Tatsuhiko Sako

4-[3,5-Bis(trimethylsilyl)benzamido] benzoic acid inhibits angiogenesis in colon cancer through reduced expression of vascular endothelial growth factor.

4-[3,5-bis(trimethylsilyl)benzamido] Benzoic acid (TAC-101) has potent antiproliferative, antiangiogenic, and antitumor effects in vitro and in vivo. These effects might be due to TAC-101 binding to retinoic acid receptor alpha (RAR-alpha) and interfering with the binding of activator protein-1 (AP-1) to DNA. However, little is known about the detailed mechanism of TAC-101 function. We investigated the mechanism of the antiangiogenic effect of TAC-101 using a rat hepatic metastatic model in vivo and DLD-1 human colon cancer cells in vitro. Liver metastases were induced by portal injection of RCN-9 rat colonic cancer cells into F344 rats. TAC-101 (8 mg/kg) was orally administered 5 days per week for 4 weeks and then hepatic tumors were immunohistochemically evaluated for microvessel density (MVD) and vascular endothelial growth factor (VEGF). TAC-101 significantly reduced both MVD and VEGF expression. Northern blot analysis and ELISA indicated that TAC-101 efficiently inhibited production of VEGF mRNA and protein in DLD-1 cells in a time- and dose-dependent manner. These findings suggest that TAC-101 may inhibit progression and metastasis in colon cancer by interfering with tumor production of VEGF.

Alterative expression of the collagenase and adhesion molecules in the highly metastatic clones of human colonic cancer cell lines

Human colonic carcinoma cell lines, KM12C, KM12SM and KM12L4, were previously established and their in vivo metastatic potentials have been well evaluated. The highly metastatic cell lines KM12SM and KM12L4 were derived from the parental low metastatic cell line KM12C in vivo. To evaluate the metastatic behavior of these cell lines in vitro, we examined colony formation on monolayers of the pulmonary arterial endothe-lial (CPAE) cells. On day 4, the highly metastatic cell lines showed an approximately 2-fold increase in number of colonies on CPAE cell monolayers relative to the parental KM12C cell line. To investigate what evidence is correlated with their metastatic and invasive abilities, Northern blot analysis and flow cytom-etry were performed in all cell lines. According to the results of Northern blot analysis, the levels of matrix metalloproteinase (MMP)-2 and c-met mRNA expression were increased in highly metastatic cell lines as compared with the parental cell line. We also examined the cell-surface expression of several adhesion mole-cules by flow cytometry. The levels of expression of sialyl Lewis a antigen (sLe a ) in KM12SM and KM12L4 were twice higher than that in KM12C. However, the levels of expression of E-cadherin in KM12SM and KM12L4 were decreased to half that in KM12C. The alterative expression of the collagenase and adhesion molecules might contribute to their metastatic/invasive abilities of these cell lines both in vivo and in vitro.

Lymphoepithelioma-Like Carcinoma of the Stomach with Epithelioid Granulomas.

An 83-year-old Japanese man was admitted to our hospital for gastric adenocarcinoma mimicking a submucosal tumor in the gastric body. Considering his general condition, partial resection of the stomach and dissection of regional lymph nodes were performed; a dome-shaped tumor that was largely covered by normal mucosa and having a shallow central stellate ulcer was removed. Histopathologically, the carcinoma cell nests were surrounded by prominent lymphoid stroma. Sarcoid-like epithelioid granulomas were noted both in the tumor stroma and in the regional lymph node with metastasis. Epstein-Barr virus (EBV)-encoded RNA (EBER) in situ hybridization showed an intense and diffuse positive reaction in the carcinoma cells and no reaction in the surrounding gastric and lymphoid tissues. While the presence of lymphoid stroma is a characteristic finding in EBV-associated lymphoepithelioma-like carcinoma, sarcoid-like epithelioid granulomas might be associated with latent EBV infection.

The prognostic significance of the expression of monocarboxylate transporter 4 in patients with right- or left-sided colorectal cancer

Monocarboxylate transporter 4 (MCT4) is a proton pump that exchanges lactate through the plasma membrane. The present study investigated the clinical significance of the expression of MCT4 in patients with right‐ or left‐sided colorectal cancer (CRC).