We concluded that lung cancer had detectable syndecan-1; however, expression of syndecan-1 protein did not correlate with survival time of lung cancer patients.

AKT activation up-regulates insulin-like growth factor-I receptor expression and promotes invasiveness of human pancreatic cancer cells

Insulin-like growth factor I receptor (IGF-IR) is frequently overexpressed in several types of human malignancy and is associated with invasion and metastasis of tumor cells. Recently, IGF-IR expression was reported to be up-regulated in the human pancreatic cancer cell line PANC-1 when cells were stably transfected with active Src. The downstream targets of Src that lead to the up-regulation of IGF-IR expression were previously unknown. We demonstrate here that AKT regulates IGF-IR expression in PANC-1 and AsPC-1 cells. Cells transfected with active Src exhibited significantly more IGF-IR protein compared with vector-transfected cells. Overexpression of wild-type or constitutively active AKT (i.e., AKT1 or AKT2) also resulted in elevated IGF-IR expression. IGF-IR protein levels were higher in cells transfected with constitutively active AKT than in cells transfected with active Src. In vitro kinase assays showed that AKT kinases are activated by active Src and inhibited by dominant negative Src or the tumor suppressor PTEN. Furthermore, AKT-induced IGF-IR expression was down-regulated by dominant-negative Src or PTEN. In addition, cells transfected with activated AKT in the presence of IGF-I were shown to have enhanced invasiveness compared with control cells. These data provide evidence for a link between AKT signaling and the regulation of IGF-IR expression and demonstrate that active AKT promotes the invasiveness of pancreatic cancer cells through the up-regulation of IGF-IR expression.