Kyoichi Tomita

Complex cadherin expression in human prostate cancer cells

Changes in cell‐cell interactions are critical in the process of cancer progression. Likewise, it has been shown that loss of expression of the cell adhesion molecule E‐cadherin is associated with grade, stage, and prognosis in many carcinomas, including prostate cancer. Impaired E‐cadherin‐mediated interactions result in an invasive phenotype; however, the mere loss of cell‐cell contact and communication is not the sole explanation for the observed correlation between loss of E‐cadherin‐mediated adhesion and poor clinical outcome. Using a degenerate cloning strategy for sequences that are highly conserved between the various cadherins, we found several other cadherins (N‐ and P‐cadherin and cadherin‐4, ‐6, and ‐11) to be expressed in human prostate cancer cells. Our data suggest that besides loss of E‐cadherin function, also (upregulation of) expression of other cadherins is involved in the acquisition of an invasive and/or metastatic phenotype. Especially, changes in the expression of N‐cadherin and cadherin‐11 may play an important role in prostate cancer progression. Int. J. Cancer 85:446–450, 2000. ©2000 Wiley‐Liss, Inc.

Promoter hypermethylation of the potential tumor suppressor DAL-1/4.1B gene in renal clear cell carcinoma

Renal clear cell carcinoma (RCCC) is a malignant tumor with poor prognosis caused by the high incidence of metastasis to distal organs. Although metastatic RCCC cells frequently show aberrant cytoskeletal organization, the underlying mechanism has not been elucidated. DAL‐1/4.1B is an actin‐binding protein implicated in the cytoskeleton‐associated processes, while its inactivation is frequently observed in lung and breast cancers and meningiomas, suggesting that 4.1B is a potential tumor suppressor. We studied a possible involvement of 4.1B in RCCCs and evaluated it as a clinical indicator. 4.1B protein was detected in the proximal convoluted tubules of human kidney, the presumed cell of origin of RCCC. On the other hand, loss or marked reduction of its expression was observed in 10 of 19 (53%) renal cell carcinoma (RCC) cells and 12 of 19 (63%) surgically resected RCCC by reverse transcription‐PCR. Bisulfite sequencing or bisulfite SSCP analyses revealed that the 4.1B promoter was methylated in 9 of 19 (47%) RCC cells and 25 of 55 (45%) surgically resected RCCC, and inversely correlated with 4.1B expression (p < 0.0001). Aberrant methylation appeared to be a relatively early event because more than 40% of the tumors with pT1a showed hypermethylation. Furthermore, 4.1B methylation correlated with a nuclear grade (p = 0.017) and a recurrence‐free survival (p = 0.0036) and provided an independent prognostic factor (p = 0.038, relative risk 10.5). These results indicate that the promoter methylation of the 4.1B is one of the most frequent epigenetic alterations in RCCC and could predict the metastatic recurrence of the surgically resected RCCC.

Identification of Toll-Like Receptor 3 as a Potential Therapeutic Target in Clear Cell Renal Cell Carcinoma

Purpose: Renal cell carcinoma (RCC) is one of the most drug-refractory cancers. The aim of this study is to discover a novel therapeutic target molecule for clear cell RCC (CCRCC), which accounts for the majority of RCC. Experimental Design: Gene expression profiles of 27 CCRCCs and 9 normal kidney tissues as well as 15 various adult normal tissues were examined by Affymetrix U133 Plus 2.0 arrays. Among the 34 genes specifically up-regulated in CCRCC, overexpression of Toll-like receptor 3 (TLR3) mRNA and its protein was validated by quantitative reverse transcription-PCR, immunoblot, and immunohistochemistry. The effects of TLR3 signaling on in vitro cell growth were examined. Results:TLR3 gene was highly expressed in CCRCC, with only limited expression in a panel of normal tissues. On immunohistochemical analysis using a monoclonal antibody against TLR3, overexpression of TLR3 was observed in 139 of 189 (73.5%) cases of CCRCC as well as in lung metastatic CCRCC (6 of 8), whereas TLR3 expression was entirely absent in chromophobe RCC (0 of 8). Polyinosinic-polycytidilic acid, a TLR3 ligand, exerted a growth-inhibitory effect against RCC cells in a TLR3-dependent manner. Moreover, a combination of polyinosinic-polycytidilic acid and IFNα exerted a synergistic growth-inhibitory effect against Caki-1 RCC cells. Conclusions: This is the first report that TLR3 is overexpressed in CCRCC. These observations suggest that TLR3 pathway may represent a novel therapeutic target in CCRCC.

