Yosuke Adachi

Depletion of CD4+CD25+ regulatory T cells enhances interleukin-2-induced antitumor immunity in a mouse model of colon adenocarcinoma

Interleukin 2 (IL)‐2 induces antitumor immunity and clinical responses in melanoma and renal cell carcinoma. However, IL‐2 also increases the number of CD4+CD25+ regulatory T (Treg) cells that suppress antitumor immune responses. The aim of the present study was to elucidate the effect of depletion of Treg cells on IL‐2‐induced antitumor immunity. IL‐2‐transfected mouse colon adenocarcinoma (MC38/IL‐2) cells were implanted subcutaneously or intrahepatically into male C57BL/6 mice, and tumor growth and the proportion of tumor‐infiltrating lymphocytes with Treg‐cell depletion in response to treatment with anti‐CD25 monoclonal antibody (PC61) were determined. In mice treated with phosphate‐buffered saline, 40–60% of MC38/IL‐2 tumors were rejected. In contrast, all MC38/IL‐2 tumors were rejected in mice treated with PC61. The number of tumor‐infiltrating CD8+ T cells in mice treated with PC61 was approximately twice that in mice treated with PBS. The numbers of tumor‐infiltrating CD4+ and natural killer cells were also increased significantly. To test the antimetastatic effects of IL‐2 treatment in combination with Treg‐cell depletion, human recombinant IL‐2 (rIL‐2) and PC61 were administered to mice implanted with MC38/mock cells in the spleen, and hepatic metastasis was investigated. The average liver weight in mice treated with rIL‐2 plus PC61 was 1.04 ± 0.03 g, less than that in mice treated with rIL‐2 (2.04 ± 0.51 g) or PC61 alone (1.81 ± 0.38 g). We conclude that IL‐2‐induced antitumor immunity is enhanced by Treg‐cell depletion and is due to expansion of the tumor‐infiltrating cytotoxic CD8+ T‐cell population. (Cancer Sci 2007; 98: 416–423)

Development of Gastric Tumors in ApcMin/+ Mice by the Activation of the β-Catenin/Tcf Signaling Pathway

Although several lines of evidence suggest the involvement of the Wnt pathway in the development of gastric cancers, the functional significance of the pathway in gastric carcinogenesis is still poorly defined. To examine the role of the Apc/beta-catenin signaling pathway in the development of gastric cancers, we investigated the gastric mucosa of the Apc(Min/+) mouse, which is a murine model for familial adenomatous polyposis, carrying a germ-line mutation at codon 850 of Apc. We found that aged Apc(Min/+) mice spontaneously develop multiple tumors in the stomach, which are accompanied by loss of heterozygosity of Apc. Such tumors consisted of adenomatous glands with strong nuclear accumulation of beta-catenin. Even a single adenomatous gland already showed nuclear accumulation of beta-catenin, suggesting that Apc/beta-catenin pathway is an initiating event in gastric tumorigenesis in Apc(Min/+) mice. Myc and cyclin D1 expressions, which are transcriptional targets of beta-catenin/Tcf, increased in the adenomatous lesions. Furthermore, beta-catenin/Tcf reporter transgenic mice with Apc(Min) allele showed higher levels of the transcriptional activity of beta-catenin/Tcf in the gastric tumors. We also treated Apc(Min/+) and wild-type mice with N-methyl-N-nitrosourea (MNU), an alkylating agent that induces adenomas and adenocarcinomas in the stomach. Consequently, MNU-treated Apc(Min/+) mice significantly enhanced the tumor development in comparison with Apc(Min/+) mice or MNU-treated wild-type mice. Several gastric tumors in MNU-treated Apc(Min/+) mice showed invasion into the submucosal layer. These results indicate that the Apc/beta-catenin pathway may play an important role in at least subset of gastric carcinomas. In addition, Apc(Min/+) mice combined with MNU could be a useful short-term model to investigate multistage carcinogenesis in the stomach.

Clinicopathological features of hepatocellular carcinoma evaluated by vascular endothelial growth factor expression

Aim:  To evaluate the significance of the expression of vascular endothelial growth factor (VEGF), its correlation with clinicopathological variables were studied in the tissue of hepatocellular carcinoma (HCC) and surrounding liver.

Adenocarcinoma in bladder diverticulum, metastatic from gastric cancer

BackgroundMetastasis to the urinary bladder from gastric cancer is rare. Metastasis to a diverticulum of the bladder from gastric cancer is extremely rare. We report a case of isolated bladder metastasis from gastric cancer and invasion localized to the muscularis propria of the primary site (stomach).Case presentationA 90-year-old female presented with nausea and vomiting that was diagnosed as gastric cancer, the patient also had intermittent hematuria. Pelvic computed tomography identified an abnormally thickened area in the bladder wall that was diagnosed as a diverticulum of the bladder. A biopsy of the bladder wall revealed well differentiated tubular adenocarcinoma metastatic from gastric carcinoma.ConclusionAlmost all cases of bladder metastasis from gastric cancer had peritoneal dissemination. This particular presentation of bladder metastasis from gastric cancer, to the best of our knowledge, has not been previously reported.

Identification of an immune tolerance reaction in response to pretreatment with frozen pancreatic tissue in islet cell transplantation in rats.

Objectives: Whereas transplantation of insulin-secreting pancreatic islets may provide long-term control of glucose metabolism in patients with diabetes mellitus, transplant rejection remains a problem. In this study, we tried pretreatment with frozen pancreatic tissue in a rat model of islet cell transplantation to determine whether induction of immune tolerance is feasible. Methods: Isolated islet cells from Wistar rats were transplanted into the spleen of recipient rats that were sensitized and rats that were not sensitized with frozen pancreatic tissue. Spleens were analyzed histologically and then examined immunohistochemically for expression of insulin, a pancreas-specific gene. With the use of cDNA primers for proinsulin, RT-PCR was performed to detect islet cells in the spleen. Results: Although islet cells were present in spleens at posttransplantation day (PTD) 1, islet cell clusters in recipients without pretreatment were markedly destroyed on PTD 14 on histologic examination. In contrast, islet cell clusters in recipients sensitized with frozen pancreatic tissue appeared similar to those at PTD 1 even at PTD 14. Proinsulin gene expression was found to be specific to pancreatic tissue. In recipients sensitized with frozen pancreatic tissue, proinsulin gene expression was identified in recipient spleens, even at PTD 14, whereas it was undetected in the absence of pretreatment. In recipients transplanted with islet cells and treated simultaneously with frozen pancreatic tissue, proinsulin gene expression was completely eliminated. The immunohistologic study also showed the presence of insulin-producing islet cells in the spleens of rats sensitized with frozen pancreatic tissue. Conclusions: Inhibition of the immune reaction in transplant rejection may be mediated by pretreatment with frozen donor tissue.

Gastric cancer invading the pancreas.

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