JC virus strains indigenous to northeastern Siberians and Canadian Inuits are unique but evolutionally related to those distributed throughout Europe and Mediterranean areas

Human polyomavirus JC virus (JCV) isolates around the world are classified into more than 10 geographically distinct genotypes (designated as subtypes). Evolutionary relationships among JCV subtypes were recently examined, and the following pattern of JCV evolution was indicated. The ancestral JCV first divided into three superclusters, designated Types A, B, and C. A split in Type A generated two subtypes, EU-a and -b, containing mainly European and Mediterranean isolates. The split in Type B generated Af 2 (the major African subtype), Bl-c (a minor European subtype), and various Asian subtypes. Type C generated a single subtype (Afl), consisting of isolates derived from western Africa. In this study, JCV isolates prevalent among northeastern Siberians and Canadian Inuits were evaluated in the context of the above-described pattern of JCV evolution. The Siberian/Arctic JCV isolates were classified as belonging mainly to Type A, based on the result of a preliminary phylogenetic analysis. We then examined, using the whole-genome approach, the phylogenetic relationships among worldwide Type A isolates. In neighbor-joining and maximum-likelihood analyses, Type A JCVs worldwide consistently diverged into three subtypes, EU-a, -b, and -c, with high bootstrap probabilities. EU-c was constructed only by northeastern Siberian isolates, derived mainly from Nanais living in the lower Amur River region, and was shown to have been generated by the first split in Type A. Most Siberian/Arctic isolates derived from Chukchis, Koryaks, and Canadian Inuits formed a distinct cluster within the EU-a subtype, with a high bootstrap probability. Based on the present findings, we discuss ancient human migrations, accompanied by Type A JCVs, across Asia and to Arctic areas of North America.

Maintenance intravesical bacillus Calmette-Guérin instillation for Ta, T1 cancer and carcinoma in situ of the bladder: Randomized controlled trial by the BCG Tokyo Strain Study Group

Objectives:  We carried out a prospective, randomized, controlled trial to investigate the efficacy and safety of both induction and maintenance therapy with intravesical instillation of bacillus Calmette‐Guérin (BCG) for high‐risk non‐muscle invasive bladder cancer (NMIBC).

Dendritic cell immunotherapy for patients with metastatic renal cell carcinoma: University of Tokyo experience

Background : Dendritic cells (DC) are the most potent antigen‐presenting cells and induce host antitumor immunity through the T‐cell response. A clinical study of immunotherapy using cultured DC loaded with tumor antigen, for patients with metastatic renal cell carcinoma (RCC) was performed.

LACTOBACILLUS CASEI のラット膀胱発癌に対する影響

The inhibitory effect of Lactobacillus casei (L. casei) in superficial bladder tumors was investigated in an experimental study using N-butyl-N (4-hydroxybutyl) nitrosamine (BBN)-induced rat bladder cancer as an experimental system. The study consisted of two experiments; in a short-term experiment, the inhibitory effect of 6-week treatment with L. casei was assessed in vitro in terms of the capacity for agglutination by concanavalin A (Con A) of bladder epithelial cells in their incipient stage of malignant transformation induced by 1-week exposure to BBN. As a result, the number of bladder epithelial cell aggregates caused by Con A was significantly smaller in the L. casei-treated group than in the non-L. casei-treated group (p < 0.001). In a long-term experiment, treatment with L. casei of varying duration was investigated for effectiveness against bladder tumors induced by 7-weeks exposure to BBN that arose 22 weeks. The results indicate that both bladder weight and tumor volume per organ were significantly lower in the L. casei-treated than non-L. casei-treated group (p < 0.05). The inhibitory effect on these parameters was more pronounced with treatment with L. casei of longer duration. While there was no significant difference among the treatment groups in the degree of extension of induced malignancy, tumors with a high degree of extension (T1b, T2) developed only in the non-L. casei-treated group. The degree of malignancy of induced tumors was significantly lower in those groups receiving L. casei while BBN was being administered as compared to the non-L. casei-treated group (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Immunotherapy against metastatic renal cell carcinoma with mature dendritic cells

Objective:  We performed a clinical trial of immunotherapy using autologous mature dendritic cells (DC) pulsed with autologous tumor lysate, for patients with metastatic renal cell carcinoma (RCC).

Activated Leukocyte Cell Adhesion Molecule (ALCAM) Expression is Associated with a Poor Prognosis for Bladder Cancer Patients

Objectives: Functional E-cadherin adhesion complexes are necessary to maintain the normal differentiated phenotype in bladder epithelial cells and dysfunction of molecules in this complex is associated with an invasive phenotype. Moreover, loss of functioning of E-cadherin and/or α-catenin in cancer cells is associated with a poor prognosis for bladder cancer patients. Clearly, other adhesion molecules are also involved in the process of invasion and/or metastasis. For example the expression of activated leukocyte cell adhesion molecule, ALCAM, an adhesion molecule belonging to the immunoglobulin superfamily, appeared to be correlated with malignant potential in human melanoma. *Present address. Department of Urology, Faculty of Medicine, University of Tokyo, Japan. Methods: The expression of ALCAM in human bladder cancer specimens was studied by immunohistochemistry and correlated with E-cadherin and α-catenin expression. Results: In normal bladder tissue, only the umbrella cells showed positive membrane...

Irinotecan as a New Agent for Urachal Cancer

The urachal carcinoma, in a 64-year-old male with multiple lung metastases, had shown the resistance to several anti-neoplastic agents including cisplatinum, methotrexate, 5-FU, doxorubicin, epirubicin, and mitomycin C. Because the tumor was adenocarcinoma producing mucin and serum carcinoembryonic antigen (CEA) increased, which resembled colorectal carcinoma, we administrated Irinotecan, which was very effective as the CEA decreased from 98.3 to 38.7 ng/ml and the pulmonary metastatic lesions were reduced by 60%. To our knowledge, this is the first case with urachal carcinoma in which Irinotecan was effective.